NCI 2018 - 1 by KAREPUBLISHING

P ISSN 2148–4902 E ISSN 2536–4553

NORTHERN CLINICS OF ISTANBUL • İSTANBUL KUZEY KLİNİKLERİ NORTHERN CLINICS OF ISTANBUL • İSTANBUL KUZEY KLİNİKLERİ

Vol. 5 • No. 1 • Year 2018

INDEXED IN WEB OF SCIENCE, EMERGING SOURCES CITATION INDEX, PUBMED, PUBMED CENTRAL, EUROPE PMC, EBSCO, DOAJ, TUBITAK TR INDEX, AND TURKIYE CITATION INDEX.

Journal Abbreviation: North Clin Istanb

Vol. 5 • No. 1 • Year 2018

KARE

Preoperative evaluation of liver volume in living donor liver transplantation • Investigation of genotoxicity risk and DNA repair capacity in breast cancer patients using anastrozole • Effect of nerve monitoring on complications of

thyroid surgery • Urban legend or real fact: Coronary artery size varies with demographics • Investigation of the attitudes of university students to discrimination of the elderly • Sleep quality and anxiety level in employees • Immunomodulator effect

of topical zinc oxide application in tuberculin skin test • Evaluation of patients with gastric polyps • Gallbladder perforation during elective laparoscopic cholecystectomy: Incidence, risk factors, and outcomes • Effect of trabeculectomy on

ocular higher-order aberrations in patients with open angle glaucoma • Gaucher disease in an adult: A rare cause of hepatosplenomegaly in adults • Renal clear cell sarcoma presenting as a spontaneous renal hematoma: A rare presentation • Autoimmune hemolytic

anemia associated with infliximab infusion in ulcerative colitis • Diagnosing between papillary carcinoma and reactive papillary changes in an infarcted thyroid nodule after fine needle aspiration and accompanied by a synchronous brain stem astrocytoma •

Reconstructive surgery of true aneurysm of the radial artery: A case report • Penetrating injury caused by a long iron bar: A case report • Fecal microbiota transplantation and its potential therapeutic uses in gastrointestinal disorders

NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ Editor

Associate Editors

Levent Doganay, M.D.

Berna Terzioglu Bebitoglu, M.D. Bekir Durmus, M.D. Derya Buyukkayhan, M.D.

Publıcatıon Coordınator Beril Tekay

Asistant to the Edıtor Aysenur Aydın

Betul Sozeri, M.D.

Managing Editor Neslihan Buyukmurat, M.D.

Scientıfıc Commıttee Abdullah Aydin, M.D.

Eren Ozek, M.D.

Kemal Memisoglu, M.D.

Recep Alp, M.D.

Adem Ozkan, M.D.

Eyup Gumus, M.D.

Kemal Nas, M.D.

Remzi Cevik, M.D.

Afitap Icagasioglu, M.D.

Fahri Ovali, M.D.

Kemalettin Koltka, M.D.

S. Tahir Eren, M.D.

Ahmet Gocmen, M.D.

Fatih Goktay, M.D.

Leyla Karadeniz Bilgin, M.D.

Alaattin Ozturk, M.D.

Fatih Saygili, M.D.

Sabahat Aksaray, M.D.

Lutfullah Orhan, M.D.

Ali Ihsan Dokucu, M.D.

Fatma Eti Aslan, M.D.

Mahmut Durmuş, M.D.

Sait Naderi, M.D.

Ali Ozdemir, M.D.

Ferruh Isman, M.D.

Mehmet Ali Ozcan, M.D.

Ali Riza Cenk Celebi, M.D.

Filiz Akyuz, M.D.

Mehmet Doganay, M.D.

Ali Riza Odabas, M.D.

Filiz Topaloglu Demir, M.D.

Mehmet Eren, M.D.

Asiye Kanbay, M.D.

Fugen Aker, M.D.

Mehmet Kanbay, M.D.

Atakan Yesil, M.D.

Fusun Mayda Domac, M.D.

Mehmet Selcuki, M.D.

Ateş Kadioglu, M.D.

Gizem Dinler Doganay, M.D.

Mehmet Tayyar, M.D.

Atilla Polat, M.D.

Gozde Kir Cinar, M.D.

Mehmet Tunca, M.D.

Ayhan Verit, M.D.

Gulbahar Sarac, M.D.

Melek Celik, M.D.

Aysel Milanlioglu, M.D.

Gulendam Kocak, M.D.

Melek Gura, M.D.

Ayse Cikim Sertkaya, M.D.

Gulnur Tokuc, M.D.

Melih Atahan Guven, M.D.

Selami Sozubir, M.D.

Ayse Serap Karadag, M.D.

H. Muammer Karakas, M.D.

Metin Akbulut, M.D.

Sema Yilmaz, M.D.

Aysegul Gunduz, M.D.

Hakan Erdogan, M.D.

Metin Kapan, M.D.

Sevki Erdem, M.D.

Aytekin Guven, M.D.

Hale Akbaylar, M.D.

Mine Hekimgil, M.D.

Soner Sanioglu, M.D.

Aytekin Oguz, M.D.

Haluk Vahaboglu, M.D.

Muhammed Fatih Onsuz, M.D.

Sukran Kose, M.D.

Ayten Kadanali, M.D.

Hamit Okur, M.D.

Muhammet Tekin, M.D.

Tamer Okay, M.D.

Baris Onder Pamuk, M.D.

H. Isin Ozisik Karaman, M.D.

Murat Acar, M.D.

Tarik Sapci, M.D.

Bekir Atik, M.D.

Hasan Bombaci, M.D.

Murat Muhcu, M.D.

Beyhan Cengiz Ozyurt, M.D.

Hasan Borekci, M.D.

Tayfun Kirazli, M.D.

Mustafa Aldemir, M.D.

Birsen Yurugen, M.D.

Haydar Sur, M.D.

Mustafa Caliskan, M.D.

Tongabay Cumurcu, M.D.

Canan Agalar, M.D.

Hilmi Ciftci, M.D.

Mustafa Girgin, M.D.

Cevdet Ugur Kocogullari, M.D.

Hulya Apaydin, M.D.

Nelgin Gerenli, M.D.

Derya Buyukkayhan, M.D.

Huseyin Bayramlar, M.D.

Nezih Ozkan, M.D.

Destina Yalcin, M.D.

Ibrahim Akalin, M.D.

Nihat Aksakal, M.D.

Didem Akcali, M.D.

Ibrahim Ali Ozemir, M.D.

Nilay Sahin, M.D.

Didem Korular Tez, M.D.

Ibrahim Ikizceli, M.D.

Nuri Aydin, M.D.

Dilaver Tas, M.D.

Ihsan Karaman, M.D.

Nusret Acikgoz, M.D.

Duygu Geler Kulcu, M.D.

Ihsan Metin Leblebici, M.D.

Onur S. Goksel, M.D.

Ebru Zemheri, M.D.

Ilknur Aktas, M.D.

Orhan Alimoglu, M.D.

Emek Kocaturk Goncu, M.D.

Ismail Islek, M.D.

O. Emek Kocaturk Goncu, M.D.

Yasar Bukte, M.D.

Emin Evren Ozcan, M.D.

Kadriye Avci, M.D.

Ozge Ecmel Onur, M.D.

Yesim Tuncok, M.D.

Emine Samdanci, M.D.

Kamil Ozdil, M.D.

Ozlem Baysal, M.D.

Yurdanur Kilinc, M.D.

Ercan Madenci, M.D.

Kaya Saribeyoglu, M.D.

Ozlem Guneysel, M.D.

Yuksel Altintas, M.D.

Eren Gozke, M.D.

Kazim Capaci, M.D.

Ozlem Tanriover, M.D.

Yuksel Ersoy, M.D.

Salih Boluk, M.D. Salih Cetinkursun, M.D. Sarenur Gokben, M.D. Sahin Senay, M.D. Selcuk Mistik, M.D. Serhat Citak, M.D. Seyhan Hidiroglu, M.D. Seyhun Kurşat, M.D. Sibel Dogan, M.D.

Tolga Baglan, M.D. Tolga Canbak, M.D. Tuba Tulay Koca, M.D. Tuba Yavuzsen, M.D. Turhan Caskurlu, M.D. Turkan Kudsioglu, M.D. Umut Kefeli, M.D. Veli Citisli, M.D. Volkan Ince, M.D.

NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ YEAR 2018 VOLUME 5 NUMBER 1

p ISSN 2148 - 4902 e ISSN 2536 - 4553

Ownership and Accountability for Contents on behalf of The Istanbul Health Directorate

Kemal Memisoglu, M.D.

Publicatıon Manager

Bekir Durmus, M.D.

Publicatıon Coordinators

Beril Tekay

Umut Elmas

Executive Office

Umraniye Teaching and Research Hospital Elmalıkent Mah., Adem Yavuz Cad. No: 1, 34764 Umraniye, Istanbul-Turkey Phone: +90 216 632 18 18 Fax: +90 216 632 71 24 http://www.kuzeyklinikleri.com e-mail: bilgi@kuzeyklinikleri.com

Indexed in Web of Science, Emerging Sources Citation Index, PubMed, PubMed Central, Europe PMC, DOAJ, TUBITAK TR Index, CINAHL, Turkiye Citation Index.

Publisher

KARE PUBLISHING Altayceşme Mah., Engin Sok., Maltepe Residence, No: 3, Daire: 20 34843 Maltepe, Istanbul, Turkey Tel: +90 216 550 61 11 Fax: +90 216 550 61 12 http://www.kareyayincilik.com e-mail: kare@kareyayincilik.com

DESIGN

Ali Cangul kare@kareyayincilik.com

Press

Info

YILDIRIM PRINTING HOUSE Yuzyil Mah., Massit Matbaacılar Sitesi, 1. Cad. No: 101, Bagcilar, Istanbul, Turkey Tel: +90 212 629 80 37 Fax: +90 212 629 80 39

English Editing by

Susan Atwood Gurkan Kazanci

Northern Clinics of Istanbul (NCI) is a peer-reviewed journal published triannually. Materials published in the Journal is covered by copyright ©2018 NCI. All rights reserved. This publication is printed on paper that meets the international standard ISO 9706:1994. National Library of Medicine recommends the use of permanent, acid-free paper in the production of biomedical literature.

KARE PUBLISHIN G

Press date: January 2018 Circulation: 200 Type of publication: Periodical

CONTENTS Vol. 5 • No. 1 • Year 2018 IV

INSTRUCTIONS FOR THE AUTHORS

1–5

Preoperative evaluation of liver volume in living donor liver transplantation A. Baskiran, A. Sagir Kahraman, I. Balikci Cicek, T. Sahin, B. Isik, S. Yilmaz

6-13

Investigation of genotoxicity risk and DNA repair capacity in breast cancer patients using anastrozole T. Yesil Devecioglu, F. Aydogan, G. Z. Omurtag, N. Senel Bese, S. Sardas

14-19

Effect of nerve monitoring on complications of thyroid surgery S. Demiryas, T. Donmez, E. Cekic

20-24

Urban legend or real fact: Coronary artery size varies with demographics M. A. Tatlisu, M. Sargin, A. Kaya, A. I. Tekkesin, Z. Nurkalem, S. Aykut Aka

25-30

Investigation of the attitudes of university students to discrimination of the elderly D. Cinar, A. Karadakovan, S. Karaca Sivrikaya

31-36

Sleep quality and anxiety level in employees A. G. Teker, N. E. Luleci

37-40

Immunomodulator effect of topical zinc oxide application in tuberculin skin test C. Nuhoglu, E. Hepkaya, Z. E. Onal, N. Akici, T. Gurbuz, V. Atasayan, O. Ceran

41-46

Evaluation of patients with gastric polyps S. Olmez, S. Sayar, B. Saritas, A. Y. Savas, U. Avcioglu, I. Tenlik, E. Ozaslan, H. T. Koseoglu, E. Altiparmak

47-53

Gallbladder perforation during elective laparoscopic cholecystectomy: Incidence, risk factors, and outcomes Y. E. Altuntas, M. Oncel, M. Haksal, M. Kement, E. Gundogdu, N. Aksakal, F. C. Gezen

54-57

Effect of trabeculectomy on ocular higher-order aberrations in patients with open angle glaucoma A. M. Fard, R. D. Sorkhabi, K. Nasiri, A. Tajlil

Original Image

58-59

Gaucher disease in an adult: A rare cause of hepatosplenomegaly in adults V. Karakus, Y. Dere, O. Dere, F. Sahin, N. Ozsan

C A S E REPORTS

60-63

Renal clear cell sarcoma presenting as a spontaneous renal hematoma: A rare presentation Z. C. Ozdemir, B. Ayvaci, Y. Duzenli Kar, M. Oguzman, M. S. Arda, M. F. Acikalin, O. Bor

64-66

Autoimmune hemolytic anemia associated with infliximab infusion in ulcerative colitis F. A. Mir, A. A. Juboori, J. D. Bragg, V. Tahan

67-71

72-73

Reconstructive surgery of true aneurysm of the radial artery: A case report S. Bayer Erdogan, S. Akansel, N. Tandogar Selcuk, S. Aykut Aka

75-78

Penetrating injury caused by a long iron bar: A case report S. Ozaydin, A. Gulleroglu, B. Karaaslan, S. Celebi, C. Besik, M. Korkmaz Toker, S. Sander

79-88

Fecal microbiota transplantation and its potential therapeutic uses in gastrointestinal disorders R.D. Heath, C. Cockerell, R. Mankoo, J.A. Ibdah, V. Tahan

ORIGINAL ARTICLES

INVITED REVIEW

INSTRUCTIONS FOR THE AUTHORS Northern Clinics of Istanbul - NCI is a peerreviewed, open-access, international journal published by the Istanbul Health Directorate (IHD). The NCI is printed 4 times a year. Free full-text articles in English are available at www.kuzeyklinikleri. com. The NCI is indexed in the Web of Science, Emerging Sources Citation Index, PubMed, PubMed Central, Europe PMC, DOAJ, ULAKBIM TR Index and Turkey Citation Index. The journal publishes research, interesting case reports, letters to the editor, review articles, editorial comments, medical news, and guidelines. The NCI accepts manuscripts written in Turkish and English. Opinions presented in published articles do not represent official endorsement of the IHD. Manuscripts should be prepared in accordance with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which is regularly updated by the International Committee of Medical Journal Editors (ICMJE), and available at http://www.icmje.org. ARTICLE TYPES

The NCI publishes the kinds of articles briefly described below.

Research Articles: These are articles on original clinical (conducted with healthy subjects or patients) or experimental (human, animal or in-vitro trials) research performed in all fields. Case Reports: This section contains reports on interesting, instructive or rarely seen cases. Review Articles: Reviews are usually written at the invitation of the editors. The NCI publishes clinical review articles related to the natural course of diseases, updated diagnostic and therapeutic approaches of concern to clinicians and specialists in basic sciences that encompass genetic, physiological, and pharmacological aspects of the underlying mechanisms of diseases, and reviews about state-ofthe art treatment strategies, technological advancements, and newly approved drugs. Editorial Comments: This section contains editors’ comments, reviews, and other relevant items. Letters to the Editor: These are com-

ments, criticism and contributions in response to a paper published in the NCI. The author(s) of a criticized article has the right to reply. The article that is the subject of the comments should be listed in the references section. Letters must be sent to the editor within 4 weeks following publication of the subject article in the NCI. PREPARATION OF MANUSCRIPT

General Format: All manuscripts should be typewritten on A4 white paper, and 2.5 cm-wide margins should be left on all sides. The references should be numbered consecutively in the order of their first mention in the text. All text material, including references, footnotes, and table and figure legends, should be typed using double-spacing in an 11 point font with left alignment and without hyphenated line breaks. The fonts Times New Roman or Arial should be used in the text, for symbols, and all other special characters. Please use the editing features of your word processing program to type bold or italic letters, mathematical symbols, Greek letters, subscript and superscript characters. Please take care not to confuse the letters O and I with the numerals 0 and 1. To set a left indent for a paragraph, click the TAB button once. Only the International System of Units (SI) should be used for units of measurement. Abbreviations and acronyms should be written in parentheses following the full name or an explanation of the usage should be provided just after the first appearance in the text. Please review the final version of the manuscript very carefully, especially for formatting and editing errors. All pages of the manuscript should be consecutively numbered starting from the title page (page 1, title page; page 2, Turkish abstract; page 3, English abstract, etc.). Page numbers should be indicated on the upper right-hand corner of each page. Final version of the manuscript should be in “.doc” or “.rtf” format. Manuscripts submitted in “.pdf” format will not be accepted.

Manuscript Sections: All research articles must contain the following sections: (1) Title page, (2) Abstract with keywords, (3) Introduction, (4) Methods, (5) Results, (6) Discussion, (7) Acknowledgements, (8) Conflict of interest, (9) Funding re-

sources, (10) References, (11) Legends of the figures, (12) Tables, (13) Figures. In case of need, presentation of Methods, Results, and Discussion sections under subheadings is preferred. Case reports should be presented following abstract section, under headings of introduction, case presentation, and discussion. In review articles, appropriate headings can be used in accordance with the development of the manuscript. Sections of the manuscript in order of their appearance in the text with relevant explanations are listed below.

Title Page: The title page should contain the following information: (1) article title, (2) full name and academic title of all participating authors, (3) department and institution of all authors, including the city and country, (4) name, full mailing address, phone and fax numbers, and e-mail address of the corresponding author, and (5) word count (including title page, abstracts, explanatory notes for figures and tables). If the study was presented elsewhere, those details should be indicated on the title page. Abstract: The abstract should be written on a separate page. It should contain at most 250 words, and be structured as follows: (1) Objective, (2) Methods, (3) Results, and (4) Conclusion. Under these headings, briefly describe the subject of the article, methods used for the study, basic findings, and author’s conclusion. No subtitles may be used in the abstract of a case report. A minimal number of abbreviations and/or acronyms should be used. Abstracts should not contain any references. A maximum of 5 keywords should be included at the end of the abstract. The Medical Subject Headings (MeSH) prepared by the US National Library of Medicine (NLM) may be used as a reference for keywords. Introduction: State the specific purpose and available data relevant to the study. Methods: All methods used to select participants and conduct the study should be described in detail. Known methods should be cited. Novel or modified methods used should be described in detail. Doses, concentrations, routes, and duration of administration of drugs and chemical agents should be indicated. A concise

INSTRUCTIONS FOR THE AUTHORS report of all statistical methods used for summarizing available data and for testing the proposed hypothesis should be provided under a subtitle, including the p value criteria determined for statistically significant difference. Statistical evaluation conducted should be explained in detail. Standard statistical methods should be used as much as possible. If rarely employed or novel statistical methods were used, then the relevant references should be cited. When necessary, more detailed explanations about unusual, complex or new statistical methods can be provided in separate files for readers as online supplementary data. The commercial name and version number of any statistical software package program used should be provided. For statistical evaluation, the recommendations in the statistics section of the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication” (http://www.ICMJE.org) should be taken into consideration.

Results: The study results should be presented in logical sequence and in detail. The findings should be supported by figures and tables. Information given in figures and tables should not be repeated in the text unless absolutely required. Discussion: Data relevant to the study subject matter should be examined, evaluated, and substantiated with references from domestic and international sources. General information irrelevant or superfluous to the report should not be included. Acknowledgement: The names of individuals who contributed to the study but who fail to meet the criteria of authorship should be mentioned in this section. The written consent of all individuals mentioned should be obtained. Conflict of Interest: All potential conflicts of interest should be declared under this heading. All affiliations with pharmaceutical firms, biomedical device manufacturers, and other service or product procurers relevant to the subject matter of the study should be explicitly indicated. If no conflict of interest exists, this should be stated as “none declared.” Declarations related to conflicts of interest should be placed at the bottom of a separate page after the acknowledgements and before

the references. A Conflict of Interest Form will be sent to the authors of accepted papers.

Funding sources: The full name of any sponsoring foundation or institution should be provided. References: References should be listed consecutively in the order of their first appearance in the text. All sources the authors made direct use of should be included as references, excluding unpublished results and personal communications. During the preparation of the manuscript for publication, additional information regarding any unconfirmed references will be requested from the authors. Titles of journals should be abbreviated as indicated in the Index Medicus. If that is not possible, then the full name of the journal should be provided. In the references, a maximum of 6 authors should be cited for any 1 article with their full surname, and then the initial(s) of their first name. If more than 6 authors contributed to the cited article, then after the name of the sixth author, the abbreviation “et al.” should be added to indicate that there are additional authors. The notation and listing of references should comply with the following sample reference citations: 1. Journal: Balci NC, Sirvanci M, Tüfek I, Onat L, Duran C. Spontaneous retroperitoneal hemorrhage secondary to subcapsular renal hematoma: MRI findings. Magn Reson Imaging 2001;19:1145-8. 2. Articles in press: Roten L, Derval N, Sacher F, Pascale P, Wilton SB, Scherr D, et al. Ajmaline attenuates electrocardiogram characteristics of inferolateral early repolarization. Heart Rhythm 2011 Sep 19 [E-pub ahead of print], doi:10.1016/j.hrthm.2011.09.013. 3. Book: Brown AM. Physiology of the liver. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2003. 4. Chapter in book: Anderson JL, Muhlestein JB. The role of infection. In: Theroux P, editor. Acute coronary syndromes: a companion to Braunwald’s Heart Disease. Philadelphia: W.B. Saunders; 2003. p. 88-107. 5. Web page: Nainggolan L. New salt paper causes controversy. Heartwire. May 3, 2011. Available at: http://

www.theheart.org/article/1220043. do. Accessed: June 12, 2011.

Figure Legends: Explanatory notes for each figure should be submitted on a separate page in order of their appearance in the text immediately after the references section under the heading “figure legends.” All abbreviations and symbols used in the figure should be defined in alphabetical order. Figures: The manuscript will not be evaluated until all figures cited in the text are submitted. The number of figures provided should be in accordance with the content and data presented in the text, and table data should not be repeated in figures. All figures should be sent in individual electronic file format ready for publication with maximum dimensions of 125 cm x 180 cm. Illustrations in color should be in CMYK format and have a minimum resolution of 300 DPI suitable for publication. Figures depicted in gray scale should have a minimum resolution of 600 DPI, and the minimum resolution required for black and white illustrations is 1200 DPI. All figures should be in TIFF format. Figures must not disclose or imply the identity of a specific individual without the written consent of the individual in question. Tables: Each table should be typed or printed with double-spacing on a separate sheet of paper. Tables should be numbered consecutively in the order of their first citation in the text. The number and title of the table should be placed just above the table. Do not use vertical lines between columns. Horizontal lines should be used only above and below the headings of the columns, and at the bottom of the table. If required, explanatory notes regarding table data should be written in footnotes. All abbreviations and acronyms used in the table should also be explained in alphabetical order in footnotes. ETHICAL POLICY

NCI follows the ethics flowcharts developed by the Committee on Publication Ethics (COPE) for dealing with cases of possible scientific misconduct and breaches of publication ethics. For detailed information please visit www.publicationethics.org.

INSTRUCTIONS FOR THE AUTHORS All submitted manuscripts are screened with plagiarism software (iThenticate) to detect instances of overlapping and similar text during the evaluation process. All manuscripts presenting data obtained from research involving human subjects must include a statement that the written informed consent of the participants was obtained and that the study was approved by an institutional review board or an equivalent body. This institutional approval should be submitted with the manuscript. Authors of case reports must submit the written informed consent of the subject(s) of the report or of the patient’s legal representative. Manuscripts with human and animal studies should describe the steps taken to eliminate pain and suffering. AUTHORSHIP

All individuals listed as “author” in the submitted manuscript must make an adequate contribution to the study, meet the criteria of authorship, and take responsibility for their part of the manuscript. For the sake of the outcomes and the integrity of the study, at least one author should be responsible for each section of the manuscript. All authors mentioned in the cover letter must meet all of the following criteria: (1) substantial contribution to conception, design of the study, analysis, and interpretation of data, or all of these criteria; (2) significant contribution to the drafting of the article or revision of its scientific content; (3) approval of the final version of the article to be published. In multicentered studies, all individuals who are named as authors under the title of the article should meet all the abovementioned requirements of authorship. Seeking or providing financial support for the study, and/or data collection do not satisfy the criteria of authorship per se, nor does general support or guidance provided to the study investigators. Individuals who contributed to the study in various ways but who fail to meet the criteria of authorship may be included in the acknowledgements with their written consent. Please refer to the ICMJE website for more information about authorship. Increasing the number of authors unnecessarily is not ethical conduct and to prevent any attempt to seek undue academic prestige or other unethical advantages, the editor may request a decla-

ration from the authors of their individual contributions to the article and publish this information, if deemed appropriate. The sequence of authors’ names should be based on a consensus reached by all the participating authors. Due to different specifications for the sequencing of authors, the order provided will be used unless otherwise stated. Authors may explain the rationale for a different sequence in a footnote. COVER LETTER

Each manuscript should be sent with a cover letter that must contain the following explicit declarations: (1) all authors meet the criteria of authorship; (2) the submitted manuscript was not simultaneously sent to another journal and it is not presently being evaluated by another journal; (3) no part of the content of the manuscript has been previously published elsewhere; and (4) the manuscript has been read and approved of by all authors. The name, full address, phone and fax number(s), and e-mail address of the corresponding author to whom all editorial correspondence will be directed must be provided. A brief paragraph describing the scientific significance of the manuscript may also be included. SUBMISSION OF THE MANUSCRIPT

All manuscripts should be submitted to the NCI via the online submission system. For questions or requests related to the submission and evaluation process of manuscripts, the editorial office may be contacted by e-mail at bilgi@kuzeyklinikleri.com. In compliance with the journal’s publication rules, the current status of the manuscript will not be discussed on the phone prior to acceptance for publication. First-time users of the online submission system will need to register. A user name and a code specific to the user will be sent by e-mail. For further details please consult the online manuscript submission page.

gin until a document with the signed approval of all authors has been received. During typesetting and other preparation of the manuscript for publication, a Copyright Transfer Form will be sent to the primary author(s) (“guarantors”) who will assume responsibility for the manuscript. All submitted manuscripts are first evaluated by the editorial board. At this stage, manuscripts not deemed suitable for publication in NCI, including those not complying with the requirements or without adequate scientific content, will be returned to the authors. Manuscripts found suitable for publication will be sent to reviewers for more detailed evaluation. Acceptability of manuscripts is dependent on originality, scientific content, and the subject of the study, in accordance with the publication protocol of the journal. All research articles deemed suitable for publication are subjected to a detailed statistical evaluation. The authors are informed of the editors’ decision on the acceptability of the manuscript via e-mail, usually within 6 weeks of its submission. The editors do not discuss their decision on the phone. All objections and requests should be communicated to the editors in a written format. If deemed necessary, the editorial board has the right to make modifications to the text without altering the main concept of the manuscript. An offprint of the manuscript will not be sent to the author(s). OPEN ACCESS

NCI is a fully open access journal. All articles published in NCI are available on the internet to all users immediately upon publication. Non-commercial use and distribution in any medium is permitted, provided the author and the journal are properly credited. PUBLISHING FEE

REVIEW OF MANUSCRIPTS

NCI is an open access journal. Manuscripts can be reached from the web page of journal without any fees. No additional fee is required from the authors for accepted manuscripts.

In order for an article to be published in the journal it should not be published elsewhere, and must be deemed suitable for publication by the editorial board selected by the NCI Executive Committee. All responsibility for the manuscript belongs to the author(s). The evaluation process of the submitted manuscript will not be-

ADDRESS OF CORRESPONDENCE KARE PUBLISHING Altaycesme Mah. Engin S. No: 3/20 Maltepe, Istanbul-Turkey Tel: 0216 550 61 11 Fax: 0216 550 61 12 E-mail: kare@kareyayincilik.com

EDITORIAL

Dear Readers, Four years have passed now since the first issue of the journal was introduced. In those four years, with the help of all the editors, we succeeded in having the journal indexed in major indices like PubMed and the Web of Science. At this moment, it is time for a change, and I am leaving the position of editorin-chief. It is not farewell; however, as I will continue to contribute as an editor. With this first issue of 2018 I announce that Assoc. Prof. Levent DoÄ&#x;anay is the editor-in-chief. For the new editorial board, it is time to focus on improving quality and increasing the impact factor. I am sure in the coming years we will see the journal indexed in even greater indices. Sincerely yours, Bekir DurmuĹ&#x;, MD

Orıgınal Article

GENERAL SURGERY

North Clin Istanb 2018;5(1):1-5 doi: 10.14744/nci.2017.14227

Preoperative evaluation of liver volume in living donor liver transplantation Adil Baskiran,1 Aysegul Sagir Kahraman,2 Ipek Balikci Cicek,3 Tolga Sahin,1 Burak Isik,1 Sezai Yilmaz1 Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya, Turkey

Department of Radiology, Inonu University, Turgut Ozal Medical Center, Malatya, Turkey

Department of Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya, Turkey

ABSTRACT OBJECTIVE: The aim of the present study was to retrospectively evaluate the difference between the preoperative estimated volume and the actual intraoperative graft volume determined in donor right hepatectomies and to evaluate the possible effect of age, gender, and body mass index on the difference. METHODS: A total of 225 donor hepatectomies performed at the center between 2016 and 2017 were evaluated for the study. Left hepatectomies and left lateral segmentectomies were excluded from the analysis. As a result, 174 donor right hepatectomies were included in the study. Volumetric analysis was performed with dynamic hepatic computed tomography (CT), including non-contrast analysis, followed by non-ionic, contrast-enhanced arterial, portal, and hepatic-phase, thin-slice scanning. Volumetric analysis was performed based on the CT images using automatic volume calculating software. RESULTS: The mean preoperatively estimated graft volume was 800±112 g and the mean intraoperatively measured actual graft volume was 750±131 g. There was a statistically significant difference (p=0.003). Age and body mass index had a significant impact on the discrepancy between the predicted and actual graft volume, while gender did not. CONCLUSION: A thorough preoperative evaluation of the donor graft volume should be performed in order to prevent donor morbidity and mortality, as well as small-for-size and large-for-size phenomena in the implanted grafts. Physicians working in the field of transplantation should be aware of the fact that a difference of 10% between the predicted and the actual graft volume is usually encountered. Keywords: Liver; liver transplantation; living donor; radiological investigation; volumetric analysis.

iver transplantation is the only treatment modality for end-stage liver failure. In countries where cadaveric liver transplantation is rarely performed, living donor liver transplantation (LDLT) has become an alternative route; however, it requires a difficult and attentive initial evaluation. Preoperative volume evaluation is one of these challenging steps, and it is of vital importance for both the donor and the recipient. The ratio of the calculated volume and the weight of the graft should be at least 0.8% in order to protect the recipient from small-for-size phenomena (cellular damage, liver with decreased ca-

pacity for metabolism, synthesis, ascites), and the ratio should be <3% to avoid large-for-size phenomena (poor liver perfusion, increased abdominal pressure). The volume of the remaining liver should be at least 30% to protect the donor from life-threatening consequences [1]. In LDLT, the preoperative donor graft volume is often calculated using computed tomography (CT) and automatic volume calculation programs. However, despite technological developments, discrepancies between the preoperative and intraoperative volume measurements are seen. Frericks et al. [2] observed that as the volume

Received: August 02, 2017 Accepted: September 07, 2017 Online: January 12, 2017 Correspondence: Dr. Adil BASKIRAN. Inonu Universitesi Karaciger Nakli Enstitusu Genel Cerrahi Anabilim Dali Malatya, Turkey. Tel: +90 422 341 06 06 - 60 14 e-mail: dr.adil.baskiran@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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ratio increased, so did the margin of error. Preoperative volume calculation is first among the important criteria that determine operative morbidity and mortality. Therefore, as the margin of error in the evaluation decreases, the rate of operative success will also increase. The aim of this study was to retrospectively compare pre- and intraoperative measurements of graft volume in donors who underwent a right hepatectomy at the Liver Transplantation Institute of Inonü University during a 2-year period, and to determine the effect of age, gender, and body mass index (BMI) on these calculations. MATERIALS AND METHODS The data of 225 liver donors who were operated on between 2016 and 2017 were reviewed. Donors who underwent a left hepatectomy or a left lateral hepatectomy were excluded. A total of 174 donors who underwent a right hepatectomy were included in the study. Preoperative CT images (Somatom Definition, 256x256; Siemens Healthineers, GmbH, Erlangen, Germany) of the patients were used for volumetric evaluation. According to routine dynamic hepatic CT protocol, pre-contrast, thin-slice scanning and non-ionic, contrastenhanced arterial, portal, and hepatic phase thin-slice scanning were performed. Automatic volume calculation software used the data from the CT images to create estimated measurements. For a right hepatectomy, the liver is divided into lobes with an imaginary line drawn along the midhepatic vein, leaving the midhepatic vein to the

donor, and then right liver volume, and remaining liver volume are calculated. The same radiological protocol and volumetric analysis program were used for all of the cases studied. The pre- and intraoperative volumetric measurements were compared, and the effect of BMI, gender, and age on preoperative volume calculations was analyzed. The difference between the preoperative calculations and the intraoperative volumetric measurements is known as the delta (∆) volume (Fig. 3). IBM SPSS Statistics for Windows, Version 22.0 software (IBM Corp., Armonk, NY, USA) was used for the statistical analysis, and the data were expressed as median (min-max) or mean±SD. Normal distribution was assessed using the Kolmogorov-Smirnov and ShapiroWilk tests. The Mann-Whitney U test, Kruskal-Wallis test, Wilcoxon test, eta coefficient, and Spearman correlation coefficient were used, where appropriate. A p value <0.05 was accepted as the level of statistical significance. RESULTS Of the total of 174 liver donors, 106 were male and 68 were female, the median age was 28.93 years, the median body weight was 69.7 kg, the median height was 170.7 cm, the median BMI was 23.911 kg/m2, and the median preoperative liver volume calculated was 779.111 g, while the volume measured intraoperatively was 757.172 g. The demographic data are presented in Table 1. The difference between the mean preoperative volume value of 800±112 g and the volume measured intraoper-

Table 1. Demographic data of the patients Variables Body mass index (kg/m2) Median (min-max) Age (years) Median (min-max) Actual volume of the extracted graft (g) Median (min-max) Preoperative estimated graft volume (g) Median (min-max) Difference in graft volume (g) Median (min-max)

Gender

Male (n=106)

22.83 (18.44-30.10) 27 (18-45)

Female (n=68)

25.29 (18.14-34.44) 28 (18-55)

760 (530-1195)

704.5 (500-1125)

800 (500-1000)

770 (450-1300)

-29 (-320-245)

-30 (-205-165)

Baskiran et al., Liver volume evaluation

200.00

Volume

200.00

.00

-200.00

-400.00

15.00000

.00

-200.00

20.00000

25.00000

30.00000

35.00000

-400.00

BMI

Figure 1. The delta volume according to body mass index. BMI: Body mass index.

AGE

Figure 2. The delta volume according to age.

Healthy Donor Liver 362 cm3 (33.52%) Liver Graft 719 cm3 (66.48%)

Figure 3. Automatic volumeter image of the resection line and hepatic veins atively of 750Âą131 g was calculated (p=0.003). A greater difference (delta volume) was observed between the estimated liver volume and the volume of the extracted liver measured intraoperatively in parallel with an increase in BMI (p=0.005; Spearman rho: 0.210) (Fig. 1). No significant difference was seen in the analysis of volume values based on gender (p=0.08); however, the variance between the preoperative and the intraoperative volume measurement did rise with increase in age (p=0.03; Spearman rho: 0.272) (Fig. 2).

DISCUSSION Preoperative estimation of the donor liver volume is the most important factor affecting surgical strategy as well as postoperative mortality and morbidity in living donor transplantation. It is important to use no more than 70% of the donor liver volume and that the graft be of the appropriate weight for the recipient [3]. We take extreme care to leave 30% of the total liver volume in the donor

and to obtain a volume/weight ratio for the recipient of between 0.8% and 2.9%. In 1970, Heymsfield et al. [4] were the first to calculate liver volume, and subsequently, many manual and automatic volume calculation programs have been developed. Our clinic utilizes an automatic liver volume calculation program that uses data obtained from CT examinations. In a study conducted by Paolo R et al. [5], a 20% discrepancy was demonstrated between estimated liver volume and intraoperative measurement of the extracted liver. Frericks et al. [2] emphasized an increased margin of error in living donor liver graft volumes weighing ≥500 g. In our study, a significant increase in delta volume was observed with increasing BMI. Increased BMI or liver volume has been reported to be due to uncalculated or underestimated hepatic blood volume [5]. In a study performed by Li et al. [8], a mean deviation in delta volume of 13.81±8.12% was observed. Although current technological volume assessments subtract the estimated mean blood volume circulating in the liver from the volume of the liver to find the delta volume, a definitive result cannot be obtained, since factors such as the volume of intrahepatic blood during transplantation, age, and heart rate are not evaluated. The cardiovascular performance of the donor, heart rate, hepatic blood flow, and the time of exhalation during the CT examination also affect liver volume measurement [6]. Hwang et al. [9] reported that 100 g of liver tissue contains 29 g of blood. The mean SD of the volumetric assessments performed in our clinic was 5±2.5%. According to the literature, a deviation of some 10% is to be expected in an automatically calculated preoperative volume assessment. Liver volume calculations in donors aged less than 36 years have been reported to be closer to intraoperative measurements [7]. In our study, the delta volume increased with age, which was consistent with other published study results. The primary reason is that as a result of alterations in liver parenchyma with aging, the demarcation line on the liver made during the CT scan cannot be done as accurately, which affects the volumetric analysis. The line drawn during radiological examination and surgery is one of the most important factors in the measurement of delta volume. The line drawn intraoperatively is determinative in the calculation of liver volume [10]. For a right hepatectomy, the liver is divided into lobes with an imaginary line drawn along the midhepatic

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vein, leaving the vein on the donor side, and then the volume of the right liver and the remaining liver tissue are calculated. The same radiological protocol and volumetric analysis program were used in all of our cases. Millimetric deviations seen on the tracing of the midhepatic vein may cause great discrepancies in the volumetric assessment. The demarcation line can be seen during the operation after temporary closure of the right portal vein and the right hepatic artery is achieved. The quantity of blood in the donor’s liver, the heart rate of the donor, the time of exhalation during imaging, age, BMI, and the imaginary line drawn along the midhepatic vein during radiological examination affect preoperative volume assessment of the liver graft. The quantity of blood in the liver, the radiologically drawn line dividing the right and left lobes, and the solution used for hepatic perfusion are important factors in the measurement of the delta value. In conclusion, regardless of technological advances, accurate calculation of delta volume is still a necessary and critical part of LDLT. It is important to keep the delta volume as small as possible, and before deciding on surgery, a 5% to 10% margin of error in radiological measurement should be taken into consideration for both the recipient and the donor. CONCLUSION Factors such as the volume of blood passing through the liver during transplantation, cardiovascular performance of the donor, age, body weight, heart rate, and time of exhalation during imaging can affect the measurement of liver volume. Since we cannot measure these parameters during a CT examination, we reduced the preoperatively estimated liver volume by 10% and we obtained values closer to the intraoperatively measured actual liver graft volume. BMI, and age rather than gender of the patients were found affect delta volume. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – A.B.; Design – A.B.; Supervision – A.S.K.; Materials – A.B.; Data collection &/or processing – A.B., I.B.C.; Analysis and/or interpretation – B.I.; Writing – A.B., T.T.S.; Critical review – S.Y.

Baskiran et al., Liver volume evaluation

REFERENCES 1. Mussin N, Sumo M, Lee KW, Choi Y, Choi JY, Ahn SW, et al. The correlation between preoperative volumetry and real graft weight: comparison of two volumetry programs. Ann Surg Treat Res 2017;92:214–20. 2. Frericks BB, Caldarone FC, Nashan B, Savellano DH, Stamm G, Kirchhoff TD, et al. 3D CT modeling of hepatic vessel architecture and volume calculation in living donated liver transplantation. Eur Radiol 2004;14:326–33. 3. Emiroglu R, Coskun M, Yilmaz U, Sevmis S, Ozcay F, Haberal M. Safety of multidetector computed tomography in calculating liver volume for living-donor liver transplantation. Transplant Proc 2006;38:3576–8. 4. Heymsfield SB, Fulenwider T, Nordlinger B, Barlow R, Sones P, Kutner M. Accurate measurement of liver, kidney, and spleen volume and mass by computerized axial tomography. Ann Intern Med 1979;90:185–7. 5. Salvalaggio PR, Baker TB, Koffron AJ, Fryer JP, Clark L, Superina RA, et al. Liver graft volume estimation in 100 living donors: measure twice, cut once. Transplantation 2005;80:1181–5.

5 6. Radtke A, Sotiropoulos GC, Nadalin S, Molmenti EP, Schroeder T, Lang H, et al. Preoperative volume prediction in adult living donor liver transplantation: how much can we rely on it? Am J Transplant 2007;7:672–9. 7. Yonemura Y, Taketomi A, Soejima Y, Yoshizumi T, Uchiyama H, Gion T, et al. Validity of preoperative volumetric analysis of congestion volume in living donor liver transplantation using three-dimensional computed tomography. Liver Transpl 2005;11:1556–62. 8. Li YC, Hu Y, Zhang MM, Jin XQ, Fan X, Pu CL, et al. Usage of 64-detector-row spiral computed tomography volumetry in preoperative volume prediction in living donor liver transplantation in children. Pediatr Surg Int 2011;27:445–9. 9. Hwang S, Lee SG, Kim KH, Park KM, Ahn CS, Moon DB, et al. Correlation of blood-free graft weight and volumetric graft volume by an analysis of blood content in living donor liver grafts. Transplant Proc 2002;34:3293–4. 10. Lemke AJ, Brinkmann MJ, Schott T, Niehues SM, Settmacher U, Neuhaus P, et al. Living donor right liver lobes: preoperative CT volumetric measurement for calculation of intraoperative weight and volume. Radiology 2006;240:736–42.

Orıgınal Article

PHARMACEUTICAL TOXICOLOGY

North Clin Istanb 2018;5(1):6-13 doi: 10.14744/nci.2017.55822

Investigation of genotoxicity risk and DNA repair capacity in breast cancer patients using anastrozole Tugce Yesil Devecioglu,1 Fatih Aydogan,2 Gulden Zehra Omurtag,3 Nuran Senel Bese,4 Semra Sardas1 Department of Pharmaceutical Toxicology, Marmara University Faculty of Pharmacy, Istanbul, Turkey

Department of General Surgery Service of Breast Diseases, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey

Departmen of Pharmaceutical Toxicology, Medipol University Faculty of Pharmacy, Istanbul, Turkey

Department of Radiation Oncology, Acıbadem University Faculty of Medicine, Istanbul, Turkey

ABSTRACT OBJECTIVE: Breast cancer is the most common cancer in women worldwide and the incidence increases in postmenopausal women. Anastrozole is a non-steroidal (type II), third-generation aromatase inhibitor (AI) that is used in the treatment of postmenopausal estrogen-related breast cancer. Several studies have been conducted to assess the efficacy, safety, and superiority of AIs to tamoxifen; however, a literature search did not reveal a study that investigated the genotoxic potential of AIs. The aim of this study was to investigate the possible DNA damage risk profile and individual DNA repair capacity of patients using anastrozole with the modified alkaline comet assay in order to contribute to public health and health economics. METHODS: Women diagnosed with breast cancer after menopause comprised the study group. Six patients who had taken anastrozole for at least 6 months were retrospectively enrolled, and 12 patients who had not yet received treatment were prospectively enrolled as a control group. Peripheral blood lymphocytes were used to measure oxidized DNA damage using formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (endo III) in a modified comet assay. Individual DNA repair capacity was evaluated with the comet assay after a hydrogen peroxide (H202) challenge to examine the difference in DNA damage susceptibility. RESULTS: Analysis of DNA damage, oxidative base damage, susceptibility to DNA damage, and repair capacity revealed no significant difference between the control group and the patients taking anastrozole (p>0.05). Susceptibility to H2O2 damage was observed to increase with age (p<0.05). CONCLUSION: According to the results obtained in this study, anastrozole did not contribute to oxidative DNA damage. An H2O2 challenge with the comet assay is useful to evaluate circumstances of increased vulnerability to damage, such as aging and cancer. Keywords: Anastrozole; aromatase inhibitors; DNA damage; DNA repair capacity; modified comet assay.

reast cancer is the second most frequently encountered type of cancer in both developed and developing countries, and it is the cancer seen most often in women. In 2012, 1.67 million new cases of breast cancer were recorded in the world, which amounted to some 25% of all cancer cases. Overall, breast cancer ranks fifth among causes of cancer-related death; however, it is first among cancer-related deaths in women. The incidence of breast cancer demonstrates regional differences: in Africa

and Eastern Asia, the incidence is 27/100.000, while in Western Europe the incidence has been reported to be 96/100.000, and the rate is higher in developed countries than in developing countries [1]. In our country, in 2014, the incidence was reported to be 43/100.000 [2]. Early menarche, late menopause, obesity, age at first instance of giving birth, and duration of breastfeeding are among the most important known risk factors for breast cancer, since the extent and duration of exposure to estrogen

Received: June 22, 2017 Accepted: August 21, 2017 Online: January 22, 2018 Correspondence: Dr. Tugce YESİL DEVECİOGLU. Marmara Universitesi Eczacılık Fakultesi Farmasotik Toksikoloji Anabilim Dali, Istanbul, Turkey. Tel: +90 216 414 29 62 - 12 00 e-mail: tugceyesil@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Yesil Devecioglu et al., Genotoxicity risk investigation of anastrozole

have been demonstrated to play a role [3-7]. The target of endocrine therapy is to decrease estrogenic stimulation of cancer cells. Two basic approaches in endocrine therapy are the use of selective estrogen receptor modulators (SERMs) and estrogen antagonists in order to regulate the activity of estrogen receptors, and aromatase inhibitors (AIs) to inhibit estrogen synthesis [8]. AIs are classified according to their chemical structure as Type I (steroidal), androstenedione derivatives binding irreversibly to aromatase, and Type II (nonsteroidal), those that competitively bind to the heme component of the aromatase-CYP complex. Three generations of AI drugs are currently on the market: the first-generation (Type I: testolactone and Type II: aminoglutethimide), second-generation (Type I: formestane and Type II: fadrozole), and third-generation AIs (Type I: anastrozole and letrozole, and steroid analogue Type II: exemestane) AIs have frequently been used in clinics for endocrine therapy of hormone-dependent breast cancer patients in the postmenopausal period [9-11]. Previously, as first-line treatment, or in the adjuvant treatment of advanced stage breast cancer, the antiestrogen tamoxifen was extensively used; however, since the 2000s, AIs have also been widely used. Tamoxifen is a SERM that inhibits the mitogenic effects of estrogen and competes with estrogen to bind to estrogen receptors. Tamoxifen has been reported to decrease the recurrence rate of early stage breast cancer and the incidence of breast cancer in higher risk women, and to increase overall survival time in premenopausal and postmenopausal women. However, the partial agonistic activity of tamoxifen and its adverse effects when used for more than 5 years (including endometrial cancer, pulmonary embolism, and stroke) have led to a decrease in use. In estrogen-receptor positive breast cancer patients, a significant (50-60%) decrease in the beneficial effects of tamoxifen over time suggests a development of resistance to tamoxifen [9]. For these reasons, new agents that will block the mitogenic effects of estrogen with greater efficacy and safety are needed. Beginning in 2000, various randomized, clinical studies have been published comparing the effectiveness and safety of AIs with tamoxifen in the treatment of breast cancer [9]. It has been reported that AIs were found to be superior to tamoxifen in many ways, including improvement in disease-free survival and recurrence rates (however, length of overall survival did not differ), though with different side-effect profiles. Long-term use of AIs led to noteworthy side effects, including complaints related to the musculoskeletal system and the cardiovascular system [12-16]. In recent years, a growing number of biomonitoring

studies have been performed to investigate the genotoxic effects of various xenobiotics, aiming at risk evaluation [17]. The comet assay is a sensitive, reliable technique, easily and rapidly applied to various tissue/special cell types, and it has gradually found widespread use in human biomonitoring studies. The broad potential application of the comet assay and the results obtained contribute to risk definition (i.e., potential genotoxic/mutagenic potential of an agent for humans), dose-response evaluation (the relationship between the dose of the substance and the possibility of inducing an adverse effect), and understanding the mechanism of activity of the substance [17, 18]. Using the technique developed by Singh et al. [19], DNA-DNA, DNA-protein cross-links of spiral strand breaks, and alkali-labile regions can be detected. Collins et al. [20, 21] incorporated lesion-specific, baseextraction enzymes (endonuclease III [endo III] and formamidopyrimidine DNA glycosylase [Fpg]) into the protocol of this technique, which enabled the identification of oxidized DNA bases (modified comet assay) [20, 21]. The comet technique can be used to measure DNA repair capacity: cells are challenged using a DNA-damaging chemical or physical agents are incubated to determine the susceptibility of the cells to damage and the rate of repair [22]. Several views have been presented regarding the widespread use of AIs [23-25]. The genotoxicity of tamoxifen has been investigated in many studies [29]. However, a literature review revealed no study thus far that has investigated the genotoxic effects of AIs. Therefore, the aim of the present study was to evaluate the genotoxicity risk of a third-generation AI, anastrozole, which is used in the endocrine therapy of breast cancer in postmenopausal women, and to assess any effect on susceptibility to DNA damage. MATERIALS AND METHODS Study groups Postmenopausal women diagnosed with breast cancer between 2009 and 2012 in the Department of General Surgery, Service of Breast Diseases were enrolled in the study. A control group consisting of 12 treatment-naĂŻve patients diagnosed with breast cancer was prospectively enrolled upon diagnosis. The study group was selected from patients who had used anastrozole for at least 6 months (n=6). The groups were consistent with regard to age, smoking history, antioxidant use, and family history of cancer. The demographic characteristics of the patients are presented in Table 1.

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Collection of blood samples, and isolation of lymphocytes After completing a questionnaire, 2-mL blood samples were collected in heparinized tubes from each patient and processed the same day. To isolate the lymphocytes, 100 µL of blood was suspended in 1 mL of phosphate buffered saline, and 100 µL of Histopaque (SigmaAldrich, St. Louis, MO, USA) cell separation medium was added. The cells were centrifuged at 250 x g at 4°C for 5 minutes. A trypan blue exclusion test of cell viability was performed, and a viability rate of ≥99% was detected.

then spread on slides coated with 0.65% high melting point agarose and covered with a coverslip and allowed to solidify. Once solidified, the coverslip was removed and the slides were left overnight in cold lysis solution (stock lysis solution: ph 10:5 M sodium chloride, 100 mM EDTA, 10 mM Tris; on the day of the analysis: 1%Triton X-100 and 10% fresh dimethyl sulphoxide solution were added) to lyse the cells. After lysis, slides used to evaluate oxidative damage were incubated with Fpg to identify oxidized purine bases, and with endo III to detect oxidized pyrimidine bases at 37°C ambient temperature. To determine susceptibility to DNA damage and evaluation of DNA repair, labeled lymphocyte samples were treated with 100µM hydrogen peroxide (H2O2), rinsed, and incubated at 37°C. The procedure used to assess oxidative purine and pyrimidine damage, susceptibility to DNA damage, and DNA repair capacity, as well as the formulas used in the calculations are summarized in Table 2. The protocol was performed in a dark room following lysis. To ensure the unwinding of DNA double strands, the slides were placed in 1 mM EDTA, 300 mM sodium hydroxide pH >13 for 40 minutes and then subjected to electrophoresis at 15 V and an electrical current of 300 mA for 30 minutes. After this phase, neutralization procedures were repeated 3 times for a total of 15 minutes using 0.4 M Tris (pH 7.5) buffer solution, and fixed with 50%, 75%, or 100% ethanol. The slides were then stained with 25µg/mL ethidium respectively bromide and examined under an Olympus BX51 fluorescent microscope (Olympus, Corp., Tokyo, Japan) at 40x magnification. All assessments were performed using the Comet Image Processing and Analysis System software (BAB Bs 200 Pro; BAB Ltd., Ankara, Turkey). For each trial, 50 cells were counted on each of 2 slides. The intensity of DNA (% DNA) in the tail was used to determine DNA damage. The formulas used to estimate oxidative damage and repair capacity are summarized in Table 2.

Measurement of oxidative base damage with modified comet assay using bacterial repair enzymes and determination of hydrogen peroxide-induced damage sensitivity and repair capacity The comet assay developed by Singh et al. [19] as modified by Collins et al. [20] with Fpg and endo III restriction enzymes was used to determine oxidative base damage. The enzymes were purchased from Dr. Andrew Collins (University of Oslo, Oslo, Norway). The lymphocytes were suspended in 0.65% low melting point agarose, and

Statistical analysis The data obtained in this study were analyzed using SPSS Statistics for Windows, Version 17.0 (SPSS, Inc., Chicago, IL, USA). Descriptive statistics of mean, SD, frequency (%), and the difference between the minimum and maximum values were calculated for the categorical variables of each data group. In the evaluation of DNA repair capacity, in addition to determining the mean, the data were also expressed as median, and 25th and 75th percentile values due to the small sample size. Normal

Table 1. Demographic characteristics of the study group and the control group Groups

Control (%)

N 12 Mean age (±SD) (years) 54.42±12.95 Smoking Smoker (n/day) 2 (16.67) Nonsmoker 10 (83.33) Family history of cancer Yes 3 (25) No 9 (75) Antioxidant use Yes 1 (8.33) No 11 (91.67) Prescription drug use Yes 7 (58.33) No 5 (41.67)

Study (%)

6 60±9.65

p>0.05

1 (16.67) p>0.05 5 (83.33) 4 (66.67) p>0.05 2 (33.33) 1 (16.67) p>0.05 5 (83.33) 6 (100) 0

p>0.05

The Ethics Committee for Clinical Investigations of the Istanbul University Cerrahpaşa Faculty of Medicine approved the study and its compliance with the Helsinki Declaration (no: 13726). The study participants were informed about the research and provided written, informed consent.

Yesil Devecioglu et al., Genotoxicity risk investigation of anastrozole

Table 2. Experiment conditions and formulas used to evaluate basal damage, oxidative base damage, susceptibility to DNA damage, and DNA repair capacity Enzyme buffer Endo III FPG Basal H2O2-induced (1/3000 dilution) (1/3000 dilution) damage damage (final concentration 100µM)

Repair

Duration of incubation/exposure and ambient temperature

60 min (37 oC) (E)

45 min (37 oC) (A)

45 min (37 oC) (B)

30 min - (37 oC) (C)

7 min (+4 oC) (D)

*each condition was tested using multiple slides (n=12). Oxidative pyrimidine base damage = B-A Oxidative purine base damage = C-A DNA repair capacity (%) = ([D-E]/D)x100 H2O2: Hydrogen peroxide; FPG: Formamidopyrimidine DNA-glycosylase

60.00

Aged <50 years Aged ≥50 years

50.00 % Tail DNA

distribution was assessed with the Shapiro-Wilk test. The differences between 2 independent groups that did not have normal distribution were measured using the Mann-Whitney U test. A chi-square test was employed to investigate the intergroup distribution of demographic findings. Since 20% of the values in the table were less than 5, Fisher’s exact test was performed. The correlation between effects of age and duration of anastrozole use determined in the comet assay and DNA repair capacity as estimated using the challenge technique was measured with Spearman’s rank correlation analysis. Spearman’s rank correlation analysis was also used to determine the relationships between methods. P<0.05 was accepted as the level of statistical significance.

40.00 30.00 20.00 10.00 0.00

DNA damage after H2O2 exposure

Residual damage after 1 hour incubation

Figure 1.

Hydrogen peroxide sensitivity and residual damage in individuals aged <50 and ≥50 years in all groups (mean±SD). *P<0.05.

RESULTS There was no statistically significant difference in basal damage determined with the comet assay between the study group (10.52±2.11) and the control group (12.54±2.61) (p>0.05) (Table 3). Nor was a statistically significant difference in pyrimidine damage found between the study group (29.14±14.48) and the control group (25.45±23.46). Comparison of purine damage also revealed no statistically significant difference between the study group (25.63±10.51) and the control group (14.71±8.38) (p>0.05) (Table 3). Furthermore, no statistically significant difference was found between the study group and the control group in terms of susceptibility to H2O2 damage with the challenge assay (40.96±14.5, 36.52±10.81, respectively), residual damage after 1 hour of incubation (22.47±6.37, 22.58±9.20,

respectively), or DNA repair capacity (42.73±11.28, 38.43±12.59, respectively) (p>0.05) (Table 3). When groups were compared based on participant age greater than or less than 50 years, susceptibility to H2O2 damage (<50 years: 30.67±8.31, ≥50 years: 41.67±12.01) and residual damage after 1 hour of incubation (<50 years: 17.38±4.05, ≥50 years: 25.12±8.59) were found to be statistically significantly greater in individuals aged ≥50 years (p<0.05). Comparisons performed for susceptibility to H2O2 damage and DNA repair capacity of individuals between individuals aged <50 and ≥50 years are shown in Figure 1. When other variables that could affect the results were analyzed, a statistically significant correlation was not found between the modified comet and challenge as-

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Table 3. Parameters of damage, repair, and susceptibility to damage in the control and study groups n Mean±SD Median Basal damage (% DNA) All patients 18 11.87±2.59 11.74 Group Study 6 10.52±2.11 10.32 Control 12 12.54±2.61 12.45 Pyrimidine damage (% DNA) All patients 18 26.68±20.52 18.02 Group Study 6 29.14±14.48 29.06 Control 12 25.45±23.46 13.67 Purine damage (% DNA) All patients 18 18.56±10.36 12.83 Group Study 6 25.63±10.51 26.42 Control 12 14.71±8.38 12.13 DNA damage induced by H2O2 (% DNA) All patients 18 38±11.92 35.2 Group Study 6 40.96±14.5 43.14 Control 12 36.52±10.81 33.05 DNA repair capacity (% DNA) All patients 18 39.86±12.02 36.72 Group Study 6 42.73±11.28 43.65 Control 12 38.43±12.59 34.66

say values for the duration of anastrozole use (p>0.05). Analysis of age in the modified comet and challenge assay results revealed that in the control group, age was related to basal damage (r=0.713; p<0.01). No correlation was observed between age and other parameters for the whole group or between groups (p>0.05). When the measured variables were compared with one another, a correlation was found between susceptibility to H2O2 damage and residual damage (damage after 1 hour of incubation) (r=0.754; p<0.01).

25th percentile 75th percentile

9.94 13.15 9.09 11.79 11.21 13.74

p>0.05

10.39 37.43 17.8 38.25 9.55 45.29

p>0.05

10.93 26.42 17.75 32.33 10.23 15.75

p>0.05

26.56 48.73 24.59 53.5 27.65 45.44

p>0.05

30.91 44.89 33.76 51.39 30.25 43.33

p>0.05

DISCUSSION Breast cancer is the most prevalent cancer type in women in both developed and developing countries. AIs rank first for adjuvant treatment of postmenopausal estrogen-dependent breast cancer; they inhibit aromatase enzymes, which catalyze the last phase of the biosynthesis of estrogen, aromatization [10, 27]. Anastrozole is a potent, selective, and nonsteroidal third-generation (Type II) AI. Investigation of the side effect profiles of AIs revealed that these molecules cause a significant in-

Yesil Devecioglu et al., Genotoxicity risk investigation of anastrozole

crease in bone loss and bone fractures, and a decrease in bone mineral density. When tamoxifen and AIs were compared, the cardiovascular risk of AIs use was found to be statistically significantly higher. In addition, musculoskeletal symptoms, as joint pain, were observed in nearly half of patients [12-16, 28, 29]. Many researchers have offered different opinions about the popularization of AIs. Seruga and Tannock [24] reported that the treatment goal for any type or stage of cancer is to increase survival time and quality of life, and if an inexpensive and established treatment like tamoxifen is to be replaced with a more costly new alternative, then the new treatment should be more effective in at least 1 of those targets. This report is an important subject of debate. Montemurro and Aglietta stated that tamoxifen is still a good adjuvant endocrine treatment for early stage, postmenopausal, hormone receptor-positive breast cancer, but indicated that AIs are superior in terms of antitumor activity and lower toxicity profile [23]. Based on the outcomes of their randomized phase III trials, Yamamoto and Iwase [25] reported that AIs are more effective than tamoxifen in the treatment of early breast cancer, but also noted that the safety profiles are quite different. For instance, a recent meta-analysis demonstrated that tamoxifen may have a more favorable safety profile with respect to cardiotoxicity [30]. Numerous studies are being performed regarding the effectiveness and reliability of AIs. However, a review of the literature did not yield a study that investigated the impact of AIs on DNA. Therefore, we aimed to investigate the effect of one AI, anastrozole, on DNA. In the present study, postmenopausal patients with a diagnosis of breast cancer who were using anastrozole were compared with treatment-naĂŻve postmenopausal women with breast cancer, and the effect (if any) of anastrozole on oxidative base damage was investigated using a modified comet assay. In addition, susceptibility to DNA damage induced by a H2O2 challenge assay and DNA repair capacity were compared. Lymphocytes, which are easily obtained with noninvasive methods, are most often used in biomonitoring studies [31]. These cells are synchronous with the G0 phase of the cell cycle. Their most important characteristic feature is that their biological effects are manifest in target organs because they circulate in the blood throughout the body. Therefore, they are frequently preferred for monitoring DNA damage and chromosomal aberrations with the goal of evaluating the risk of genotoxicity [32]. We also used lymphocytes isolated from peripheral blood samples of our volunteer patients. We did not find

any statistically significant difference between patients using anastrozole and the control group according to results of the conventional comet assay examining peripheral blood lymphocytes (p>0.05). Furthermore, application of the modified comet assay did not reveal any statistically significant difference with respect to pyrimidine or purine damage (p>0.05). To our knowledge, there is no study investigating the potential role of anastrozole in DNA damage. Wozniak et al. [26] investigated the genotoxic effect of tamoxifen with the modified comet assay (using endo III and Fpg enzymes) and found that tamoxifen increased the comet parameters in peripheral blood lymphocytes and Michigan Cancer Foundation-7 breast cancer cells. Liu et al. [33] also investigated DNA damage induced by tamoxifen metabolites in breast cancer cell lines using the comet assay and reported that catechol metabolites induced more severe DNA damage. In our study, we did not find a statistically significant difference between the study group and the control group in susceptibility to H2O2 damage incurred during 1 hour of incubation (residual damage) or DNA repair capacity (%) following the H2O2 challenge assay (p>0.05). We observed that the sensitivity to H2O2 damage demonstrated great interindividual difference. We think that this may reveal individual differences in cellular susceptibility to the agent we used. Similarly, Sterpone et al. [34] used radiation as a challenge agent and reported great variation in damage in all groups, which they related to potential individual genetic sensitivities independent of cancer. In our study, we compared groups <50 and â&#x2030;Ľ50 years of age, and found a statistically significantly higher susceptibility to H2O2 damage and residual damage in individuals aged â&#x2030;Ľ50 years (p<0.05). It was observed that DNA repair capacity had decreased, though not significantly, and that DNA damage and oxidative base damage had increased. Piperakis et al. [35] also investigated age, DNA damage, and related sensitivities, comparing susceptibility to damage in 3 groups of 20 male participants of distinct age using an alkaline comet assay, H2O2, and radiation challenge assays. Consistent with our results, the researchers reported that basal damage, residual damage, and sensitivity in the 60-70 years age group were significantly higher compared with that found in groups aged 40-50 years and 5-10 years, with the smallest values seen in the group aged 5-10 years. Diem et al. [36] also performed a study using an alkaline comet assay and reported increased DNA damage with age. It is very well known that individual changes in DNA repair capacity affect the predisposition to cancer [21].

Not all individuals exposed to the same carcinogen at the same concentration will eventually develop cancer [37]. Individual repair capacity is related to many factors, including genetic and environmental factors, lifestyle-related influences, and dietary habits [21]. This relationship between cancer and susceptibility to DNA damage is also important with respect to cancer treatment, and suggests that the susceptibility of patients to the mutagenic effects of drugs should be better understood. According to the results we obtained from this study, anastrozole was not seen to have an impact on oxidative DNA damage. The most important limitation of our study was the small number of samples. However, since this was an in vivo study, it was not possible to include a large number of patients who met our criteria. Therefore, in vitro evaluation of the effect of anastrozole on DNA damage may be helpful to further clarify any genotoxic effect. Based on our results, cellular susceptibility to damage increases and the repair process slows with age, which is similar to the findings of other studies. This suggests that the use of an H2O2 challenge test in combination with the comet assay is useful in the investigation of conditions that increase susceptibility to damage, such as aging and cancer. Ethics Committee Approval: The Ethics Committee for Clinical Investigations of the Istanbul University Cerrahpaşa Faculty of Medicine approved the study and its compliance with the Helsinki Declaration (no: 13726). Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: This study was supported by Research Foundation of Marmara University (grant no: SAG-C-YLP-211009-0313). Authorship contributions: Concept – T.Y.D., S.S., G.O., N.S.B.; Design – T.Y.D., S.S., G.O., N.S.B.; Supervision – S.S.; Materials – F.A., N.S.B.; Data collection &/or processing – T.Y.D., S.S.; Analysis and/or interpretation – T.Y.D.; Writing – T.Y.D., S.S.; Critical review – T.Y.D., S.S., F.A.

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13 97. 33. Liu X, Pisha E, Tonetti DA, Yao D, Li Y, Yao J, et al. Antiestrogenic and DNA damaging effects induced by tamoxifen and toremifene metabolites. Chem Res Toxicol 2003;16:832–7. 34. Sterpone S, Cornetta T, Padua L, Mastellone V, Giammarino D, Testa A, et al. DNA repair capacity and acute radiotherapy adverse effects in Italian breast cancer patients. Mutat Res 2010;684:43–8. 35. Piperakis SM, Kontogianni K, Karanastasi G, Iakovidou-Kritsi Z, Piperakis MM. The use of comet assay in measuring DNA damage and repair efficiency in child, adult, and old age populations. Cell Biol Toxicol 2009;25:65–71. 36. Diem E, Ivancsits S, Rüdiger HW. Basal levels of DNA strand breaks in human leukocytes determined by comet assay. J Toxicol Environ Health A 2002;65:641–8. 37. Au WW. Abnormal chromosome repair and risk of developing cancer. Environ Health Perspect 1993;101 Suppl 3:303–8.

Orıgınal Article

GENERAL SURGERY

North Clin Istanb 2018;5(1):14-19 doi: 10.14744/nci.2017.93764

Effect of nerve monitoring on complications of thyroid surgery Suleyman Demiryas,1 Turgut Donmez,2 Erdinc Cekic3 Department of General Surgery, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey

Department of General Surgery, Lutfiye Nuri Burat State Hospital, Istanbul, Turkey

Department of Otolaryngology Surgery, Lutfiye Nuri Burat State Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: The most frequent and critical complications of thyroid surgery are recurrent laryngeal nerve palsy and hypocalcemia. In first years of the 21st century, intraoperative neuromonitoring (IONM) was introduced as a new technique to avoid the recurrent laryngeal nerve (RLN) injury. However, the role and the benefits of IONM are still controversial. In this study, we aimed to compare the postoperative complication rates during thyroid surgery with IONM usage (Group 1) and conventional direct visual technique without IONM usage (Group 2). METHODS: We conducted retrospective review of all patients undergoing thyroid surgery in Lütfiye Nuri Burat State Hospital General Surgery Department between 2014 and 2016 years. Patients have been classified in to two groups: Group 1 and 2. RESULTS: Overall, 191 patients were included in the study; Group 1 comprised 79 patients and Group 2 comprised 112 patients. Unilateral RLN paralysis was observed in 7 patients in Group 1 (8.9%) and 15 patients in Group 2 (13.4%) without any significant difference between the groups (p=0.368). Hypocalcemia was encountered in 5 patients (6.3%) in Group 1 and 18 patients (16.1%) in Group 2; this difference was statistically significant (p=0.045). Other complications (such as hematoma and suture reaction) were not significantly different. Operation time was found to be significantly shorter in Group 1 (Mean time, 93.08 min) than in Group 2 (116.54 min) (p=0.03). CONCLUSION: Proven effect of IONM on RLN paralysis is still controversial. However, easy identification of RLN, which gives more confidence to surgeon, and shorter operation time may be factors to lower hypocalcemia rates. Keywords: Hypocalcemia; intraoperative neuromonitoring; nerve identification; recurrent laryngeal nerve injuries; thyroidectomy.

he most frequent and critical complications of thyroid surgery are recurrent laryngeal nerve palsy and hypocalcemia [1]. Malignancy, Graves’ Disease, huge size multinodular goiter, reoperative surgery, urgent reoperation due to bleeding, central compartment neck dissection, prolonged surgery, and inadequacy of experience of surgeon are the factors related to complication risk increment in thyroid surgery [1-6]. The best and most acceptable technique to avoid RLN (Recurrent laryngeal nerve) injury the identification of RLN during surgery [3, 7]. To avoid the RLN injury and increase the comfort and confidence of surgeon during operation, intraoperative neuromonitoring (IONM) was introduced as a new technique in addition

to direct visual technique in first years of the 21st century [3, 7, 8]. IONM helps the surgeon to identify and verify the functional integrity of the RLN [9, 10]. However, unfortunately the role and benefits of IONM are still controversial [11]. RLN injury was resulted with vocal cord paralysis, which may be transient or permanent. This impairment in cord mobility causes postoperative dyspnea, dysphagia, and dysphonia. The type of the injury (such as heat, compression, stripping, neuritis, cut, or difficult intubation) is important in predicting the progression of symptoms. Generally, traumas due to vocal cord or RLN edema result with transient palsy [1, 2]. In case of an absence of an accepted consensus regarding IONM usage,

Received: October 04, 2017 Accepted: October 09, 2017 Online: January 19, 2018 Correspondence: Dr. Suleyman DEMİRYAS. Istanbul Universitesi, Cerrahpasa Tip Fakultesi, Genel Cerrahi Anabilim Dali, Istanbul, Turkey. Tel: +90 212 414 30 00 e-mail: suleyman.demiryas@istanbul.edu.tr © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Demiryas et al., Neuromonitoring in thyroid surgery

the guideline of the American Academy of Otolaryngology Head and Neck Surgery advise IONM usage during thyroid surgery for voice quality preservation [1, 3, 12]. Both the German Association of Endocrine Surgeons and the International Neural Monitoring Study Group advise the IONM usage in all thyroid surgeries [13, 14], but the American Head and Neck Society advises its usage only for patients with thyroid cancer. In this study, we aimed to compare the postoperative complication rates during thyroid surgery with IONM usage and conventional direct visual technique without IONM usage. MATERIALS AND METHODS Patients and groups This retrospective study was approved with local Ethic Committee of Haseki Training and Research Hospital, Istanbul-Turkey (Date/No:10.08.2016/366). Retrospective review of all patients undergoing thyroid surgery in Lütfiye Nuri Burat State Hospital General Surgery Department in 2014-2017 was conducted. Patients have been classified in to two groups. Patients operated with IONM were classified as Group 1 (IONM group); patients operated with conventional direct visual technique without IONM were classified as Group 2 (Non-IONM group). All patients were preoperatively and postoperatively examined for vocal cord mobility as a routine by an otolaryngologist in the ENT (Ear Nose Throat) Department with flexible fiberoptic laryngocscope. Inclusion criteria were multinodular or nodular goiter; Graves’ disease; thyroid cancer; male and female patients aged 18-80 years; and ASA scores I, II, and III. Exclusion criteria were pregnancy, patients aged less than 18 years, preoperative laryngeal surgical history, preoperative vocal cord pathology, and radiation history to neck. All patients were operated in a single department with an experienced surgeon. Preoperative hospital records, age, sex, Body Mass Index (BMI, kg/m²), comorbidities, laboratory results, ultrasonographic findings, and ENT consultation notes were retrospectively recorded. Surgery type, IONM usage, parathyroids situation, RLN visualization, drainage usage, operation time were recorded intraoperatively. Duration of hospital stay, complications, pathological results, and postoperative vocal cord mobility were recorded postoperatively. Retrospective review of all 212 patients undergoing

thyroid surgery in 2014-2016 was conducted. Of them, complete operative and follow-up data were found on 191 patients. All patients’ postoperative calcium levels were measured first at the 8th hour. Calcium levels less than 8.5 mg/dl were accepted as hypocalcemia. Acute hypocalcemia may lead to cardiovascular effects such as syncope, congestive heart failure, neuromuscular such as drowsiness and tingling sensation in the perioral region or fingers, carpopedal spasm, tetani, wheezing, bronchospasm and laryngospasm, and neurologic symptoms such as irritability, personality changes may occur. Patients with hypocalcemia and clinical findings were treated with oral calcium±vitamin D preparations and intravenous calcium gluconates. Patients who need calcium replacement treatment more than 6 months were accepted as permanent hypocalcemia, others were accepted as transient hypocalcemia. All hypocalcemic patients were consulted with the Endocrinology Department and the permanent ones were taken under surveillance of the Endocrinology Department. Surgical site controls were done at the end of first week. Patients having shortness of breath or dyspnea were examined immediately after surgery but asymptomatic patients were examined on postoperative 2nd day for laryngeal functions. Patients with vocal cord paralysis were followed periodically at 1, 2, 3, 6, 12, and 24 months after the surgery. Permanent RLN paralysis was accepted if the vocal cord functions did not resolve by the end of the 1st year follow-up. Beginning of the mobility in flexible fiberoptic laryngoscopy and resolution of symptoms were recorded in transient vocal cord paralysis. All patients were operated under general anesthesia with endotracheal intubation. Sevoflorane was used for maintenance treatment in both groups and additional muscle relaxants (rocuronium) were used only patients in group 2. Operative technique Patients were operated under semi-fowler position, low collar skin incision was performed, and subcutaneous tissue and platysma muscle were dissected. Strep muscles were longitudinally dissected and laterally retracted. Middle thyroid vein was ligated using LigaSure Precise® (LigaSure Vessel Sealing System, Medtronic, USA) and started to dissection of upper pole . In all patients, upper thyroid poles were clamped adjacent to the thyroid gland

and ligated using no: 2/0 silk sutures. In all patients, RLN was dissected and visualized in tracheoesophageal groove. Parathyroid glands were found and preserved using LigaSure. Finally, tracheal ligamentous connections were resected, and hemithyroidectomy procedure was completed. Same procedures were performed for the other side, and total thyroidectomy was completed. In near-total thyroidectomy procedure, total hemithyroidectomy performed in one side, and following this, less than one-gram thyroid tissue is left behind and RLN was partially visualized. In addition, negative pressure hemovac drains were used if necessary. All thyroid surgeries in both groups were performed under general anesthesia. In Group 1, patients were operated using Nerve Integrity Monitor (Dr Langer Medical, Germany). An endotracheal tube with an integrated surface electrode was inserted between the vocal folds by an anesthesiologist under direct vision during intubation. Neuromonitorization started after resolution of the muscle relaxants’ effect. Repetitive 1-mA–2-mA stimulation of the RLN was performed with a standard intermittent monopolar or bipolar probe. Proper stimulation was defined with both the audible alarm of the NIM system and observation of a recognizable EMG waveform (>100 μV for RLN). In Group 2, patients were operated and all RLNs were tried to be identified only with direct visualization. Statistical analysis SPSS 15.0 for Windows was used for statistical analysis. In descriptive statistics, the categorical variables were expressed as number and percentage and the numerical variables were expressed as mean, standard deviation, and median. If the numerical variables were normally distributed, Student’s ttest was used to compare two independent groups. If the numerical variables were not normally distributed, Mann-Whitney U-test was used to compare two independent groups. Chi-square test was used to compare ratios in groups. P<0.05 was considered statistically significant. RESULTS Of 212 patients, complete data, which fit the inclusion criteria of this study, was found in 191 patients. Group 1 comprised 79 patients and Group 2 comprised 112 patients. M/F ratio was 72/7 in Group 1 and 102/10 in Group 2. In the comparison of the groups with demographic parameters; mean age in Group 1 was 49.28±11.419 and in Group was 47.11±11.994. Mean

North Clin Istanb

BMI of the patients in Group 1 was 26.8965 and in Group 2 was 26.6905. According to these two parameters, there is no significant difference between the groups (age, p:0.210; BMI, p:0.684). Surgical procedures and number of nerves under the risk (NUR) are presented in Table 1. Operation time was defined as the duration starting from skin incision and lasting to the end of the skin closure. Operation time was found to be significantly shorter in Group 1 (Mean time, 93.08 min) than in Group 2 (Mean time, 116.54 min) (p=0.03). Pathologic results included benign nodule, cyst, adenoma, Hashimato’s thyroiditis, lymphocytic thyroiditis, and papillary carcinoma. Impairment in vocal cord mobility unilaterally was observed in 7 patients in Group 1 (8.9%) and 15 patients in Group 2 (13.4%) on the postoperative 1st day. According to the statistical tests, we did not find significant difference between the groups (p=0.368). In Group 1, vocal cord paralysis and clinical symptoms recovered in 3 patients at 1st month control , in 1 patient at 3rd month control, and in 1 patient at 6th month control; these 5 patients were accepted as transient RLN paralysis. Only two patients did not show any improvement or recovery in the first year control so they were accepted as permanent RLN paralysis. In Group 2, vocal cord paralysis and clinical symptoms recovered in 7 patients at 1st month control, in 2 patients at 3rd month control, and in 2 patients at 6th month; these 11 patients were accepted as transient RLN paralysis. Four patients did not show any improvement or recovery in 1st year control, so they were accepted as permanent RLN paralysis (Table 2). We did not perform any vocal cord surgery for permanent paralytic patients.

Table 1. Surgical procedures and the number of nerves under the risk (NUR) Group 1 Total Thyroidectomy Near-Total Thyroidectomy Hemithyroidectomy Total

Patients (n)

NUR

42 32 5 79

84 64 5 153

46 59 7 112 191

92 118 7 217 370

Group 2 Total Thyroidectomy Near-Total Thyroidectomy Hemithyroidectomy Total Total

Demiryas et al., Neuromonitoring in thyroid surgery

Table 2. Distribution of complications in the groups

Group 1 n (%)

Group 2 n (%)

Transient VC paralysis Permanent VC paralysis Transient hypocalcemia Permanent hypocalcemia Hematoma Suture reaction

5 2 4 1 1 2

11 (5.06) 4 (1.84) 14 (12.5) 4 (3.57) 3 (2.67) 3 (2.67)

NS NS NS NS NS NS

(3.26) (1.30) (5.06) (1.26) (1.26) (2.53)

Both permanent and transient hypocalcemia was encountered in 5 patients (6.3%) in Group 1, 18 patients (16.1%) in Group 2; this difference was statistically significant (p=0.045). Four of the 5 patients recovered during follow-up period, only 1 of them was accepted as permanent in Group 1. Of 18 patients, 14 recovered during follow-up period and were accepted as transient hypocalcemia and 4 were accepted as permanent hypocalcemia. Hematoma was encountered in one patient (1.3%) in Group 1 and in three patients (2.7%) in Group 2. Two patients in Group 2 and one patient in Group 1 were reoperated on postoperative 1st day, and bleeding control was achieved under the general anesthesia. Other patient in Group 2 had relatively minor bleeding and was followed closely without reoperation. Suture reaction was encountered in two patients (2.5%) in Group 1 and in three patients (2.7%) in Group 2. There is no significant difference between the groups according to these complication rates (hematoma p=0.796, suture reaction p=0.796). In our case series, we did not encounter bilateral vocal cord paralysis, necessity of intensive care, and mortality. According to hospitalization of patients there is no significant difference between two groups (in Group 1, 1.07Âą0.27 days; in Group 2, 1.06Âą0.28 days). Mean recovery time for transient paralysis in Group1 was 8 weeks (3-18 weeks) and in Group 2 was 9 (3-19) weeks.Cessation of calcium replacement therapy in transient hypocalcemic patients in Group 1 was 5 weeks (3-9) and in Group 2 was 5 weeks (3-9). DISCUSSION RLN injury is the most scary and serious complication because of the decline in quality of life and labor loss [6, 15], but hypocalcemia is the most frequent complication in thyroid surgery [16, 17]. In this study we aimed to

investigate the effect of IONM usage on thyroidectomy complications. In literature, the incidence of RLN paralysis varies with a wide range of 0-26% [1-3, 5, 18, 19]. Fortunately, most of these RLN paralyses are transient, and the incidence of permanent paralysis varies with a range of 0-5.8% in literature [5, 6, 20, 21]. Permanent paralysis is accepted when the nonfunctioning or dysfunctioning of the vocal cord lasts for more than 1 year [3]. This study presented the median recovery time for transient RLN paralysis as 8 (4-12) weeks, and in some instance it may last up to 12 months [3]. Joliat et al. [3] reported the incidence of RLN paralysis in their case series including 456 thyroidectomy as 14%; in addition, they encountered 8 cases of paralyses even with IONM usage. In this study, the incidence of permanent paralysis is 1.1%. In another more recent study with 5252 cases series, permanent paralysis incidence was reported to be 1.2% [4]. Dissection and identification of RLN may be problematic in reoperation, malignancy, anatomic distortion due to huge sized tumors, inflammation, and radiation history [1]. In these situations, IONM usage is strictly advised by many authors [7, 15]. Wojtczak et al. [10] reported the incidence of transient and permanent paralysis in recurrent thyroid surgery as 12.5 % and 3.8%, respectively. Hermann et al. [2] reported the incidence of permanent RLN paralysis if the nerve just localized as 0.9%, if partially dissected as 0.3%, if totally dissected as 0.1%. Therefore, they advocate that the detailed and careful dissection of RLN significantly decrease the risk of RLN injury. After the introduction of IONM in 1990, improvement in RLN injury incidence is expected; however, there exists is a discrepancy about the results in literature [4, 10, 19, 22]. Shindo et al. [23] reported in their study with 684 cases that IONM does not change the incidence of transient or permanent vocal cord paralysis. Calo et al. [24] did not show any significant difference between the direct visualization and IONM usage for incidence of either transient or permanent vocal cord paralysis. Pisanu et al. [25] compared direct visual technique with IONM usage in their metaanalysis and analyzed 20 retrospective study with total 35513 nerves (24038 IONM and 11475 direct visualization) and did not find any significant difference in the incidence of RLN paralysis (IONM group, 3.47% and direct visualization, 3.67%). Malik et al. [22] also found similar results in their systematic review. Yang et al. [9] found statistically significant decrease in transient and overall RLN paralysis incidence but did not find significant difference in permanent paralysis incidence.

Rulli et al. [26] also reported similar results with Yang and associate this finding with higher frequency of transient paralysis and complete resolution in longer periods. Brajcich et al. [5], an experienced endocrine surgeon “in a high-volume thyroidectomy practice,” stated that IONM usage is not a proven tool to decrease the RLN injury risk; however, in the case of lost signal of RLN in one side may be helpful to give up the otherside operation. In their retrospective study with 243.527 thyroidectomy cases, Chung et al. reported higher incidence of RLN paralysis in IONM patients. However, they attributed this finding with higher incidence of complications in the first year of IONM usage, and they also stated that this complication risk decreases by the higher experience of this device. In the subgroup analysis of this study, IONM usage significantly decreased the risk of RLN injury in total thyroidectomy patients with neck dissection [19]. To identify and predict postoperative vocal cord functions, intermittent-type IONM is frequently used; however, in recent years, continuous-type IONM usage is getting popular [4, 5, 8]. In their study with 195 caes with vagal nerve stimulation, Farizon et al. reported the incidence of transient RLN paralysis as 3.1% and incidence of permanent RLN paralysis as 0.51%. In this study, they prefer to use the bipolar trans-cricothyroid ligament electrode and indirect stimulation of RLN with vagal nerve stimulation [27]. However, unfortunately, necessity of carotid sheat dissection, difficulty of electrode implantation in complex cases, potential side effects of vagal nerve stimulation, and cost effectiveness are the limitation factors of continuous-type IONM usage [20]. Liu et al. in their study used standard intermittent IONM in thyroid surgeries with 208 nerves under risk. Of 19 cases with 50% loss of EMG amplitude, they stopped surgical procedure, prevented the total signal loss, and finally experienced only two transient paralyses with 2 months of recovery time [20]. In our series, according to NUR, the incidence of transient paralysis was 4.32% and that of permanent paralysis was 1.62% (Table 2), which is consistent with literature. In our study, we did not find significant advantages of intermittent-type IONM usage in the prevention of RLN injury. In our study, we found significantly shorter operation time in Group 1. Similarly, Sarı et al. found significantly shorter duration of operation in IONM group in their study. They did not find significant difference according to incidence of RLN paralysis but they advocated that IONM usage significantly decreases the identification time of RLN [1]. However, using neuromonitoring in thyroid surgery is related with increased preoperative setup

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time [23]. However, total operative time was not significantly different between the groups in metaanalysis [25]. According to these results, the shortness of the operation in Group 1 seems as a secondary advantage of IONM usage. Hypocalcemia is the most frequent complication of thyroidectomy. The most important factors influencing postoperative development of hypocalcemia include intraoperative trauma to parathyroid gland or its vasculature, inability to identify parathyroid gland during operation, incidental parathyroidectomy, central dissection, bilateral thyroidectomy, and inadequate experience of the surgeon [6, 16, 28]. Luo et al. [30] described symptomatic hypocalcemia as specific numbness, spasm, muscular cramp, and Chevok’s syndrome. Again, in this study, the incidence of biochemical hypocalcemia was 26.97% and symptomatic hypocalcemia was 12.5%. The rates of temporary and permanent hypocalcemia in the literature are widely distributed with 1.6%-50% and 0.7%-4.8%, respectively [6, 16, 28, 29]. These widely-distributed prevalence of hypocalcemia is mostly related with uncertainty on the definition of hypocalcemia, different dissection technique, and variations in calcium and vitamin D replacement treatment plan [30]. In that study, they found female gender, hypomagnesia, and lower level of intact PTH as the risk factors for hypocalcemia. In addition to female gender and lower levels of intact PTH levels, Noureldine et al., [16] in their study with 304 total thyroidectomy patients, found malignancy as an independent predictive factor for hypocalcemia. In our study, according to the hypocalcemia complication rates, we found significantly lower hypocalcemia in Group 1. We did not perform any different techniques to the groups for parathyroid preservation; however, it was significantly lower in Group 1. This may be incidental or may be related with giving relatively more attention to the adjacent tissues in Group 1. Again, early and easy identification of RLN gives more confidence to surgeon and decreases the stress level [1, 24]. We suggest that this easy identification of RLN is a major factor for significant hypocalcemia in Group 1. In our study, we did not find any significant difference between the groups for hematoma incidence (Group1, 1.26%; Group 2, 2.67%). In literature, we found hematoma incidence to be 1.2%-1.3% in thyroidectomies [6, 16, 29]. CONCLUSION Our series and similar studies in literature did not reveal the benefits of intermittent IONM usage for decreasing the rates of RLN injury. However, we found significant decrease in operation time and hypocalcemia rates. Increasing the confidence of surgeon by easy identification of RLN may be a factor for lower hypocalcemia rates.

Demiryas et al., Neuromonitoring in thyroid surgery

Wider prospective studies and series may be helpful for understanding the effect of IONM on RLN injury and other complications. Ethics Committee Approval: This retrospective study was approved with local Ethic Committee of Haseki Training and Research Hospital, Istanbul-Turkey (Date/No:10.08.2016/366). Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – S.D., T.D., E.C.; Design – S.D., T.D., E.C.; Supervision – S.D., T.D., E.C.; Materials – S.D., T.D., E.C.; Data collection &/or processing – S.D., T.D., E.C.; Analysis and/ or interpretation – S.D., T.D., E.C.; Writing – S.D., T.D., E.C.; Critical review – S.D., T.D., E.C.

REFERENCES 1. Sarı S, Erbil Y, Sümer A, Agcaoglu O, Bayraktar A, Issever H, et al. Evaluation of recurrent laryngeal nerve monitoring in thyroid surgery. Int J Surg 2010;8:474–8. 2. Hermann M, Alk G, Roka R, Glaser K, Freissmuth M. Laryngeal recurrent nerve injury in surgery for benign thyroid diseases: effect of nerve dissection and impact of individual surgeon in more than 27,000 nerves at risk. Ann Surg 2002;235:261–8. 3. Joliat GR, Guarnero V, Demartines N, Schweizer V, Matter M. Recurrent laryngeal nerve injury after thyroid and parathyroid surgery: Incidence and postoperative evolution assessment. Medicine (Baltimore) 2017;96:e6674. 4. Bergenfelz A, Salem AF, Jacobsson H, Nordenström E, Almquist M; Steering Committee for the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA). Risk of recurrent laryngeal nerve palsy in patients undergoing thyroidectomy with and without intraoperative nerve monitoring. Br J Surg 2016;103:1828–38. 5. Brajcich BC, McHenry CR. The utility of intraoperative nerve monitoring during thyroid surgery. J Surg Res 2016;204:29–33. 6. Karamanakos SN, Markou KB, Panagopoulos K, Karavias D, Vagianos CE, Scopa CD, et al. Complications and risk factors related to the extent of surgery in thyroidectomy. Results from 2,043 procedures. Hormones (Athens) 2010;9:318–25. 7. Wong KP, Mak KL, Wong CK, Lang BH. Systematic review and metaanalysis on intra-operative neuro-monitoring in high-risk thyroidectomy. Int J Surg 2017;38:21–30. 8. Anuwong A, Lavazza M, Kim HY, Wu CW, Rausei S, Pappalardo V, et al. Recurrent laryngeal nerve management in thyroid surgery: consequences of routine visualization, application of intermittent, standardized and continuous nerve monitoring. Updates Surg 2016;68:331–41. 9. Yang S, Zhou L, Lu Z, Ma B, Ji Q, Wang Y. Systematic review with meta-analysis of intraoperative neuromonitoring during thyroidectomy. Int J Surg 2017;39:104–13. 10. Wojtczak B, Barczyński M. Intermittent neural monitoring of the recurrent laryngeal nerve in surgery for recurrent goiter. Gland Surg 2016;5:481–9. 11. Lin HS, Terris DJ. An update on the status of nerve monitoring for thyroid/parathyroid surgery. Curr Opin Oncol 2017;29:14–9. 12. Chandrasekhar SS, Randolph GW, Seidman MD, Rosenfeld RM, Angelos P, Barkmeier-Kraemer J, et al; American Academy of Otolaryngology-Head and Neck Surgery. Clinical practice guideline: improving voice outcomes after thyroid surgery. Otolaryngol Head Neck Surg 2013;148:S1–37.

19 13. Randolph GW, Dralle H; International Intraoperative Monitoring Study Group, Abdullah H, Barczynski M, Bellantone R, et al. Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: international standards guideline statement. Laryngoscope 2011;121 Suppl 1:S1–16. 14. Musholt TJ, Clerici T, Dralle H, Frilling A, Goretzki PE, Hermann MM, et al; Interdisciplinary Task Force Guidelines of the German Association of Endocrine Surgeons. German Association of Endocrine Surgeons practice guidelines for the surgical treatment of benign thyroid disease. Langenbecks Arch Surg 2011;396:639–49. 15. Gardner IH, Doherty GM, McAneny D. Intraoperative nerve monitoring during thyroid surgery. Curr Opin Endocrinol Diabetes Obes 2016;23:394–9. 16. Noureldine SI, Genther DJ, Lopez M, Agrawal N, Tufano RP. Early predictors of hypocalcemia after total thyroidectomy: an analysis of 304 patients using a short-stay monitoring protocol. JAMA Otolaryngol Head Neck Surg 2014;140:1006–13. 17. Inversini D, Rausei S, Ferrari CC, Frattini F, Anuwong A, Kim HY, et al. Early intact PTH (iPTH) is an early predictor of postoperative hypocalcemia for a safer and earlier hospital discharge: an analysis on 260 total thyroidectomies. Gland Surg 2016;5:522–8. 18. Jeannon JP, Orabi AA, Bruch GA, Abdalsalam HA, Simo R. Diagnosis of recurrent laryngeal nerve palsy after thyroidectomy: a systematic review. Int J Clin Pract 2009;63:624–9. 19. Chung TK, Rosenthal EL, Porterfield JR, Carroll WR, Richman J, Hawn MT. Examining national outcomes after thyroidectomy with nerve monitoring. J Am Coll Surg 2014;219:765–70. 20. Liu XL, Wu CW, Zhao YS, Wang T, Chen P, Xin JW, et al. Exclusive real-time monitoring during recurrent laryngeal nerve dissection in conventional monitored thyroidectomy. Kaohsiung J Med Sci 2016;32:135– 41. 21. Randolph GW, Kamani D. Intraoperative electrophysiologic monitoring of the recurrent laryngeal nerve during thyroid and parathyroid surgery: Experience with 1,381 nerves at risk. Laryngoscope 2017;127:280–6. 22. Malik R, Linos D. Intraoperative Neuromonitoring in Thyroid Surgery: A Systematic Review. World J Surg 2016;40:2051–8. 23. Shindo M, Chheda NN. Incidence of vocal cord paralysis with and without recurrent laryngeal nerve monitoring during thyroidectomy. Arch Otolaryngol Head Neck Surg 2007;133:481–5. 24. Calò PG, Pisano G, Medas F, Tatti A, Pittau MR, Demontis R, et al. Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful? Clin Ter 2013;164:e193–8. 25. Pisanu A, Porceddu G, Podda M, Cois A, Uccheddu A. Systematic review with meta-analysis of studies comparing intraoperative neuromonitoring of recurrent laryngeal nerves versus visualization alone during thyroidectomy. J Surg Res 2014;188:152–61. 26. Rulli F, Ambrogi V, Dionigi G, Amirhassankhani S, Mineo TC, Ottaviani F, et al. Meta-analysis of recurrent laryngeal nerve injury in thyroid surgery with or without intraoperative nerve monitoring. Acta Otorhinolaryngol Ital 2014;34:223–9. 27. Farizon B, Gavid M, Karkas A, Dumollard JM, Peoc’h M, Prades JM. Intraoperative monitoring of the recurrent laryngeal nerve by vagal nerve stimulation in thyroid surgery. Eur Arch Otorhinolaryngol 2017;274:421–6. 28. Ozemir IA, Buldanlı MZ, Yener O, Leblebici M, Eren T, Baysal H, et al. Factors affecting postoperative hypocalcemia after thyroid surgery: Importance of incidental parathyroidectomy. North Clin Istanb 2016;3:9– 14. 29. Rosato L, Avenia N, Bernante P, De Palma M, Gulino G, Nasi PG, et al. Complications of thyroid surgery: analysis of a multicentric study on 14,934 patients operated on in Italy over 5 years. World J Surg 2004;28:271–6. 30. Luo H, Yang H, Zhao W, Wei T, Su A, Wang B, et al. Hypomagnesemia predicts postoperative biochemical hypocalcemia after thyroidectomy. BMC Surg 2017;17:62.

Orıgınal Article

CARDIOLOGY

North Clin Istanb 2018;5(1):20-24 doi: 10.14744/nci.2017.07269

Urban legend or real fact: Coronary artery size varies with demographics Mustafa Adem Tatlisu,1 Murat Sargin,2 Adnan Kaya,3 Ahmet Ilker Tekkesin,3 Zekeriya Nurkalem,4 Serap Aykut Aka2 Department of Cardiology, Sivas Numune State Hospital, Sivas, Turkey

Department of Cardiovascular Surgery, Dr. Siyami Ersek Cardiovascular Surgery Research and Training Hospital, Istanbul, Turkey

Department of Cardiology, Dr. Siyami Ersek Cardiovascular Surgery Research and Training Hospital, Istanbul, Turkey

Department of Cardiology, Istanbul Medipol University Faculty of Medicine, Istanbul, Turkey

ABSTRACT OBJECTIVE: This study aimed to determine the relationship between the diameter of coronary artery stents and age, gender, diabetes mellitus (DM), left ventricular ejection fraction (LVEF), renal dysfunction, and the clinical presentation of myocardial ischemia in the cohort of patients with implanted stents in coronary arteries with severe stenotic lesions. METHODS: This study included 2256 patients (mean age, 59.3±10.9 years; men, 62%) who underwent percutaneous coronary intervention (PCI). The clinical status of the patients at presentation was subcategorized as follows: ST-segment elevation myocardial infarction, non-ST segment elevation myocardial infarction, unstable angina pectoris, and stable angina pectoris. The diameters, without any type or brand differentiation, were divided into two groups as follows: Group I, which included 2.5- and 2.75-mm-diameter stents, and Group II, which included ≥3-mm-diameter stents. RESULTS: The type of procedure, including primary PCI, early invasive strategy, and elective stenting, was not found to be a significant factor affecting the diameter of coronary artery stents. Univariate and multivariate analyses revealed a relationship between the diameter of coronary artery stents and age, gender, DM, and LVEF. CONCLUSION: This study demonstrated that the diameter of coronary artery stents was independently associated with gender, age, a history of DM, and moderate-to-severe systolic left ventricular dysfunction. Keywords: Coronary artery stent diameter; diabetes mellitus; effect; percutaneous coronary intervention.

ender, age, and diabetes mellitus (DM) are some of the many claimed factors that affect the outcomes of coronary artery diseases related to mortality [1]. Besides these, the diameter of coronary artery is another parameter affecting the outcomes [2]. Several studies have shown that the luminal diameter after percutaneous revascularization is a strong predictor of restenosis [3, 4]. Similarly, in coronary artery bypass surgery (CABG), the target vessel size correlates with long-term graft patency [5, 6]. Several angiographic and autopsy studies have ex-

amined the possible relation between coronary arterial size and gender differences, and most of these studies have shown that women have smaller diameters of coronary artery [7, 8]. DM and gender are other possible parameters that are related to coronary artery sizes. However, a study of the diameters of coronary artery has several limitations, such as in cases of patients with angiographically normal coronary arteries or with an eccentric disease, diffuse atherosclerosis, and arterial compensatory enlargement or a study using nonstandard-

Received: July 05, 2017 Accepted: September 15, 2017 Online: January 11, 2018 Correspondence: Dr. Mustafa Adem TATLISU. Sivas Numune Devlet Hastanesi Kardiyoloji Anabilim Dali, Sivas, Turkey. Tel: +90 536 443 99 06 e-mail: ademtatlisu@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Tatlisu et al., Coronary artery size varies with demographics

ized measurement techniques. In patients with coronary artery stents, the diameter of the implanted stents reflects the diameter of the coronary vessel at the lesion. Our study aimed to determine the relationship between the diameter of coronary artery stents and age, gender, DM, left ventricular ejection fraction (LVEF), renal dysfunction, and the clinical presentation of myocardial ischemia in a cohort of patients with implanted stents in coronary arteries with severe stenotic lesions. MATERIALS AND METHODS Study Participants Our retrospective study included 2256 consecutive patients undergoing stent implantation to native coronary artery at Dr. Siyami Ersek Cardiovascular and Thoracic Surgery Training and Research Hospital, which serves as a tertiary catheterization laboratory of a high volume center [1194 primary percutaneous coronary intervention (pPCI) and 2032 elective PCI were performed by 25 interventional cardiologists in 2010] between January 1 and December 31, 2013. Patients with native coronary stent implantation were included. A total of 46 patients were excluded because of the fact that transthoracic echocardiography was not performed in the first 24 h of admission. Demographic parameters were defined as age, gender, DM, LVEF, and creatinine levels. Creatinine levels and LVEF values were recorded before PCI. The clinical status of the patients at presentation was subcategorized as follows: ST-segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI), unstable angina pectoris (USAP), and stable angina pectoris (SAP). Stent diameters varied from 2.5 to 4 mm. The diameter of stents, without any type or brand differentiation, was divided into two groups as follows: Group I, which included 2.5- and 2.75-mm-diameter stents, and Group II, which included ≥3-mm-diameter stents. This study was approved by the Institutional Ethics Committee. Analysis of Patient Data Data on the clinical history of risk factors, such as age, gender, hypertension, DM, hyperlipidemia, and renal insufficiency was collected from the hospital’s medical database. Echocardiographic and coronary angiographic findings were also obtained from the same database. A transthoracic echocardiogram was performed in 98% of patients in the first 24 h of admission to the coronary

care unit, and LVEF was calculated using the Simpson method [9]. Patients with LVEF ≤40% were considered to have moderate-to-severe left ventricular systolic dysfunction [10]. Non-ionic low osmolality contrast media (616 mosmol/kg) were used in all patients. Patients with creatinine levels of ≥1.4 mg/dL were considered to have renal insufficiency [11, 12]. After coronary angiography or pPCI, patients were admitted to the coronary care unit for follow-up. Drugs were administered during and after hospitalization as per the European Society of Cardiology Guidelines [13-15]. Blood values obtained from venous blood samples at hospital admission were recorded from medical reports. White blood cell counts, hemoglobin levels, and platelet counts were measured as part of the automated complete blood count using a Coulter LH 780 Hematology Analyzer (Beckman Coulter Ireland, Inc, Galway, Ireland). Biochemical measurements were performed using Siemens Healthcare Diagnostic Products kits and calibrators (Marburg, Germany). Creatine kinase isoenzyme–MB (CKMB) levels were measured using an immune-inhibition method (Architect C 8000; Abbott Inc). Analysis of Patient Data All STEMI patients underwent pPCI within 1 h of admission, and all NSTEMI patients underwent PCI within 24 h of admission. All PCI procedures were performed using the standard femoral approach with a 6-Fr guiding catheter. Medication before pPCI included 600 mg of clopidogrel and 300 mg of chewable aspirin. Direct stenting was performed whenever possible, and balloon predilatation was performed in the remaining cases. The drug-eluting stent was used whenever possible. To achieve maximal dilation, an intracoronary injection of nitroglycerin (100 µg) was administered in each coronary angiogram. All patients were treated with maintenance doses of clopidogrel (75 mg, once daily for 12 months) and aspirin (100 mg, indefinitely). Statistical Analysis Kolmogorov-Smirnov test was used for testing the normality. Continuous variables with normal distributions were expressed as mean±SD and compared using oneway analysis of variance. Continuous variables with skewed distributions were expressed as median (25th and 75th percentiles) and compared using Kruskal– Wallis test. Categorical variables were expressed as number and percentages, and Pearson’s chi-square or Fisher’s exact tests were used to evaluate the differences. Differ-

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ences between the groups were analyzed using the logrank test. A forward Cox proportional regression model was used for multivariable analysis. In multivariable models, confounders in bivariate analysis as predictors of coronary stent diameter determinators were considered. A two-tailed p-value of <0.05 was considered statistically significant, and 95% CIs were presented for all odds ratios and hazard ratios. Analyses were performed using Statistical Package for Social Sciences software, version 20.0 (SPSS; IBM, Armonk, New York, USA). RESULTS A total of 2256 patients (mean age, 59.3±10.9 years; men, 62%) undergoing stent implantation to native coronary artery were included. Patients’ baseline characteristics are listed in Table 1. Of the patients, 30.3% had DM, 13.9% had renal dysfunction, and 71.8% had systolic left ventricular dysfunction, as shown in Table 1. With respect to the clinical status of patients at presentation, the percentages of patients were as follows: STEMI, 56.2%; NSTEMI and USAP, 24.2%; and SAP, 19.7%. Of the

Table 1. Baseline characteristics of patients

n=2256 (%)

Age Aged ≥65 Gender (male) Diabetes mellitus Left ventricular ejection fraction (≤40%) Creatinine (≥1.4 mg/dL) Patients’ status at admission ST-segment elevation myocardial infarction Non-ST segment elevation myocardial infarction, Unstable angina pectoris Stable angina pectoris Coronary stent diameters <3 mm ≥3 mm Coronary arteries Left anterior descending artery Diagonal artery Circumflex artery Right coronary artery

59.3±10.9 783 (34.7) 1399 (62) 684 (30.3) 1621 (71.8) 314 (13.9) 1267 (56.2) 545 (24.2) 444 (19.7) 440 (19.5) 1816 (80.5) 1270 (56.3) 194 (8.6) 55 (2.4) 737 (32.7)

Continuous variables are presented as median and 25-75 percentiles; nominal variables presented as frequency (%). Mann-Whitney-U test was used for continuous variables. Pearson-Chi-Square test was used for nominal variables.

patients, 19.5% received coronary artery stents of <3mm diameter. Table 2 lists unadjusted and adjusted hierarchical logistic regression analysis for diameters of coronary artery stents. The type of the procedure, including pPCI, early invasive strategy, and elective stenting, was not found to be a significant factor affecting the diameter of coronary artery stents (Table 2). Although renal dysfunction was found to be a factor affecting the diameter of coronary artery stents in univariate analysis, this significant relationship did not persist after adjustment for all confounders. The significant relationship was found between the diameter of coronary artery stents and age, gender, DM, and LVEF in univariate analysis (p<0.001), which persisted even after adjusting for all confounders (Table 2). DISCUSSION Gender, age, chronic renal failure, congestive heart failure, and DM are significant predictors of clinical outcomes after PCI. Patients with smaller target vessels have a significantly higher rate of restenosis; however, this does not imply that coronary stents should not be placed into smaller vessels. A meta-analysis of 11 randomized trials has shown that stenting is superior to balloon angioplasty in small coronary vessels [16]. Although several studies have been conducted on vessel sizes with angiographically normal coronary arteries [17-19], those on vessel sizes with atherosclerotic coronary arteries are rare. In multivariate analysis, age, a history of DM, systolic left ventricular dysfunction, and female gender were found to be associated with coronary vessel size. Our findings support those of previous studies on vessel sizes. Several studies have focused only on gender [17, 18]; therefore, we investigated the relationship between coronary vessel sizes and age, DM, LVEF, renal dysfunction, and the clinical presentation of myocardial ischemia. Before coronary intervention, interventional cardiologists have several preconceptions regarding elderly patients [20] and/or patients with DM that they have considerably smaller coronary vessels than other patients. Our findings were consistent with those observed in our practical experience. Because we received only coronary vessels that were intervened, we could not receive those that could not be intervened. As known by several interventional cardiologists, vessels that cannot be intervened are comparatively smaller than those that are intervened, particularly in patients with DM. Nevertheless, older age, DM, LVEF, and female gender were found to be as-

Tatlisu et al., Coronary artery size varies with demographics

Table 2. Univariate predictors and multivariate hierarchical logistic regression analysis for coronary artery stent diameters. All clinically relevant parameters were included in the model Univariate analysis Age (<65 years) Gender (male) Diabetes mellitus LVEF (≤40%) Creatinine (≥1.4 mg/dL) Type of the procedure Primary PCI Early invasive strategy Elective stenting Multivariate analysis Age (<65 years) Gender (male) Diabetes mellitus LVEF (≤40%) Creatinine (≥1.4 mg/dL)

Stent size <3 mm n (%)

Stent size ≥3 mm p n (%)

OR (95% CI)

173 (11.7) 164 (11.7) 192 (28.1) 358 (22.2) 47 (15.0)

1300 (88.3) 1235 (88.3) 492 (71.9) 1263 (77.9) 267 (85.0)

<0.001 <0.001 <0.001 <0.001 <0.05

3.891 3.577 0.480 0.523 1.442

276 (21.8) 82 (15.0) 82 (18.5)

981 (78.2) 463 (85.0) 362 (81.5)

>0.05 >0.05 >0.05

0.813 (0.618-1.069) 1.278 (0.914-1.788) 1.056 (0.729-1.365)

Stent size <3 mm n (%) 173 (11.7) 164 (11.7) 192 (28.1) 358 (22.2) 47 (15.0)

Stent size ≥3 mm p n (%) 1300 (88.3) 1235 (88.3) 492 (71.9) 1263 (77.9) 267 (85.0)

<0.001 <0.001 <0.001 <0.001 0.08

(3.134-4.830) (2.880-4.444) (0.387-0.595) (0.403-0.678) (1.038-2.005)

OR (95% CI)

4.791 (3.761-6.102) 2.267 (1.762-2.914) 0.569 (0.444-0.730) 0.416 (0.307-0.562) 1.231 (0.915-1.742)

Only parameters that reached statistical significance at univariate analysis were given in the rows below. OR: Odds ratio; CI: confidence interval; LVEF: left ventricular ejection fraction; PCI: percutaneous coronary intervention.

sociated with smaller final stent sizes in our study. Furthermore, we could not find the association between final stent size and the presentation of ischemic heart diseases such as STEMI, NSTEMI, USAP, and SAP. Although patients with STEMI have increased catecholamine and inflammatory cells that may cause coronary spasm during the procedure, we did not find any relationship between STEMI and diameters of coronary stents, which might be because of the routine intracoronary injection of nitroglycerin before stent implantation. Because of intracoronary nitrates, the implanted stent size in patients with STEMI reflects the appropriate final stent size. Limitations There are some limitations to our study. Forty-six patients were excluded because transthoracic echocardiography was not performed in the first 24 h of admission. Our study population was limited to patients undergoing PCI. Therefore, our results cannot be generalized to patients with normal coronary vessels. The study was conducted in a single tertiary referral heart center. Because high-risk patients are referred for PCI to our heart

center, it may have affected our results. As shown in Table 1, 71.8% of the patients had moderate-to-severe systolic left ventricular dysfunction. Another limitation of the study is its retrospective design because of which we could not calculate the body mass index that may affect the diameter of coronary artery vessels and also could not utilize more accurate diagnostic tools, such as intravascular ultrasound and optical coherence tomography, to measure the diameter of vessels. CONCLUSION This study demonstrated that diameters of coronary artery stents were independently associated with gender, age, a history of DM, and moderate-to-severe systolic left ventricular dysfunction. Ethics Committee Approval: This study was approved by the Institutional Ethics Committee. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support.

24 Authorship contributions: Concept – M.A.T.; Design – M.A.T.; Supervision – O.K.; Materials – A.K., M.K.; Data collection &/or processing – A.K., M.K.; Analysis and/or interpretation – M.A.T.; Writing – M.A.T.; Critical review – O.K.

REFERENCES 1. Pilote L, Dasgupta K, Guru V, Humphries KH, McGrath J, Norris C, et al. A comprehensive view of sex-specific issues related to cardiovascular disease. CMAJ 2007;176:S1–44. 2. Hoffmann R, Mintz GS. Coronary in-stent restenosis - predictors, treatment and prevention. Eur Heart J 2000;21:1739–49. 3. Tsai ML, Chen CC, Chen DY, Yang CH, Hsieh MJ, Lee CH, et al. Review: The outcomes of different vessel diameter in patients receiving coronary artery stenting. Int J Cardiol 2016;224:317–22. 4. Saucedo JF, Popma JJ, Kennard ED, Talley JD, Lansky A, Leon MB, et al. Relation of coronary artery size to one-year clinical events after new device angioplasty of native coronary arteries (a New Approach to Coronary Intervention [NACI] Registry Report). Am J Cardiol 2000;85:166–71. 5. O’Connor NJ, Morton JR, Birkmeyer JD, Olmstead EM, O’Connor GT. Effect of coronary artery diameter in patients undergoing coronary bypass surgery. Northern New England Cardiovascular Disease Study Group. Circulation 1996;93:652–5. 6. Mickleborough LL, Carson S, Ivanov J. Gender differences in quality of distal vessels: effect on results of coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003;126:950–8. 7. Yang F, Minutello RM, Bhagan S, Sharma A, Wong SC. The impact of gender on vessel size in patients with angiographically normal coronary arteries. J Interv Cardiol 2006;19:340–4. 8. Dickerson JA, Nagaraja HN, Raman SV. Gender-related differences in coronary artery dimensions: a volumetric analysis. Clin Cardiol 2010;33:E44–9. 9. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358–67. 10. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European

Tatlisu et al., Coronary artery size varies with demographics

Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847. 11. Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001;134:629–36. 12. Shlipak MG, Simon JA, Grady D, Lin F, Wenger NK, Furberg CD; Heart and Estrogen/progestin Replacement Study (HERS) Investigators. Renal insufficiency and cardiovascular events in postmenopausal women with coronary heart disease. J Am Coll Cardiol 2001;38:705–11. 13. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, Borger MA, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569–619. 14. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999–3054. 15. Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F, et al. Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27:1341–81. 16. Moreno R, Fernández C, Alfonso F, Hernández R, Pérez-Vizcayno MJ, Escaned J, et al. Coronary stenting versus balloon angioplasty in small vessels: a meta-analysis from 11 randomized studies. J Am Coll Cardiol 2004;43:1964–72. 17. Kucher N, Lipp E, Schwerzmann M, Zimmerli M, Allemann Y, Seiler C. Gender differences in coronary artery size per 100 g of left ventricular mass in a population without cardiac disease. Swiss Med Wkly 2001;131:610–5. 18. Sheifer SE, Canos MR, Weinfurt KP, Arora UK, Mendelsohn FO, Gersh BJ, et al. Sex differences in coronary artery size assessed by intravascular ultrasound. Am Heart J 2000;139:649–53. 19. Zindrou D, Taylor KM, Bagger JP. Coronary artery size and disease in UK South Asian and Caucasian men. Eur J Cardiothorac Surg 2006;29:492–5. 20. Russ MA, Wackerl C, Zeymer U, Hochadel M, Kerber S, Zahn R, et al. Gender based differences in drug eluting stent implantation - data from the German ALKK registry suggest underuse of DES in elderly women. BMC Cardiovasc Disord 2017;17:68.

Orıgınal Article

GERIATRICS

North Clin Istanb 2018;5(1):25-30 doi: 10.14744/nci.2017.10437

Investigation of the attitudes of university students to discrimination of the elderly Derya Cinar,1 Ayfer Karadakovan,2 Sibel Karaca Sivrikaya3 Balıkesir Provincial Health Directorate, Public Hospitals Services, Balikesir, Turkey

Department of Internal Medicine Nursing, Ege University Faculty of Nursing, Izmir, Turkey

Department of Nursing, Balikesir University School of Health, Balikesir, Turkey

ABSTRACT OBJECTIVE: This study was conducted to determine the attitudes of university students studying in different fields toward discrimination of the elderly. METHODS: This descriptive study was conducted with students who were still studying in the 2015-2016 period. A sample size of 416 students was determined by the stratified sampling method, and students were selected by simple random sampling. Data were collected using an identifying information form and an Age Discrimination Attitude Scale (ADAS) by face-toface interview. Statistical analysis was performed using the program SPSS 20.0. RESULTS: The mean total ADAS score of students was 67.7±6.0. The total ADAS scores and the scores of male students on limiting the life of the elderly was significantly higher than those of female students (p<0.05). CONCLUSION: It was determined that university students studying in different fields have a positive attitude toward the elderly. Action must be taken to remove discrimination of the elderly, and policies must be developed to increase social sensitivity. Keywords: Attitude; discrimination; discrimination of elderly.

n the present day, aging population is one of the most important items on the demographic agenda. The opportunities brought by the advances in science and technology, reduction in illness and death rate, fall in birth rate, improvements in environmental conditions, and increased life expectancy have caused an increase in the proportion of the elderly in society. According to figures published by the World Health Organization, 11.7% of the world population (of over seven billion) is aged ≥60 years [1, 2]. In Turkey, 4% of the population was aged ≥65 years in 1965; according to the Turkish Statistics Institute, this proportion had doubled to 8% by 2014 [3]. With advancing age, a reduction in independence and a limitation in social participation affect society’s approach toward elderly. Values, attitudes, and approaches toward

the aging process are completely attributed to age, and not to individual characteristics. Because of these attitudes, the elderly are stereotyped and subjected to either positive or negative prejudice. The social and societal results of this are expressed as discrimination of the elderly [4, 5]. Discrimination of the elderly, or ageism, is defined as positive or negative attitudes displayed toward individuals because of their age, as a multi-dimensional concept covering prejudiced behavior and actions. The concept “Discrimination against the elderly” was first used in 1969 by Robert Butler, the Chairman of US National Institute on Aging Authority and gerontologist [1, 4-10]. Examining the literature on ageism, it is observed that this attitude generally appears in families, at work, in social life, and in health care services [11-14]. The contributions of elderly to social life

Received: July 03, 2017 Accepted: September 09, 2017 Online: January 10, 2018 Correspondence: Dr. Derya CINAR. Balikesir Devlet Hastanesi Dernegi Genel Sekreterligi Egitim ve Arastirma Dairesi Baskanligi, Balikesir, Turkey. Tel: +90 266 245 95 95 e-mail: deryacinar73@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

and their use of social resources are seen as problems. The idea that young and productive groups should be given priority in the use of resources is becoming more widespread [6, 8]. It has been reported in previous studies that the attitudes of young people to discrimination of the elderly may be negative, positive, or mixed [5, 8, 13, 15]. It was observed that the studies examined in the literature were mostly carried out on young people receiving health education. It is thought that the reason for this is that discrimination of the elderly is most often seen in health care services [8, 15, 16]. In order to enable the perceptions of young people toward discrimination of the elderly, it is important to determine the attitudes of students groups in different fields. For this reason, our study was conducted with the objective of determining the opinions of university students studying in different fields toward discrimination of the elderly. MATERIALS AND METHODS This research was conducted as a descriptive cross-sectional study with university students studying in different fields in the autumn term of the 2015-2016 academic year.The study population consisted of 22.677 university students. The size of the research sample was calculated as 378 by the method of stratified random sampling in relation to size. However, considering the problems of participitans the number determined was increased by 10%, and 416 students were contacted. The students to be included in the sample were decided using a simple random number table, with numbers given to each of students in the beginning of the research days. Collection of Data Ethical approval has been obtained from the local Ethics Committee for research (50687469-1491-31315/1648.4-794). Data were collected after obtaining a

North Clin Istanb

written permission certificate from the students who accepted to participate in the study. The data collection application was performed outside of class hours with oral permission from the teaching staff. This data collection process took approximately 20 min for each class. Instruments Data were collected by a descriptive information form containing the socio-demographic characteristics of the participants and information on their relations with elderly. The Age Discrimination Attitude Scale (ADAS) was used to determine the students’ attitudes to discrimination of the elderly. ADAS, which was developed in 2008 by Yılmaz Vefikuluçay, consists of 23 items [15]. Its Cronbach Alpha Reliability Coefficient was found to be 0.80. There are positive and negative attitude statements on the scale. The positive attitude statements were scored as follows: 5= I agree completely, 4= I agree, 3= I am undecided, 2= I don’t agree, 1= I definitely disagree. The statements of negative attitude toward discrimination of the elderly were scored in the exact opposite way to the scoring described above. The maximum score obtainable was 115, and the minimum score was 23. A high score on the scale indicated a positive attitude in relation to discrimination of the elderly. ADAS consists of three sub-dimensions. These are as follows: limiting the lives of elderly, positive discrimination toward elderly, and negative discrimination toward elderly. The sub-dimension of limiting the lives of elderly is the beliefs and attitudes relating to limiting the social lives of elderly. The highest possible score on this dimension is 45 and the lowest is 9. The dimension of positive discrimination to elderly is the positive beliefs and attitudes of society to elderly. The highest possible score on this dimension is 40 and the lowest is 8. The dimension of negative discrimination to elderly is the negative beliefs and attitudes of society to elderly. The highest possible score on this dimension is 30 and the lowest is 6 (Table 1).

Table 1. Aged discrimination attitude scale sub-dimensions distribution Aged discrimination attitude scale sub-dimensions

Scale items

Life limitation of the elderly 1, 5, 12, 14, 17, 19, 21, 22, 23 Positive discrimination towards elderly 2, 4, 6, 7, 8, 9, 13, 20 Negative discrimination towards elderly 3, 10, 11, 15, 16, 18 ADA overall score

Min points

Max points

9 8 6 23

45 40 30 115

Cinar et al., Elderly discrimination

Statistical Analysis The Statistical Package of Social Sciences (SPSS 20.0 for Windows version; SPSS, Chicago, II, USA) was used to manage and analyze the collected survey data. Normality of the data to share house with an old person was examined with the Shapiro–Wilk test. In comparisons of two groups, t-test in independent groups was used for variables showing normal distribution, whereas the Mann–Whitney U-test was used for variables thatdid not show normal distribution. In comparing three or more groups, One-way ANOVA was used for variables showing normal distribution, whereas Kruskal–Wallis analysis was used for variables that did not have a normal distribution. The level of significance for statistical tests was considered as p<0.05. Also, in the evaluation of the findings of the research, standard deviation, median, minimum and maximum values, and percentage numbers were used. In statistical calculations, the students’ fields of study were grouped under the headings Physical Sciences, Social Sciences, and Health Sciences for ease in determining the level of significance. RESULTS The mean age of the students included in the study was found to be 20.54±2.01 years, and more than half stu-

Table 2. Distribution of the students according to their ADAS and subscale mean scores (n=416) ADAS Sub-Scales

X±SD* Med (Min-Max)**

Life limitation of the elderly 20.4±4.7 20.0 (9-43) Positive discrimination towards elderly 30.1±5.4 31.0 (8-40) Negative discrimination towards elderly 18.8±3.6 19.0 (9-28) ADAS overall score 68.0±6.0 68.0 (44-88) *SD: Standard Deviation; **Med: Medium; Min.: Minimum; Max: Maximum.

dents (59.6%) were females. Almost half of the participants (46.2%) were second-year students. More than half of the participants (61.6%) had a nuclear family, and more than a third of the participants (38.2%) reported that they had experience of living in the same house with an elderly. The proportion of the students who had lived in the same house as an old person for at least one year was 14.4%, whereas 28.9% had lived in the same house as an old person all their lives. It was found that 75% of the students who stated that they lived with an old person lived with at least one old person, and 37.5% of these stated that they only lived with their grandmothers. Of the participants who lived in the same house with more than one old person (25%), it was found that 92.5% lived with their grandfather and grandmother. Table 2 shows the students’ mean scores for ADAS total and sub-dimensions. It was found that according to the total mean scores on the scale, the students’ attitudes to elderly were positive. It was found that male students included in the study, had higher average scores on ADAS than female students and that the difference was statistically significant (p<0.005). No statistically significant difference was found between the ADAS total scores and the mean subscale scores according to the place where they had lived the most (p>0.005). The difference between the students according to their field of study was not found to be statistically significant although their mean scores for positive attitudes toward elderly were high. The difference between the total ADAS and mean subscale scores according to the students’ year of study was not found to be statistically significant (p>0.005) (Table 3). The total ADAS score and mean scores of positive discrimination toward elderly of students who stated that they lived in the same house as an old person were

Table 3. Comparison of ADAS and subgroup scores according to the fields of learning of students participating in the survey (n=416) Fields of learning n=416 Department of science 150 Department of social sciences 223 Department of health sciences 43 p ***

Life limitation of the elderly X±SD

Positive discrimination towards elderly X±SD

Negative discrimination towards elderly X±SD

ADAS overall score X±SD

20.6±5.1 20.1±4.4 20.5±4.9 0.676

29.7±5.8 30.0±5.2 31.8±4.17 0.074

18.5±3.6 18.8±3.5 19.4±3.5 0.267

67.8±6.1 67.3±5.9 68.9±5.8 0.252

*SD: Standard deviation; ** Med: Median; Min.: Minimum; Max: Maximum; *** p <0.05 Significance Level.

North Clin Istanb

Table 4. The Comparison of the ADAS and Subscale Mean Scores of the Students According to Their Sociodemographic Characteristics (n=416)

Variables n Gender Female 248 Male 168 Living in the same House with elderly Individuals Yes 159 No 257 Elderly individual in the family Yes 211 No 179 There was 26

Life limitation of the elderly X±SD

Positive discrimination towards elderly X±SD

Negative discrimination towards elderly X±SD

ADAS overall scores X±SD

19.8±4.7 21.1±4.7 MWU= -3.231 *p=0.001

29.8±5.3 30.5±5.5 MWU= -1.719 p=0.086

18.7±3.4 18.9±3.7 MWU= -0.567 p=0.571

66.9±5.8 68.7±6.0 MWU= -3.454 p=0.001

20.1±4.4 20.5±4.9 t= 1.168 p= 0.280

30.8±4.8 29.7±5.6 t= 2.744 p= 0.098

19.1±3.2 18.6±3.8 t= 5.666 p= 0.018

67.8±5.4 67.6±6.3 t= 3.930 p= 0.048

20.13±4.2 20.6±5.11 20.6±5.9 KW= 0.471 p= .790

29.9±5.7 30.3±5.09 30.1±5.4 KW= 0.132 p= .936

18.7±3.7 18.9±3.6 18.9±2.2 KW= 0.493 p= .782

67.3±5.9 68.0±6.2 67.8±4.6 KW= 1.491 p= .474

*P<0.05

found to be significantly higher than those of students who did not live with elderly (p<0.005). The difference between the total ADAS score and mean sub-dimension scores of students who stated that there was an old person in their family was not found to be significant (p>0.005) (Table 4). DISCUSSION Aging is a physiologically occurring part of the lifecycle. This natural process includes physical, social, and psychological changes [17]. These changes should be accepted by society, but elderly are often seen as a social and economic burden. The prejudices caused by this kind of perception form the basis of discrimination of the elderly, which is seen at individual, cultural, and structural levels [6]. At the individual level, discrimination of the elderly stems from the cultural interaction between the individual and society. Examining the literature, it is seen that the attitudes of young people regarding discrimination of the elderly

have been more researched [5, 8, 13, 15, 17]. It has been found that young people display a more negative attitude toward old age than other age groups [18-20]. In the present study, the attitudes of university students studying in different fields toward discrimination of the elderly were examined, and it was found that they generally had a positive attitude. There are many other similar studies with similar results in literature [11-13, 21-26]. The results of various studies carried out with university students have yielded higher ADAS scores than in the present study and a positive attitude toward elderly [5, 13, 15, 26, 27]. The results of a study by Uysal et al. [17] are similar to our study. A significant difference was found between the total ADAS scores and the scores on the sub-dimension of negative discrimination toward elderly of the male and female students included in the study (p<0.005). In a study by Uysal et al., [17] which was similar to the present study, male students were reported to have a more positive attitude toward elderly than female students. It is thought that this is because women take on more of a

Cinar et al., Elderly discrimination

caring role, and this affects their attitude to elderly negatively. In contrast to these results, it was reported in a study by Güven et al. [27] that female students’ attitudes to elderly were more positive than those of male students. Studies by Yılmaz Vekifuluçay and Soyuer et al. [5, 15] report different results: in these studies, no difference was found between the males and females in terms of attitudes toward discrimination of the elderly, and this does not accord with our study. No statistically significant difference was found between the ADAS scores of the students who participated in the study according to their year of study. Different from our study, it was found in some other studies that as students’ age and education level increased, their positive discrimination toward elderly also increased [5, 13, 15, 17, 27].This is explained as an understanding of old age with the maturity of individuals with increasing age. It was found in our study that the total ADAS scores and the mean scores for negative discrimination toward elderly of students who stated that they lived in the same house as an old person were significantly higher than those who did not live in the same house as an old person (p<0.005). The students who lived with an old person, have an opportunity to observe old age directly, to establish a relationship with an old person, and to see their family as a role model in becoming accustomed to living with an old person. This may have an effect. It is shown in the studies by Yılmaz Vekifuluçay and Soyuer et al. that living with an old person causes a positive attitude toward elderly [15, 17]. The results of our study are similar to results in the literature [28, 29]. Most studies of discrimination of the elderly have been conducted on students in health education [5, 8, 13, 17, 26, 27]. It is thought that factors such as the education that these students receive on geriatric health, illnesses, the process of aging, their contact with old patients during their hospital experience, and their care giving affect their attitude toward elderly. In contrast to studies showing health education students with positive attitudes toward elderly [5, 13, 17, 27], a study was found showing that they had a negative attitude [8]. In contrast to the large number of studies that have been carried out on students in the field of health, there have been few studies conducted with students in different fields of study [27]. Although the mean scores on positive discrimination toward elderly of students participating in our study were found to be high, these were not statistically significant. This result shows that the education

received by young people in school does not affect their attitudes toward elderly. It is thought that the education received within the individuals’ families and the culture of the society in which they live contribute to their attitudes toward elderly. Limitations of the Study: The fact that the research included only the students of one university campus can be seen as its most important limitation. If it were to be carried out in different areas with larger sample groups the results obtained might be different. Because data collection was performed on weekdays between 08.00 and 17.00, it was not possible to include evening batches. Foreign students were not included in the sample, because it was thought that they might have difficulty with completing the forms at the data collection stage and that they might have cultural differences. Ethics Committee Approval: Ethical approval has been obtained from the local Ethics Committee for research (50687469-1491-31315/1648.4-794). Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – A.K., D.C.; Design – A.K., D.C.; Supervision – A.K.; Materials – D.C., A.K.; Data collection &/ or processing – D.C., S.K.S.; Analysis and/or interpretation – S.K.S., D.C.; Writing – D.C.; Critical review – A.K., S.K.S.

REFERENCES 1. Ucun Y, Mersin S, Öksüz E. Youth attitudes toward elderly people. Int J Soc Res Methodol 2015;8:1143–49. 2. World Health Organization. The World Health Report 2003-Shaping the Future. Available at: http://apps.who.int/iris/bitstream/10665/42789/1/9241562439.pdf. Accessed Jan 9, 2018. 3. General Population Census Results, 1935-2000 and Adreses Based Population Registration System Results, 2007- 2014. Available at: http://www.tuik.gov.tr/. Accessed Jan 9, 2018. 4. van den Heuvel WJ, van Santvoort MM. Experienced discrimination amongst European old citizens. Eur J Ageing 2011;8:291–9. 5. Soyuer F, Ünalan D, Güleser N, Elmalı F. Attitudes of elderly students of health vocational schools on elderly discrimination and its relation to some demographic variables. Mersin University J Health Sci 2010;3:20–5. 6. Buz S. Age discrimination for elderly persons. Electronic J Soc Sci 2015;14:268–78. 7. Özdemir Ö, Bilgili N. Elderly discrimination in health services. Gülhane Med J 2014;56:128–31. 8. Köse G, Ayhan H, Taştan S, İyigün E, Hatipoğlu S, Açıkel C. Determining the attitudes of the students who study in different sectors to the elderial discrimination in the field of health. Gülhane Med J 2015;57:145–51. 9. Arun Ö, Pamuk D. Ageism in Institutional Care: Causes of the Discriminatory Attitudes of Older Care Staffs towards Ageing and Old Age and Intervention Strategies. Med J Humanities 2014;IV/2:19–33. 10. Liu YE, Norman IJ, While AE. Nurses’ attitudes towards older people: a systematic review. Int J Nurs Stud 2013;50:1271–82.

30 11. Hughes NJ, Soiza RL, Chua M, Hoyle GE, MacDonald A, Primrose WR, et al. Medical student attitudes toward older people and willingness to consider a career in geriatric medicine. J Am Geriatr Soc 2008;56:334–8. 12. Kishimoto M, Nagoshi M, Williams S, Masaki KH, Blanchette PL. Knowledge and attitudes about geriatrics of medical students, internal medicine residents, and geriatric medicine fellows. J Am Geriatr Soc 2005;53:99–102. 13. Yılmaz E, Özkan S. Attitudes of nursing students to old age discrimination. Maltepe University Nurs Sci Art Rev 2010;3:35–52. 14. Sheikh RB, Mathew E, Rafiquel AM, Suraweera RSC, Khan H, Sreedharan J. Attitude of medical students toward old people in Ajman, United Arab Emirates. Asian Journal of Gerontology and Geriatrics 2013;8:85–9. 15. Yılmaz Vefikuluçay D, Terzioğlu F. The development of the elderly discrimination attitude scale and psychometric evaluation in university students. Turk J Geriatrics 2011;14:259–68. 16. McGuire SL, Klein DA, Chen SL. Ageism revisited: a study measuring ageism in East Tennessee, USA. Nurs Health Sci 2008;10:11–6. 17. Uysal G, Beydağ D, Sensoy F, Özaydin N, Kıyak M. Attitudes of students who receive health education in a foundation university regarding age discrimination. Procedia Soc Behav Sci 2014;152:430–34. 18. Yılmaz M, Altıok M, Polat B, Darıcı M, Sungur MA. Attitudes towards the elderly discrimination of young adults. Turk J Geriatrics 2012;15:416–23. 19. Bodner E, Lazar A. Ageism among Israeli students: structure and demographic influences. Int Psychogeriatr 2008;20:1046–58.

North Clin Istanb 20. Özkan Y, Bayoğlu AS. Ageism: college students perceptions about older people. Soc Sci 2011;6:107–15. 21. Ehrlich AR, Burton W, Greenberg D. Positive attitudes of first year medical students towards older persons. J Am Geriatr Soc 2003;51:627–35. 22. McKinlay A, Cowan S. Student nurses’ attitudes towards working with older patients. J Adv Nurs 2003;43:298–309. 23. McConatha JT, Rieser-Danner L, Harmer K, Hayta V, Polat TS. Life Satisfaction in three countries. Psychol Rep 2004;94:795–806. 24. Schigelone AS, Ingersoll-Dayton B. Some of my best friends are old: A qualitative exploration of medical students’ interest in geriatrics. Educ Gerontol 2004;30:643–61. 25. Ryan A, Melby V, Mitchell L. An evaluation of the effectiveness of an educational and experiential intervention on nursing students’ attitudes towards older people. Int J Older People Nurs 2007;2:93–101. 26. Cheong SK, Wong TY, Koh GC. Attitudes towards the elderly among Singapore medical students. Ann Acad Med Singapore 2009;38:857–61. 27. Güven ŞD, Ucakan Muz G, Efe Ertürk N. The attitudes of university students on the elderly discrimination and its relation to some variables. Journal of Anatolia Nursing and Health Sciences 2012;15:99–105. 28. Gallagher S, Bennett KM, Halford JC. A comparison of acute and longterm health-care personnel’s attitudes towards older adults. Int J Nurs Pract 2006;12:273–9. 29. Voogt SJ, Mickus M, Santiago O, Herman SE. Attitudes, experiences, and interest in geriatrics of first-year allopathic and osteopathic medical students. J Am Geriatr Soc 2008;56:339–44.

Orıgınal Article

PUBLIC HEALTH

North Clin Istanb 2018;5(1):31-36 doi: 10.14744/nci.2017.58855

Sleep quality and anxiety level in employees Ayse Gulsen Teker,1 Nimet Emel Luleci2 Health Directorate, Nigde, Turkey

Department of Public Health, Marmara University Faculty of Medicine, Istanbul, Turkey

ABSTRACT OBJECTIVE: The aim of this study was to measure the sleep quality and anxiety level of a group of employees, as well as determine the relationship between sleep quality and anxiety and other factors. METHODS: A total of 130 of 185 employees at a university campus were enrolled in this cross-sectional study. A descriptive questionnaire, the Pittsburgh Sleep Quality Index, and the Beck Anxiety Inventory were the data collection instruments. In addition to univariate analysis, the relationship between the 2 scales was examined with Spearman correlation analysis. RESULTS: Of the participants, 38.9% had poor sleep quality. Gender, income level, presence of a chronic disease, regular medication use, and relationship with family and the social environment were found to affect both sleep quality and anxiety. A decrease in sleep quality was associated with an increase in the level of anxiety. CONCLUSION: Poor sleep quality and a high anxiety level are common in this country, as in the rest of the world. Socioeconomic interventions and psychosocial support to improve the status of individuals with risk factors, such as chronic disease, will reduce anxiety and improve sleep quality and overall psychosocial health. Further prospective studies should be conducted with different groups of participants and with larger samples to expand knowledge of the relationship between sleep quality and anxiety. Keywords: Anxiety; anxiety disorders; occupational health; public health; sleep; sleep-wake disorders.

leep-wake disorders are divided into 10 types of disorder or group of disorders that encompass a wide spectrum. More than 100 disorders have been defined [1]. Sleep-wake disorders cause complaints related to the timing, quality, and quantity of sleep. All sleep-wake disorders lead to insufficient sleep and reduced daily performance [2]. The most frequently seen sleep-wake disorder is difficulty falling sleep and staying asleep [3]. Sleep-wake disorders are common. In the USA alone, 50 to 70 million people suffer from a sleep-wake disorder [4]. It has been reported that these disorders affect 20% to 30% of the general population, and in some studies the incidence rate was as high as 37% [5, 6]. Though sleep-wake disorders are not unusual, they often go uninvestigated. They are directly related to an

individual’s health status, are a major factor in morbidity, and are associated with increased mortality. They are also associated with increased susceptibility to the common cold [7]. In addition to physical health effects, sleep-wake disorders are closely related to a regression in psychomotor functions, and people with sleep-wake disorders are more likely to have an accident [8]. It has also been found that absenteeism is greater patients with sleepwake disorders, they experience difficulty concentrating, have weaker job performance, and a greater probability of experiencing a workplace accident [6]. The effect of productivity loss and increased healthcare expenditures related to sleep-wake disorders was reported to be an annual cost of $30 to 35 billion in the USA, with total

Received: June 29, 2017 Accepted: August 16, 2017 Online: January 18, 2018 Correspondence: Dr. Ayse Gulsen TEKER. Nigde Saglik Mudurlugu, Nigde, Turkey. Tel: +90 388 212 00 11 e-mail: agulsenteker@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

direct costs for insomnia estimated to be $13 billion [9]. A close relationship between sleep-wake disorders and mental disorders has been demonstrated in many studies. Anxiety disorders, the most common class of mental disorder, are associated with the severity and chronicity of sleep-wake disorders [10]. Common features of anxiety disorders include excessive fear and worry, which can lead to behavioral disorders [2]. In a systematic review, the 1-year and lifetime prevalence rate of anxiety disorders was found to be 10.6% and 16.6%, respectively [11]. In another survey, individuals with insomnia were found to be 17.35 times more likely to have clinically significant anxiety [12]. In a study performed with 14915 participants, about 28% of those with insomnia had a current diagnosis of a mental disorder and 25.6% had a psychiatric history. Past or present anxiety disorders were the most frequently seen mental disorders in association with insomnia [13]. The number of studies investigating the incidence rate of sleep-wake and anxiety disorders in this country is very limited. Saracoglu et al. [14] found that 10.4% of the study population reported daytime sleepiness, and that there was a significant and positive correlation between daytime sleepiness and anxiety risk. The most recent, reliable study on the epidemiology of anxiety disorders in Turkey was performed in 1998, and the researchers found that 6.7% of the participants had received a diagnosis of an anxiety disorder in the previous year [15]. Both sleep quality and anxiety level are important, in terms of both the effects on the health of the individual and quality of life, as well as the effects on the health of an employee, the health of the community, and the healthcare system. The objective of this study was to determine the sleep quality and anxiety level of a group of employees, and to examine the correlation between them, as well as other factors. MATERIALS AND METHODS Approval for this cross-sectional study was obtained from the ethics committee of the Marmara University Faculty of Medicine (no. 09.2014.0318). The study participants were advised about the research both orally and in writing, and informed consent was obtained. Sampling The participants in this research were employees of a university. At the time of the study, a total of 185 employees worked at the university campus. With an assumption

North Clin Istanb

of 50% poor sleep quality, for a 95% confidence interval with a 5% margin of error, an adequate sample size was calculated to be 126 employees. Shift workers were not included. Data collection tools Questionnaires and scales completed by volunteer participants were used to collect the study data. Descriptive questionnaire The investigators prepared a questionnaire containing 29 questions related to the sociodemographic characteristics of the study participants. Pittsburgh Sleep Quality Index The Pittsburgh Sleep Quality Index (PSQI) was developed by Buysse et al. [16]. Validation and reliability studies were conducted by Ağargün et al. in 1996, and the Cronbach’s alpha coefficient for reliability was 0.80 [17]. The PSQI provides information about sleep quality and the type and severity of sleep-wake disorders experienced within the previous month. The scale consists of a total of 24 questions; 19 answers are provided by the participant and 5 by his/her bed partner or roommate, when present. Only the self-rated responses are included in the assessment. The PSQI consists of 7 components (subjective sleep quality rating, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction) that each yield a score of 0 to 3. The sum of the 7 component scores is the global PSQI score. A total score of 5 or greater indicates a poor sleeper; the disruption to sleep quality is worse as the PSQI score increases. Beck Anxiety Inventory The Beck Anxiety Inventory (BAI) measures the frequency of anxiety symptoms experienced by the individual. It is a Likert-type self-assessment consisting of 21 items, each scored between 0 and 3. The maximum total score is 63 points. A greater total score indicates increased anxiety. The scale was developed by Beck et al. [18] in 1988. Validation and reliability of the Turkish version was conducted by Ulusoy et al. 19 in 1998, with a Cronbach’s alpha reliability coefficient of 0.93. Statistical analysis SPSS for Windows, Version 15.0 (SPSS, Inc., Chicago, IL, USA) was used to evaluate the study data. Descriptive findings were expressed as numbers, percentiles, and means. The data were not normally distributed; there-

Teker et al., Sleep and anxiety

fore, for intergroup comparisons of measurable values, the Mann-Whitney U test and the Kruskal-Wallis test were applied. Correlation between the 2 scales was evaluated using Spearman correlation analysis. P<0.05 was accepted as the level of statistical significance. RESULTS Individual characteristics of the participants An adequate sample was achieved with a total of 130 participants: 89 (68.5%) women and 41 (31.5%) men. The mean age of the study population was 36.6±10 years (range: 18-63 years). The education level of the group was university (n=105; 80.8%), high school (n=10; 7.7%), middle school (n=5; 3.8%), and primary school (n=10; 7.7%). The participants were married (n=82; 63.1%), single (n=41; 31.5%), and separated/divorced (n=7; 5.4%). There were instructors (n=27; 20.8%), research workers (n=41; 31.5%), office-workers (n=29; 22.3%), laborers (n=16; 12.3%), nurses (n=7; 5.4%), and employees with other professions (n=5; 3.8%) included. In the study population, 82.2% lived with family and 13.2% lived alone. While 54.6% of the participants had children, 45.4% did not. The question “Does your income meet your expenses?” was responded to affirmatively by 50.8% of the participants and negatively by 49.2%.

Sleep quality and anxiety scale scores The PSQI and BAI scores are presented in Table 1. The mean overall PSQI scale score was 5.6±3.3 (range: 0-17). The PSQI score of 38.9% of the participants was >5 points, which indicates poor sleep quality. The mean BAI score of all of the respondents was 8.6±9.9 (range: 0-53). When the scores were compared according to gender, the anxiety level of the female participants was significantly higher (p=0.044). The mean and median BAI scores of female participants were 9.76 and 5.5, respectively, while the corresponding scores of male participants were 5.05 and 4.0, respectively. Sleep quality was not statistically significantly different between genders (p=0.323). The group of patients who had difficulty meeting their expenses had both poor sleep quality and higher anxiety levels (p=0.002 and p=0.001, respectively). Age, education level, vocation, and marital status were not statistically significantly correlated with either sleep quality (p=0.783, p=0.609, p=0.956, and p=0.065, respectively) or anxiety level (p=0.969, p=0.074, p=0.578, and p=0.522, respectively). The BAI score of participants who regularly used medication and/or had a chronic disease was found to

Table 1. The Pittsburgh Sleep Quality Index and Beck Anxiety Inventory scores of the participants according to their individual characteristics Pittsburgh Sleep Quality Index Beck Anxiety Inventory

Median

Min-max

Median

Min-max

Gender Female

5.0

0.0-17.0

5.5

0.0-53.0

Male

3.0

2.0-13.0

4.0

0.0-29.0

Meets expenses

4.0

0.0-15.0

3.0

0.0-24.0

Does not meet expenses

6.0

1.0-17.0

6.0

0.0-53.0

0.323

0.044

Income level 0.001

0.007

Chronic disease Yes

5.0

1.0-17.0

8.0

0.0-53.0

5.0

0.0-15.0

4.0

0.0-46.0

0.299

0.02

Regular use of medication Yes

5.50

1.0-17.0

14.5

0.0-53.0

5.0

0.0-15.0

4.0

0.0-45.0

Yes

10.0

4.0-15.0

14.5

0.0-53.0

4.0

0.0-46.0

0.081

0.02

Known sleep disorder 0-17.0

p<0.001

0.002

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Table 2. The Pittsburgh Sleep Quality Index and Beck Anxiety Inventory scores of the participants according to their relationship with their family/members of household and social environment

Pittsburgh Sleep Quality Index

Beck Anxiety Inventory

(median/min-max)

Very good Good Moderate Bad

Relationship with

4.5/

5.0/

7.5/

Very good Good

4.0-14.0

3.0/

family/ members

0.0-

of household

15.0

17.0

46.0

30.0

Relationship

3.5/

5.0/

4.0/

5.0/

0.013

5.0/

11.0

with social

0.0-

environment

13.0

17.0

2.0-14.0

0.045

0.0-

46.0

34.0

Moderate Bad 19.0/

2.0-53.0 12.0/

<0.001

9.0

0.0-53.0

0.005

Table 3. Correlation Analysis of the Pittsburgh Sleep Quality Index and the Beck Anxiety Inventory*

Subjective

Sleep

Habitual sleep

Sleep

Use of sleeping

Daytime

Total PSQI

sleep quality

latency

duration

efficiency

disturbances

medication

dysfunction

score**

BAI

r=0.471

r=0.299

r=0.089

r=0.216

r=0.446

r=0.111

r=0.433

r=0.480

score

p<0.001

p=0.001

p=0.326

p=0.016

p=<0.001

p=0.219

p<0.001

*Spearman correlation analysis. BAI: Beck Anxiety Inventory; PSQI: Pittsburgh Sleep Quality Index.

be statistically significantly higher (p=0.02 for both). However, their PSQI scores did not differ significantly (p=0.081). Participants known to have a sleep disorder had poorer sleep quality (p<0.001) and a higher anxiety level (p=0.02). However, there was not a significant difference in the sleep quality (p=0.354) or the anxiety level (p=0.595) between participants with a known psychiatric problem and those without. Similarly, the sleep quality (p=0.071) and the anxiety level (p=0.120) of patients with a history of psychiatric illness did not differ significantly from those without. The participants were asked to classify their relationship with their family/members of the household as very good, good, moderate, or bad, and a significant correlation was found between the state of participantsâ&#x20AC;&#x2122; relationships and sleep quality (p=0.013) as well as anxiety level (p<0.001). Favorable social relationships were associated with better sleep quality and less anxiety. The same relationship was seen with regard to connection to the social environment and the participantâ&#x20AC;&#x2122;s sleep quality (p=0.045) and anxiety level (p=0.005) (Table 2).

Results of correlation analysis of the Pittsburgh Sleep Quality Index and the Beck Anxiety Inventory The association between the total PSQI, the 7 component PSQI scores, and BAI scores was analyzed using the Spearman rank correlation coefficient. Correlation analysis indicated that BAI scores were statistically significantly but only moderately correlated with subjective sleep quality, sleep disturbances, daytime dysfunction, and total PSQI score, while BAI scores were statistically significantly but weakly correlated with sleep latency and habitual sleep efficiency (Table 3). These results demonstrate that a deterioration in sleep quality increases anxiety and/or an increase in anxiety worsens sleep quality. DISCUSSION In the present study, 38.9% of the participants had poor sleep quality. In previous studies conducted in our country, poor sleep quality was detected in 41.1% to 53.2% of the participants [20-22]. Research performed abroad

Teker et al., Sleep and anxiety

indicated an incidence rate of poor sleep quality between 32.5% and 57.5% [23-25]. Our investigation revealed a higher anxiety level in female participants; however, a correlation between gender and sleep quality was not found. Similarly, previous studies failed to find a correlation between gender and sleep quality [20, 23, 25]. However, James et al. [23] indicated that female gender was associated with a risk for bad sleep quality. Consistent with the literature, no correlation between sleep quality and age, education level, profession, or marital status was found in our survey [23, 25]. Research has not determined a correlation between income level and sleep quality and anxiety. However, in this study, sleep quality and anxiety were worse in individuals who could not meet their expenses. Lower socioeconomic status constitutes a disadvantage with regard to sleep quality and anxiety level, as is the case with many aspects of health. As indicated by Acheson et al. [26], improvement in individual socioeconomic status will lead to improvement in public health indicators. In this survey, poorer sleep quality and a higher level of anxiety were detected in participants known to have a sleep-wake disorder, which is consistent with literature findings [20]. According to the results of our research, anxiety was greater in participants with a chronic disease and users of medication; however, no significant difference was found in sleep quality. James et al. [23] and Tirgari et al. [25] both reported a greater incidence rate of anxiety and sleep-wake disorders in individuals with chronic disease and those who use medication. In these surveys, the authors emphasized that chronic disease and continued use of medication constituted a risk for poor sleep quality. Therefore, in cases of chronic disease, psychological care should be part of the overall treatment plan and these individuals should be periodically evaluated by health professionals [26]. Our data also suggest that changes in sleep quality and anxiety level were related to the state of the individual’s relationship with his/her family and social environment: good relationships were associated with improved sleep quality and a lower anxiety level. Dogan et al. [28] demonstrated that anxiety decreased with increases in the level of perceived social support. Efforts to increase the level of social support for individuals will positively change their psychosocial well-being. Previous investigations have analyzed and noted a relationship between sleep-wake disorders and anxiety

disorders. In this investigation, an association was found between poor sleep quality and increased anxiety. Kara et al. [29] found a positive correlation between improvement in anxiety and sleep quality. In conclusion, a significant level of poor sleep quality was detected in this study of employees in our community. Gender, income level, presence of chronic disease, regular use of medication, and the quality of relationships with family and the social environment were found to affect sleep quality and anxiety level. Ameliorative interventions targeting socioeconomic conditions and psychosocial care for the individuals with risk factors, such as chronic disease, will improve sleep quality and general psychosocial health, and decrease anxiety levels. Poor sleep quality has been found to be associated with increased anxiety. However, larger, prospective, in-depth investigations with diverse groups should be performed. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – A.G.T., N.E.L.; Design – A.G.T., N.E.L.; Supervision – A.G.T., N.E.L.; Materials – A.G.T., N.E.L.; Data collection &/or processing – A.G.T., N.E.L.; Analysis and/or interpretation – A.G.T., N.E.L.; Writing – A.G.T., N.E.L.; Critical review – A.G.T., N.E.L.

REFERENCES 1. Kumar VM. Sleep and sleep disorders. Indian J Chest Dis Allied Sci 2008;50:129–35. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington: American Psychiatric Association; 2013. 3. Hilty D, Young JS, Bourgeois JA, Klein S, Hardin KA. Algorithms for the assessment and management of insomnia in primary care. Patient Prefer Adherence 2009;3:9–20. 4. Senthilvel E, Auckley D, Dasarathy J. Evaluation of sleep disorders in the primary care setting: history taking compared to questionnaires. J Clin Sleep Med 2011;7:41–8. 5. Arroll B, Fernando A 3rd, Falloon K, Goodyear-Smith F, Samaranayake C, Warman G. Prevalence of causes of insomnia in primary care: a cross-sectional study. Br J Gen Pract 2012;62:e99–103. 6. Morphy H, Dunn KM, Lewis M, Boardman HF, Croft PR. Epidemiology of insomnia: a longitudinal study in a UK population. Sleep 2007;30:274–80. 7. Pigeon WR, Heffner K, Duberstein P, Fiscella K, Moynihan J, Chapman BP. Elevated sleep disturbance among blacks in an urban family medicine practice. J Am Board Fam Med 2011;24:161–8. 8. Lee M, Choh AC, Demerath EW, Knutson KL, Duren DL, Sherwood RJ, et al. Sleep disturbance in relation to health-related quality of life in adults: the Fels Longitudinal Study. J Nutr Health Aging 2009;13:576–83. 9. Walsh JK, Engelhardt CL. The direct economic costs of insomnia in the

36 United States for 1995. Sleep 1999;22 Suppl 2:S386–93. 10. Staner L. Sleep and anxiety disorders. Dialogues Clin Neurosci 2003;5:249–58. 11. Somers JM, Goldner EM, Waraich P, Hsu L. Prevalence and incidence studies of anxiety disorders: a systematic review of the literature. Can J Psychiatry 2006;51:100–13. 12. Taylor DJ, Lichstein KL, Durrence HH, Reidel BW, Bush AJ. Epidemiology of insomnia, depression, and anxiety. Sleep 2005;28:1457–64. 13. Ohayon MM, Roth T. Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res 2003;37:9–15. 14. Saracoglu GV, Tokuc B, Dogan S, Celikkalp U, Saracoglu A. Frequency of daytime sleepiness and risk of anxiety and depression among shift workers in two selective factories. Turk J Public Health 2015;13:206– 16. 15. Erol N, Kılıç C, Ulusoy M, Keçeci M, Şimşek Z. Türkiye ruh sağlığı profili raporu. 1. baskı. Ankara: 1998. p. 81. 16. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193–213. 17. Agargun MY, Kara H, Anlar O. Pittsburgh Sleep Quality Index Validity and Reliability. Turk Psikiyatri Dergisi 1996;7:107–15. 18. Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988;56:893–7. 19. Ulusoy M, Şahin NH, Erkmen H. Turkish Version of the Beck Anxiety Inventory: Psychometric Properties. J Cogn Psychother 1998;12:163–72. 20. Sari OY, Uner S, Buyuakkus B, Bostanci EO, Celiksoz AH, Budak M.

North Clin Istanb Sleep Quality and Some Factors Affecting Sleep Quality in the Students Living in the Residence Hall of a University. TAF Prev Med Bull 2015;14:93–100. 21. Üstün Y, Çınar Yücel Ş. The investigation of sleep quality of nurses. Maltepe Universitesi Hemsirelik Bilim ve Sanat Dergisi 2011;1:29–38. 22. Aktas H, Sasmaz CT, Kilincer A, Mert E, Gulbol S, Kulekcioglu D. Study on the Factors Related to Physical Activity Levels and Sleep Quality in Adults. Mersin Univ Saglık Bilim Derg 2015;8:60–70. 23. James BO, Omoaregba OJ, Igberase OO. Prevalence and correlates of poor sleep quality among medical students at a Nigerian university. Ann Nigerian Med 2011;5:1–5. 24. Lemma S, Patel SV, Tarekegn YA, Tadesse MG, Berhane Y, Gelaye B, et al. The Epidemiology of Sleep Quality, Sleep Patterns, Consumption of Caffeinated Beverages, and Khat Use among Ethiopian College Students. Sleep Disord 2012;2012:583510. 25. Tirgari B, Forouzi MA, Iranmanesh S, Shahraki SK. Predictors of Sleep Quality and Sleepiness in the Iranian Adult: A population Based Study. Journal of Community Health Research 2013;1:144–52. 26. Acheson D, Alleyne GA, Casas JA, Castillo-Salgado C, Barzach M, Braveman P, et al. Round table discussion. Health inequalities and the health of the poor. Bull World Health Organ 2000;78:75–85. 27. Özdemir Ü, Taşcı S. Psychosocial problems and care of chronic diseases. Erciyes Üniversitesi Sağlık Bilimleri Fakültesi Dergisi 2013;1:57–72. 28. Doğan T. Psikolojik Belirtiler, Sosyal Destek ve İyilik Hali. Türk Psikolojik Danısma ve Rehberlik Dergisi 2008;3:30–44. 29. Kara N. Sleep disturbance, psychopathology, and quality of life. Arch Neuropsychiatr 2016;53:102–7.

Orıgınal Article

CHILD HEALTH & DISEASES

North Clin Istanb 2018;5(1):37-40 doi: 10.14744/nci.2017.88896

Immunomodulator effect of topical zinc oxide application in tuberculin skin test Cagatay Nuhoglu,1 Evrim Hepkaya,1 Zehra Esra Onal,1 Narin Akici,1 Tamay Gurbuz,1 Vildan Atasayan,1 Omer Ceran2 Department of Pediatrics, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey

Department of Pediatrics, Istanbul Medipol University Faculty of Medicine, Istanbul, Turkey

ABSTRACT OBJECTIVE: We aimed to evaluate the sensitivity of tuberculin skintest (purified protein derivative-PPD) by topical zinc application on test site to improve diagnostic reliability. METHODS: We performed this study in 100 children aged 6–14 years, and plasma zinc levels were analyzed after 10–12 hours fasting. After PPD,we applied 40% zinc oxide cream on one forearm and placebo on the other forearm. PPD indurations were measured 72 hours later. RESULTS: In this study, 26% of the children showed increases in PPD induration following local zinc applications. There was no correlation between indurations size and serum zinc levels. CONCLUSION: We concluded that topical zinc cream application can enhance sensitivity of tuberculin reactivityin the diagnosis of tuberculosis. Keywords: Purified protein derivative; tuberculin skin test; zinc.

uberculosis, is a serious illness in developing countries, particularly in asymptomatic, immunosuppressed children. It is estimated annual risk of tuberculosis infection in children in developing countries is 2–5% [1]. The estimated risk of developing tuberculosis diseases for a young child infected with mycobacterium tuberculosis as indicated by positive tuberculin test is approximately 10% [2]. Nearly 8–20% of the deaths caused by tuberculosis occur in children [3]. We can diagnose the latent infection by means of tuberculin skin test (purified protein derivative-PPD). However, the reliability of this test is limited by false-negative results, particularly in children who have poor nutritional status. Deficiency of zinc, a micronutrient that modulates immune response and supports antibacterial immunity, can cause false-negative results in PPD skin test [4-6]. Therefore,

we investigated whether the application of topical zinc application would enhance the sensitivity of PPD for the diagnosis of the disease. MATERIALS AND METHODS This study was performed in 100 children aged 3–14 years (mean age, 8.98±2.75 years) and hospitalized in Haydarpasa Numune Training and Research Hospital Pediatric Department. After receiving ethical approval and informed written consent, venous blood of the children after 10–12 hours fasting were collected. Plasma zinc levels were analyzed using atomic absorption spectroscopy. The patients who had severe infections that could affect immune system anergic viral infections, steroid administration, and immune suppressive status were excluded.

Received: August 15, 2017 Accepted: August 21, 2017 Online: January 11, 2018 Correspondence: Dr. Cagatay NUHOGLU. Haydarpasa Numune Egitim ve Arastirma Hastanesi, Cocuk Klinigi, Istanbul, Turkey. Tel: +90 216 542 32 32 e-mail: cnuhoglu@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

RESULTS This study included 41% males and 59% females in a total of 100 children (mean age, 8.98±2.75 years). All patients had scars. The mean serum zinc level in females was 89.86 mcg/dl, while it was 90.15 mcg/dl in males. Serum zinc levels of 12 patients was lower than normal (<70 mcg/dl). The mean serum zinc levels of the children were 89.98±24.61 mcg/dl. There was no significant correlation among plasma zinc levels between the PPD induration sizes with placebo and with zinc application (r=0.139; p=0.167). The mean age of the children was 8.98±2.75 (min: 3, max: 14) years. When the mean PPD indurations size of the children with placebo ointment was 2.53±4.44 (min: 0, max: 20) the mean PPD indurations size with zinc application was 3.55±5.67 (min 0, max: 20) mm (p=0.001). The mean PPD indurations size with zinc application was significantly higher than that with placebo (p<0.001) (Table 1). Seventy six percent induration of the responses to PPD with placebo cream were smaller than 5 mm, while 22% were 6–14 mm and 2% were larger than 15 mm. Induration responses to PPD with zinc ointment were as follows: 71% were smaller than 5 mm, 21% were 6–14 mm, and 8% were larger than 15 mm (Fig. 1).

Table 1. Distribution of mean purified protein derivative-PPD indurations size with zinc and placebo Mean value±Standard Deviation (SD) Min. Median Max.

PPD with placebo

PPD with zinc

2.53±4.44

3.55±5.67

0.001*

0 0 20

*Wilcoxon Signed Rank test.

PPD with placebo PPD with zinc

80 70 60 50 %

PPD was performed and evaluated by the same doctor during the study. The doctor injected 0.1 ml tuberculin (5U in 0.1 ml Aventis-Pasteur) in the volar surfaces of both the forearms. After implementations, he covered skin-test side on the left arm with zinc oxide dissolved in aqueous cream of 40% elemental zinc, whereas he covered skin-test sides on the right arm with 1 ml of placebo creams. Both creams had the same color and odor and were provided in a similar looking cup. After 72 hours, he measured the sizes of indurations in both arms by ‘’ball-point-pen.” Number Cruncher Statistical System (NCSS) 2007 and PASS (Power Analysis and Sample Size) 2008 Statistical Software (Utah, USA) were used. While evaluating the data of the study, we used defining statistical methods such as mean value, standard deviation, median, and rate. We performed student’s t test order to demonstrate serum zinc levels according to genders. We used Mann– Whitney U test and Wilcoxon Signed Rank test in evaluating PPD indurations with placebo and zinc supplementation. For evaluating the associations of the parameters with each other, we used Spearman’s correlation analysis. Statistical significance was accepted as p<0.05.

North Clin Istanb

40 30 20 10 0

0-5 mm

6-14 mm

≥15 mm

Figure 1.

Distribution of PPD indurations size with placebo and zinc supplementation.

Of 100 children, 74 of did not show induration with placebo or zinc cream application following PPD. Topical zinc cream application did not have an effect in nonreactive tuberculin test. The remaining 26 children had indurations larger than 0 mm. In this study, 26 of the patients showed increases in PPD indurations, following local zinc application. When 5 of them had a negative PPD response in the placebo sites, PPD response was evaluated as suspiciously positive following topical zinc application. When 6 of them had indurations of6–14 mm in the placebo cream sites, they were measured as positive (>15 mm) in the local zinc cream sites. Of 26 patients, 11 had significantly higher PPD induration sizes on zinc cream sites than placebo cream sites. Applying zinc creams modulated response of PPD by increasing induration sizes (Fig. 2). DISCUSSION Zinc is essential for normal development and function of cell-mediated immunity, neutrophils, and natural killer

Nuhoglu et al., Tuberculin skin test

18 16

PPD with placebo PPD with zinc

12 10 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Figure 2. Subjects showing increased PPD indurations following zinc supplementation. (NK) cells. It is needed for DNA synthesis, RNA transcription, cell division, and cell activation. Zinc deficiency adversely affects the secretion and functions of cytokines, which are the basic messengers of the immune system. Zinc is involved in maturation and differentiation of T cells. The gene expression of interleukin (IL)-2 and interferon (IFN)-γ are zinc dependent. IL-2 is involved in the activation of NK and T cytolytic cells. IFN-γ and IL-12 together play a major role in killing of parasites, viruses, and bacteria by macrophages–monocytes. Zinc deficiency is associated with impaired phagocyte function, lymphocyte depletion, decreased immunoglobulin production, reduced T4/T8 ratio, and decreased IL-2 production. Severe zinc deficiency is characterized by severely depressed immune function, frequent infections, bullous pustular dermatitis, diarrhea, and alopecia. Zinc circulates at a concentration of 70–120 mcg/dl, with 60% percent bound to albumin and 30%tightly bound to macroglobulin [7-13]. Low plasma zinc is usually defined as a value less than 60 mcg/dl. Some investigators argue that plasma zinc measurements are relatively insensitive and that zinc levels in neutrophils and lymphocytes may be more sensitive. The criteria for zinc deficiency is the decreased zinc level either in lymphocytes (<50 mcg/10 cells) or in granulocytes (<42 mcg/10cells) [14, 15]. Rao et al. performed a study on 50 volunteer healthy adults. They evaluated serum zinc levels. They placed PPD at the proximal sides of the palmar forearms and placed Candida antigens at distal sides ofthe forearms. They placed placebo cream in one forearm and zinc cream in the other one. The indurations sizes were measured in 24, 48, and 72 hours. The induration size of PPD was

larger than 32% percentage of the zinc cream applied arm. Topical zinc caused greater tuberculin skin test augmentation in zinc deficient subjects. Zinc cream had no effect on subjects with normal zinc levels. Skin tests with zinc applications were significantly more likely to have positive results than the contra lateral control skin tests with placebo cream application (94% zinc, 76% placebo) [16]. The main difference of this study from ours was statistically significant difference in PPD responses of patients with lower zinc levels; however, there was no difference in the patients within normal serum zinc levels. In our study, there was a significant difference in PPD induration sizes after local zinc application independently plasma zinc levels. The similarity of our study with this one was the evaluation of immunomodulatory effect of using local zinc application to enhance PPD response. Kwok et al. investigated the effect of topical zinc application to increase the sensitivity of PPD. Of 58 elderly patients, 38 (66%) had negative reactions with placebo ointment. Of these negative responders, 14 (37%) showed positive reactions with topical zinc ointment, 12 (32%) had weakly positive reactions, and 12 (32%) remained negative. They determined that 37%of patients with negative PPD had reacted as positive after applying zinc cream ointment. There was no significant difference in the plasma zinc levels between the different grades of topical zinc effect in the negative responders [17]. Although this study was different because it included elderly people, it supported the findings of our study because it had shown that topical zinc application modulated the immune response. Cuevas et al. investigated the differences of positive PPD responsiveness in patients younger than 15 years old. PPD was performed in patients at an interval of 2 years. The group receiving oral zinc application before applying the test showed increase in positive responsiveness and indurations measurements compared with the placebo group [18]. In this study patients were given oral zinc supplements but, our patients were given topical zinc application, differently from the previous study. However, the findings of both studies supported each other because they revealed that zinc modulates the cellmediated immune responsiveness. Castillo-Duran et al. evaluated the immunity and development after adding zinc application in 32 marasmic infants. Half of the subjects were given 2 mg/kg oral zinc during 3 months, and the other half were given placebo. They evaluated PPD responses in the first and 90th day.

Before applying zinc, 33% of the patients showed positive PPD results. After zinc application, 67% of the patients showed positive PPD results. There was no significant difference of PPD responsiveness in placebo group [19]. This study supported the immunomodulatory effect of the zinc application for enhancing the PPD reactivity. Kramer TR et al. investigated T lymphocyte proliferation in 140 children aged 6–13 years by evaluating the PPD responsiveness after oral zinc application with 25 mg/day during 6 months. The group receiving zinc application showed significant increase in PPD responsiveness compared with the one receiving placebo [20]. This study differed from ours by systemic use of zinc combined with vitamin A in a longer duration. However, it also supported our findings that zinc application increased the immunomodulatory effect. Although PPD plays a major role in the diagnosis of latent tuberculosis, nutritional status, immunity, chronic illness of the patients, and environmental factors can decrease its sensitivity. The incidence of tuberculosis increases not only in adulthood but also in childhood. As a result, the effect of zinc on PPD responsiveness gains more importance in diagnostic approach. Although systemic use of zinc application had been preferred in the previous studies, we aimed to benefit from local zinc cream application providing simple and inexpensive effect on enhancing the sensitivity of PPD for the diagnosis of the diseases. We believe that future studies including more subjects can support the sensitivity of PPD responses in the cases with lower plasma zinc levels following topical zinc applications. We recommend using local zinc ointments without screening plasma zinc levels after performing PPD, to enhance the sensitivity of the test so that we can decrease the false-negative results. If we use the booster effect of topical zinc after performing PPD, we can enhance tuberculin reactivity, causing optimal diagnostic approach. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – C.N.; Design – C.N.; Supervision – C.N.; Materials – E.H., N.A.; Data collection &/or processing – E.H., V.A.; Analysis and/or interpretation – C.N., Z.E.O., T.G.; Writing – C.N., Z.E.O., T.G.; Critical review – C.N., O.C.

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REFERENCES 1. Chugh S. Paediatric tuberculosis and DOTS strategy under RNTCP. J Indian Med Assoc 2008;106:799–802. 2. Enarson DA. The International Union Against Tuberculosis and Lung Disease model National Tuberculosis Programmes. Tuber Lung Dis 1995;76:95–9. 3. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974;99:131–8. 4. Golden MH, Harland PS, Golden BE, Jackson AA. Zinc and immunocompetence in protein-energy malnutrition. Lancet 1978;1:1226–8. 5. Lin RY, Busher J, Bogden GJ, Schwartz RA. Topical zinc sulfate augmentation of human delayed type skin test response. Acta Derm Venereol 1985;65:190–3. 6. Karyadi E, West CE, Schultink W, Nelwan RH, Gross R, Amin Z, et al. A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am J Clin Nutr 2002;75:720–7. 7. Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr 1998;68:447S– 63S. 8. Prasad AS. Zinc Deficiency. In: Trace Element in Human Disease. 1995;573-86. 9. Prasad AS. Diagnostic approaches to Trace Element Deficiencies. In: Chandra RK, editor. Trace Elements in Nutrition of Children. New York: 1995. p. 17–40. 10. Prasad AS. Zinc in growth and development and spectrum of human zinc deficiency. J Am Coll Nutr 1988;7:377–84. 11. Prasad AS. Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Exp Gerontol 2008;43:370–7. 12. Overbeck S, Rink L, Haase H. Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases. Arch Immunol Ther Exp (Warsz) 2008;56:15–30. 13. Fraker PJ, Haas SM, Luecke RW. Effect of zinc deficiency on the immune response of the young adult A/J mouse. J Nutr 1977;107:1889– 95. 14. Hambidge KM, Casey CE, Krebs NF. In: Mertz W, editor. Trace elements in human and animal nutrition. Orlando: Academic Press; 1986. p. 1. 15. Wood RJ. Assessment of marginal zinc status in humans. J Nutr 2000;130:1350S–4S. 16. Rao VB, Pelly TF, Gilman RH, Cabrera L, Delgado J, Soto G, et al. Zinc cream and reliability of tuberculosis skin testing. Emerg Infect Dis 2007;13:1101–4. 17. Kwok T, Fotherby MD, Cookson J, Potter JF, Castleden CM. Can topical zinc accentuate tuberculin reactivity in the elderly? Respir Med 1994;88:47–8. 18. Cuevas LE, Almeida LM, Mazunder P, Paixão AC, Silva AM, Maciel L, et al. Effect of zinc on the tuberculin response of children exposed to adults with smear-positive tuberculosis. Ann Trop Paediatr 2002;22:313–9. 19. Castillo-Duran C, Heresi G, Fisberg M, Uauy R. Controlled trial of zinc supplementation during recovery from malnutrition: effects on growth and immune function. Am J Clin Nutr 1987;45:602–8. 20. Kramer TR, Udomkesmalee E, Dhanamitta S, Sirisinha S, Charoenkiatkul S, Tuntipopipat S, et al. Lymphocyte responsiveness of children supplemented with vitamin A and zinc. Am J Clin Nutr 1993;58:566–70.

Orıgınal Article

GASTROENTEROLOGY

North Clin Istanb 2018;5(1):41-46 doi: 10.14744/nci.2017.50480

Evaluation of patients with gastric polyps Sehmus Olmez,1 Suleyman Sayar,2 Bunyamin Saritas,3 Ayla Yildiz Savas,4 Ufuk Avcioglu,5 Ilyas Tenlik,6 Ersan Ozaslan,7 Hasan Tankut Koseoglu,7 Emin Altiparmak7 Department of Gastroenterology, Adana Numune Training and Research Hospital, Adana, Turkey

Deparment of Gastroenterology, Umraniye Training and Research Hospital, Istanbul, Turkey

Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey

Department of Gastroenterology, Balıkesir University Faculty of Medicine, Balikesir, Turkey

Department of Gastroenterology, Ozel Koru Hospital, Ankara, Turkey

Department of Gastroenterology, Turkiye Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey

Department of Gastroenterology, Ankara Numune Training and Research Hospital, Ankara, Turkey

ABSTRACT OBJECTIVE: The incidence of gastric polyps (GPs) greatly differs according to study populations and was found to be 0.33%–6.7% in various studies. The majority of GPs are composed of hyperplastic polyps (HPs), fundic gland polyps (FGPs), and adenomatous polyps (APs). Although APs have a high risk of malignant potential, sporadic FGPs have no malignant potential. Conversely, HPs have a low risk of malignant potential. It is not sufficient to perform a biopsy to identify the polyp type and the presence of dysplasia; thus, some polyps may require multiple biopsies or total excision. METHODS: This retrospective study included patients with GPs or polypoid lesions found on esophagogastroscopy with polyp or malignant histology on biopsy at Ankara Numune Training and Research Hospital Endoscopy Unit between 2005 and 2011. RESULTS: In a series of 56.300 upper endoscopies, 192 patients (0.34%) were found to have GPs. Among the patients, 51 (26.6%) were men and 151 (73.4%) were women. The average age of the patients was 61.9±13.3 (14–90) years. The frequency of HPs, APs, and FGPs were 88%, 2.6%, and 1.6%, respectively. The size of the polyps was ≤1 cm in 137 (70%) patients. One polyp was determined in 141 (73.4%) patients. The most common localizations of polyps were the antrum and corpus. Endoscopic snare polypectomy was performed in 64 patients. One bleeding episode was observed, which required endoscopic treatment after ESP. CONCLUSION: In our study, the GP frequency was low (0.34%), whereas the frequency of HP maybe high due to the high frequency of Helicobacter pylori (HPy) infection in our country. The frequency of FGP is probably low due to the high frequency of HPy infection and the short-term use of proton-pump inhibitors. Keywords: Endoscopic polypectomy; hyperplastic polyp; gastric polyp.

olyps are usually asymptomatic and >90% of polyps were coincidentally detected on esophagogastroduodenoscopy performed for other reasons. Large polyps may cause bleeding, anemia, abdominal pain, or may lead to obstruction rarely due to its localization [1]. A definite diagnosis of polyps should be made by histological examination [2]. The frequency of gastric

polyps (GPs) and types of polyps greatly varies depending on the population in which the study is conducted. The frequency of polyps is 0.6%–6% [3, 4]. The great majority of polyps detected in the stomach are hyperplastic polyps (HPs), fundic gland polyps (FGPs), and adenomatous polyps (APs) [5]. HPs are the most common in populations in which Helicobacter pylori (HPy)

Received: December 18, 2016 Accepted: July 31, 2017 Online: January 10, 2018 Correspondence: Dr. Sehmus Olmez. Adana Numune Egitim ve Arastirma Hastanesi, Gastroenteroloji Bolumu, Adana, Turkey. Tel: +90 535 618 19 80 e-mail: drsehmusolmez@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

infection is common [6]. In countries where HPy infection is low, FGP is more common [3]. In addition, the frequency of FGP increases with the use of long-term proton-pump inhibitors (PPIs) [7]. The importance of GPs arises from the fact that some GPs have malignant potential or are associated with some hereditary syndromes [1]. Although GPs are seen in some congenital diseases such as familial adenomatous polyposis, juvenile polyposis, and Peutz– Jeghers syndrome, the great majority are coincidentally detected [8]. There is an increased risk of cancer in polyps other than FGPs and inflammatory fibrinoid polyp (IFPs). While the risk of malignancy is low in HPs, malignant transformation is seen more frequently in APs. Due to their malignant potential and symptomatic nature, the treatment of GPs is complete removal of the polyps by endoscopic or surgical excision [1]. In this study, we aimed to evaluate the demographic, clinical, endoscopic, and histological data of patients with polyps or polyp-like lesion or malignancy in their histological examination. In addition, we aimed to evaluate the diagnostic procedures, treatment modalities which were applied to treated patients, complications of these treatments, and relationship between age and polyp’s size and number. MATERIALS AND METHODS At the Ankara Numune Training and Research Hospital Gastroenterology Clinic Endoscopy Unit, we retrospectively screened the findings in 56.300 consecutive esophagogastroduodenoscopy (EGD) procedures that were performed for various reasons between September 2005 and December 2011. Permission was obtained from the local ethics committee for the study. Patients in whom GPs or polyp-like lesions were found on EGD and polyps or malignant histology on biopsy were included in the study. Patients without polyps on biopsy, previously taken for the study and inaccessible to their pathology records, were excluded from the study. Patients were screened in detail. We evaluated the age, sex, endoscopic indications, endoscopic findings, GP count, size and localization, diagnostic methods used for histology, and complications of endoscopic treatment if it was performed. The relationship between age and polyp size and count was also evaluated. The endoscope used was a Fujinon EG 530 WR

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video gastroscope (Fujinon, Omiya, Japan; diameter 9.4 mm, working channel 2.8 mm). The polyp size was estimated by comparing it with the opening size of the biopsy forceps. In patients with multiple polyps, the diameter of the polyp was calculated by measuring the diameter of the largest polyp. Statistical Analysis SPSS for Windows 18 package program (SPSS Inc, Chicago, Illinois) was used to analyze data. Descriptive statistics were used to describe continuous variables. The χ² (Fisher’s exact) test was used for categorical variables and expressed as observation counts (and percentages). Statistical signiﬁcance was accepted when a twosided p-value was <0.05. The Kolmogorov–Smirnov test was used to analyze categorical data that fit normal distribution whereas Spearman correlation was used if the distribution of variables was not normal. RESULTS A total of 56.300 patients who underwent EGD in our endoscopy unit was included. GPs were found in 192 patients. We found the incidence of GP as 0.34%.

Table 1. Demographics data and clinical characteristics of patients

Sex Male Female Age (years) Male Female Total patients Symptom Dyspepsia Anemia Abdominal pain Other Polyp size (Mean±SD) (mm) Distribution of polyp size (mm) <6 6-10 11-20 >20

Patients n(%)

51 (26.6) 141 (73.4) 65.9±11.6 (35-90) 60.5±13.7 (14-88) 61.9±13.3 (14-90) 60 (31.3) 44 (22.9) 39 (20.3) 49 (25.5) 11.0±8.4 (3-75) 51 (26.6) 86 (44.8) 43 (22.4) 12 (6.3)

Olmez et al., Gastric polyps

40 30 20 10 0 <41

41-50

51-60

61-70

71-80

>80

Figure 1. The age distribution of patients with gastric polyps. Patient characteristics are shown in Table 1. The age distribution of patients was evaluated. Of the patients, 5.7% were under the age of 41 years, 14.6% were 41– 50 years, 20.8% were 51–60 years, 30.2% were 61–70 years, 24% were 71–80 years, and 4.7% were >80 years. The age distribution of the patients is summarized in Figure 1. The average polyp diameter of the patients was 11.0±8.4 (range: 3–75) mm. The diameters of the polyps were ≤5 mm in 51 (26.6%) patients, 6–10 mm in 86 (44.8%) patients, 11–20 mm in 43 (22.4%) patients, and >20 mm in 12 (6.3%) patients. There was no statistically significant correlation between age and polyp size (p>0.05). Endoscopically, one polyp was found in 73.4% of the study patients. More than one polyp was found in 26.6% of the patients. There was no relation between age and polyp count (p>0.05). Histopathologic diagnosis of polyps was made with only biopsy in 52 (27.1%) patients, with polypec-

Table 2. The distribution of histopathologic types of gastric

polyps

Hyperplastic polyp Foveolar hyperplasia Fundic gland polyp Adenomatous polyp Adenomatous and hyperplastic polyp Inflammatory fibroid polyp Fibrotic polyp Adenocarcinoma Carcinoid Tumor

n (total=192)

169 9 3 5 1 1 1 2 1

88 4.7 1.6 2.6 0.5 0.5 0.5 1 0.5

tomy using biopsy forceps in 75 (39.1%) patients, with polypectomy with snare in 64 (33.3%) patients, and with enucleation via surgical procedure in one patient who could not be diagnosed with endoscopic biopsy. Histologically, the polyp diagnosed with enucleation was reported to be an IFP. Foveolar hyperplasia was found in nine cases (4.7%). The histological distribution of the patients is summarized in Table 2. Only two cases (1%) with GP were diagnosed with adenocarcinoma. The most common localizations of GPs were the antrum (35.9%), followed by the corpus (25.5%) and cardia (15.1%). Polypectomy was performed in 75 patients (39.1%) using biopsy forceps. No complications were seen in 74 patients who underwent polypectomy using biopsy forceps; only one patient experienced bleeding in the form of leakage during polypectomy, and hemorrhage was controlled with sclerotherapy. Polypectomy with snare was performed in 64 patients (33.3%). Polypectomy with snare was performed alone or in combination with other sclerotherapy, endoclip, or endoloop treatments. The distribution of different methods of polypectomy with snare is given in Table 3. In patients who underwent polypectomy with snare, the diameter of the polyp was 16.0±10.5 (3–75) mm. Complications related to polypectomy with snare were not seen in 59 (92%) patients; bleeding was observed in four patients during polypectomy with snare. Bleeding spontaneously stopped in two patients during endoscopic polypectomy, and sclerotherapy was applied to two patients. In one patient, bleeding was observed at the base of the polyp, with hematemesis occurring 4 hours after the polypectomy with snare. Bleeding was controlled by sclerotherapy and blood transfusion was not required.

Table 3. The distribution of snare polypectomy Polypectomy with snare (PS) PS + sclerotherapy PS + endoloop PS + sclerotherapy + endoloop PS + sclerotherapy + endoclip Total PS: Polypectomy with snare

Patients no

37 21 3 2 1 64

57.8 32.8 4.7 3.1 1.6 100

DISCUSSION In our study, we found that the most common symptoms in patients with GPs were dyspepsia, anemia, and abdominal pain. We also found that GPs were localized mostly in the antrum, and the most common histopathologic type was an HP. Carmack et al. found the incidence of GP as 6.35% in 121.564 EGD operations. The most frequent polyp type was FGPs, which accounted for 77% of all polyps, whereas HPs and FHPs were 17% of all polyps. The 16% of lesions defined as polyps did not have histopathological polyp or malignant histology. They related high frequency of FGP with long-term PPI use and low frequency of HPy infection [3]. Elhanafi et al. reported that the most frequent polyp type was HP in 7,090 endoscopic procedures. They concluded that it might be caused by increased HPy infection [9]. However, Macenlle-Garcia et al. reported that GP was found in 18 patients (0.33%) and the most frequent type was HP in 5.314 EGD procedures [10]. In a study performed by Roseau et al., GP was found in 191 (1.3%) patients in 13.000 EGD procedures. Histology of the polyps was HP in 48 patients, FGP in 17 patients, and AP in 6 patients, whereas the histology of 118 patients (61.8%) was either gastritis or normal histology [11]. In 157,902 endoscopic procedures performed by Fann et al., the incidence of polyps was found to be 2.56% and the most frequent type was FGP [12]. In our study, the most frequent type of polyp was HP. HPy infection frequency in our country is 82% [13]. In countries where the HPy frequency is high as in our country, the most frequent polyps are HPs [14]. In a study performed by GarcĂa-Alonso et al., polypoid lesions were found in 269 patients (4.2%) in 6.307 EGD procedures. The mean age of the patients was 65 years, and the proportion of the women was 61%. Histology of polyps were 50.9% HP, 7.4% FGP, and 3% AP. Also, the incidence of adenocarcinoma was 1.9%. Histopathologic diagnosis was normal mucosa in 29.7% of patients who had polyp in EGD [8]. Morais et al. reported GPs in 153 patients (0.59%) in 26,000 endoscopic procedures. Of these patients, 41.2% were females and the mean age of the patients was 64 years. The frequency of polyps was HP in 71.3%, FGP in 16.3%, and AP in 12.4%. Adenocarcinoma was found in one patient with HP and one patient with AP [4]. Molaei et al. reported the frequency of GP as 69.2% for HP, 6.6% for FGP, and 4.7% for AP. The mean age of the patients was 49 years and 73% were

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males. The size of the polyps was <10 mm in 87% of the cases [14]. In a study performed by Fann et al., the mean age was 54.7 years, 63% of patients were females, and 37% of patients were males [12]. In our study, approximately 80% of the patients who were diagnosed with GPs were >50 years. There was no relation between age and polyp size and count. HPs and APs usually appear in older individuals [8]. The incidence of GPs was 0.59%â&#x20AC;&#x201C;3.4% in previous studies in our country [6]. In our study, the incidence of GP was 0.34%, which was lower than that in most of the other studies. The reasons for this may be due to the exclusion of patients with benign pathology or inappropriate sampling of polyps. There are few studies on GP in our country. In a study performed by Gencosmanoglu et al., the GP incidence was 3.4%, and 46% of polyps were found to be HPs, 18% were found to be FHPs and 14% were found to be FGPs. The mean age of the patients was 51 years and the proportion of women was 58%. Polyp size was found to be <5 mm in 58% of the patients [6]. In a study performed by Karaman et al., GP was found in 69 (0.59%) patients in 11.598 EGD procedures. While 69% of all polyps were HPs, 10% were FGPs [15]. In the study performed by Buyukasik et al., HPs were found in 66.7% of 55.987 EGD procedures [16]. The incidence of GP was 2.22% and the highest frequency of HP was found as 36.2% in a study performed by Vatansever et al [17]. In our study, the most common polyps were HPs. However, the frequency of HP was higher than that in previous studies. In addition, the FGP frequency was significantly lower than that in other studies. However, GP was found in 66 (1.95%) patients in 3.375 EGD procedures in a study performed by Demiryilmaz et al.[18] A total of 88 gastric polypoid lesions was detected in these patients. Histopathological examination of polyps revealed 80.7% as HPs, 17% as inflammatory polyps, and 2.3% as APs. No FGP was detected in this study [18]. FGP was the most frequent polyp in some studies [3-7]. The frequency of these polyps has increased due to the decrease in the frequency of HPy infection and increased use of PPIs [3]. Graham first described the development of FGP in three patients treated with omeprazole in 1992 [19]. After this definition, increased FGP frequency with the use of PPI has been shown in many studies [20, 21]. The existence of such a relationship causes anxiety in both physicians and patients who need long-term PPI use. In a study performed by Jalving et al., there was no increase in the frequency of FGP in patients using PPI for <1 year. However, long-term PPI

Olmez et al., Gastric polyps

use was found to increase the risk of developing FGP 4-fold. However, there was no increase in the risk of dysplasia. When subgroup analysis was performed, the risk of developing FGP was observed increased significantly in patients with PPI use for more than 5 years. The increased risk of developing FGP due to long-term PPI use was not different between patients using omeprazole and those using other PPIs [7]. However, increased FGP frequency with PPI use has not been observed in some studies [22]. A total of 30,347 HPy-negative patients were evaluated and FGP frequency was found to be similar to that in 28.096 patients who do not use PPI and 2251 patients who use PPI, and there was no increased risk of polyps in PPI users [22]. This may be due to shortterm PPI use [7]. In a study performed by Choudhry et al., patients using PPI had the highest risk of developing FGPs after a mean of 37 months [23]. Hongo et al. investigated the development of FGPs and HPs in patients with prolonged PPI use in a prospective study. Longterm PPI use has been associated with increased FGP frequency in HPy-negative patients. The formation of these polyps was not associated with hypergastrinemia. However, HP development was associated with HPy positivity and hypergastrinemia [24]. In our study, FGPs were found in three patients. The association of FGPs with HPy is known. HPy infection reduces FGP formation. These polyps are common in HPy-negative patients [25]. This low incidence may be related to the high frequency of HPy infection in our country. However, even in countries with high HPy infection rate, the FGP frequency may be high [14], These polyps have never been observed in some studies [9]. The frequency of FGP has been associated with long-term PPI use. No increased risk for short-term use was observed [7, 14, 18]. The most common cause of EGD procedures in our patients was dyspeptic complaints. FGP frequency, which is very low in our patients, is probably due to the short duration of our patients’ use of PPI therapy. Moreover, since these polyps are quite small, they may be missed during EGD operations or because they may be ignored due to their partially indistinguishability because of their endoscopic appearance. In our study, FHPs were found in nine patients (4.7%). These lesions are thought to be HP precursors. It is not known how often these lesions will turn into HP. The lesions may be stable or may grow or shrink [26]. However, whether they are HP precursors or not is still being debated. Stolte et al. showed that the basic structures and cytological criteria of FHPs and HPs can easily

be distinguished in biopsy materials taken by endoscopic forceps . These lesions are not the result of HP precursors [27]. FHPs are highly common lesions in studies [6, 14]. In our study, APs were detected in five patients. APs constitute ≤10% of GPs [5]. These polyps are more common in communities where stomach cancers are common and have high malignant potential [5]. Malignant potential of AP is 6.8%–55.3% [28]. The size of the lesion, high-grade dysplasia, and presence of intestinal epithelium are risk factors for malignancy development [5]. Even adenomas with low-grade dysplasia in the long-term follow-up have been shown to have a malignant potential. For this reason, excision of these lesions is recommended [29]. In addition, IFP was detected in one patient. These polyps are not always diagnosed with endoscopic biopsy because they are deeply localized [30]. Since our case could not be diagnosed with endoscopic biopsy, it was diagnosed with surgical enucleation. A total of 64 patients (33.3%) underwent polypectomy with snare. One patient had hemorrhage requiring endoscopic control. This patient’s bleeding was controlled by endoscopic treatment. The low frequency of bleeding due to ESP may be treated by sclerotherapy, endoclip, or endoloop procedures. Mortality and perforation did not occur in any patient. Polypectomy with snare is a safe and effective method for the correct diagnosis and treatment of polyps. As a result, the GP frequency in our study was very low (0.34%). The most common type of gastric polyp was HP, but it must be kept in mind that GPs may have adenocarcinoma or precancerous histology, and removal of GP with appropriate technique (removal with biopsy forceps or polypectomy with snare) is recommended. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – S.O.; Design – S.O., H.T.K., S.S.; Supervision – E.A.; Materials – S.O., S.S.,U.A., I.T., A.Y.S.; Data collection &/or processing – A.Y.S., U.A, I.T.; Analysis and/or interpretation – S.O., B.S., E.O.; Writing – S.O., B.S.; Critical review – B.S., H.T.K.

REFERENCES 1. Goddard AF, Badreldin R, Pritchard DM, Walker MM, Warren B; British Society of Gastroenterology. The management of gastric polyps. Gut 2010;59:1270–6. 2. Oberhuber G, Stolte M. Gastric polyps: an update of their pathology and biological significance. Virchows Arch 2000;437:581–90.

46 3. Carmack SW, Genta RM, Schuler CM, Saboorian MH. The current spectrum of gastric polyps: a 1-year national study of over 120,000 patients. Am J Gastroenterol 2009;104:1524–32. 4. Morais DJ, Yamanaka A, Zeitune JM, Andreollo NA. Gastric polyps: a retrospective analysis of 26,000 digestive endoscopies. Arq Gastroenterol 2007;44:14–7. 5. Makar GA, Ginsberg GG. Gastric Polyps. In: Faigel DO, Kochman ML, editors. Endoscopic Oncology. New Jersey: Humana Press; 2006. p. 109–20. 6. Gencosmanoglu R, Sen-Oran E, Kurtkaya-Yapicier O, Avsar E, Sav A, Tozun N. Gastric polypoid lesions: analysis of 150 endoscopic polypectomy specimens from 91 patients. World J Gastroenterol 2003;9:2236– 9. 7. Jalving M, Koornstra JJ, Wesseling J, Boezen HM, DE Jong S, Kleibeuker JH. Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther 2006;24:1341–8. 8. García-Alonso FJ, Martín-Mateos RM, González Martín JA, Foruny JR, Vázquez-Sequeiros E, Boixeda de Miquel D. Gastric polyps: analysis of endoscopic and histological features in our center. Rev Esp Enferm Dig 2011;103:416–20. 9. Elhanafi S, Saadi M, Lou W, Mallawaarachchi I, Dwivedi A, Zuckerman M, et al. Gastric polyps: Association with Helicobacter pylori status and the pathology of the surrounding mucosa, a cross sectional study. World J Gastrointest Endosc 2015;7:995–1002. 10. Macenlle García R, Bassante Flores LA, Fernández Seara J. Gastric epithelial polyps. A retrospective study 1995-2000. Rev Clin Esp 2003;203:368–72. 11. Roseau G, Ducreux M, Molas G, Ponsot P, Amouyal P, Palazzo L, et al. Epithelial gastric polyps in a series of 13000 gastroscopies. Presse Med 1990;19:650–4. 12. Fan NN, Yang J, Sun G, Lu ZS, Ling Hu EQ, Wang XD, et al. Changes in the spectrum of gastric polyps in the Chinese population. World J Gastroenterol 2015;21:9758–64. 13. Ozaydin N, Turkyilmaz SA, Cali S. Prevalence and risk factors of Helicobacter pylori in Turkey: a nationally-representative, cross-sectional, screening with the ¹³C-Urea breath test. BMC Public Health 2013;13:1215. 14. Molaei M, Mashayekhi R, Zojaji H, Haghazali M, Zali MR. Gastric polypoid lesions: analysis of histopathologic features of 107 endoscopic polypectomy specimens. Gastroenterology and Hepatology From Bed to Bench 2008;1:127–32. 15. Karaman A, Deniz K, Karaman H, Gürsoy Ş, Başkol M, Güven K, et al. Prevalence and histopathological condition of gastric polyps in Central Anatolia. Endoskopi Dergisi 2011;2:56–8.

North Clin Istanb 16. Buyukasik K, Sevinc MM, Gunduz UR, Ari A, Gurbulak B, Toros AB, et al. Upper gastrointestinal tract polyps: what do we know about them? Asian Pac J Cancer Prev 2015;16:2999–3001. 17. Vatansever S, Akpınar Z, Alper E, İpek S, Yazıcıoğlu N, Ekinci N, et al. Gastric polyps and polypoid lesions: Retrospective analysis of 36650 endoscopic procedures in 29940 patients. Turk J Gastroenterol 2015;26:117–22. 18. Demiryilmaz I, Albayrak Y, Yilmaz SP. Frequency of various types of gastric polyp. Cumhuriyet Med J 2011;33:209–14. 19. Graham JR. Gastric polyposis: onset during long-term therapy with omeprazole. Med J Aust 1992;157:287–8. 20. Stolte M, Sticht T, Eidt S, Ebert D, Finkenzeller G. Frequency, location, and age and sex distribution of various types of gastric polyp. Endoscopy 1994;26:659–65. 21. el-Zimaity HM, Jackson FW, Graham DY. Fundic gland polyps developing during omeprazole therapy. Am J Gastroenterol 1997;92:1858– 60. 22. Vieth M, Stolte M. Fundic gland polyps are not induced by proton pump inhibitor therapy. Am J Clin Pathol 2001;116:716–20. 23. Choudhry U, Boyce HW Jr, Coppola D. Proton pump inhibitor-associated gastric polyps: a retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics. Am J Clin Pathol 1998;110:615–21. 24. Hongo M, Fujimoto K; Gastric Polyps Study Group. Incidence and risk factor of fundic gland polyp and hyperplastic polyp in long-term proton pump inhibitor therapy: a prospective study in Japan. J Gastroenterol 2010;45:618–24. 25. Yamamoto A, Ishiguro H, Kondo T, Naruse S, Goto H. Low prevalence of Helicobacter pylori infection in patients with fundic gland polyps. Nihon Rinsho 2005;63 Suppl 11:621–4. 26. Turner JR, Odze RD. Polyps of the Stomach. In: Odze R, Goldblum J. Surgical pathology of GI tract, Liver, Bilary tract and Pancreas. Saunders-Elsevier; p. 415–44. 27. Stolte M. Clinical consequences of the endoscopic diagnosis of gastric polyps. Endoscopy 1995;27:32–7. 28. Park DI, Rhee PL, Kim JE, Hyun JG, Kim YH, Son HJ, et al. Risk factors suggesting malignant transformation of gastric adenoma: univariate and multivariate analysis. Endoscopy 2001;33:501–6. 29. Nam KW, Song KS, Lee HY, Lee BS, Seong JK, Kim SH, et al. Spectrum of final pathological diagnosis of gastric adenoma after endoscopic resection. World J Gastroenterol 2011;17:5177–83. 30. Matsushita M, Hajiro K, Okazaki K, Takakuwa H. Endoscopic features of gastric inflammatory fibroid polyps. Am J Gastroenterol 1996;91:1595–8.

Orıgınal Article

GENERAL SURGERY

North Clin Istanb 2018;5(1):47-53 doi: 10.14744/nci.2017.88155

Gallbladder perforation during elective laparoscopic cholecystectomy: Incidence, risk factors, and outcomes Yunus Emre Altuntas,1 Mustafa Oncel,2 Mustafa Haksal,2 Metin Kement,1 Ersin Gundogdu,1 Nihat Aksakal,3 Fazli Cem Gezen2 Department of General Surgery, Kartal Training and Research Hospital, Istanbul, Turkey

Department of General Surgery, Medipol University Faculty of Medicine, Istanbul, Turkey

Department of General Surgery, Istanbul University Faculty of Medicine, Istanbul, Turkey

ABSTRACT OBJECTIVE: This study aimed to reveal the risk factors and outcomes of gallbladder perforation (GP) during laparoscopic cholecystectomy. METHODS: Videotapes of all patients who underwent an elective cholecystectomy at our department were retrospectively analyzed, and the patients were divided into two groups based on the presence of GP. The possible risk factors and early outcomes were analyzed. RESULTS: In total, 664 patients [524 (78.9%) females, 49.7±13.4 years of age] were observed, and GP occurred in 240 (36.1%) patients, mostly while dissecting the gallbladder from its bed (n=197, 82.1%). GP was not recorded in the operation notes in 177 (73.8%) cases. Among the studied parameters, there was no significant risk factor for GP, except preoperatively elevated alanine transaminase level (p=0.005), but the sensitivity and specificity of this measure in predicting GP were 14.2% and 7.4%, respectively. The two groups had similar outcomes, but the operation time (35.4±17.5 vs 41.4±18.7 min, p=0.000) and incidence of drain use (25% vs 45.8%, p=0.000) increased in the GP group. CONCLUSION: The present study reveals that GP occurs in 36.1% of patients who undergo laparoscopic elective cholecystectomy, but it may not be recorded in most cases. We did not find any reliable risk factor that increases the possibility of GP. GP causes an increase in the operation time and incidence of drain use; however, the other outcomes were found to be similar in patients with GP and those without. Keywords: Alanine transaminase; gallbladder perforation; laparoscopic cholecystectomy.

n general surgery practice, cholecystectomy is the second most commonly performed abdominal operation [1, 2]. Laparoscopic cholecystectomy has some advantages over the conventional technique, including better cosmetic results, lesser postoperative pain, a shorter hospital stay, and early return to daily activities [3]. Besides, cholecystectomy is not a risk-free procedure and may cause severe complications, including bile duct injury, bleeding, abscess, and pancreatitis.

Gallbladder perforation (GP), which is a common intraoperative complication during cholecystectomy, has been reported to occur with a high incidence of 10%33% [4]. The risk factors and consequences of GP have also been studied [4-9]. It has been advocated that male sex, a history of acute cholecystitis or previous laparotomies, the use of a laser, an inflamed or nonvisualized gallbladder, and a difficult operation increase the risk of GP [5-7]. In addition, bile and stone spillage have rarely

Received: June 24, 2017 Accepted: August 22, 2017 Online: January 12, 2018 Correspondence: Dr. Yunus Emre ALTUNTAS. Kartal Egitim ve Arastirma Hastanesi, Genel Cerrahi Klinigi, Istanbul, Turkey. Tel: +90 216 441 39 00 e-mail: emrey43@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

been reported to lead to severe problems [10-15]. GP does not worsen the outcomes of the procedure, but it has been stated that lost stones after GP may infrequently cause secondary complications, including pain, fever, or intraabdominal abscesses, because they are a potential nidus of infection and bile spillage may lead to chemical peritonitis [4, 10-16]. However, most of the information present in the literature may be misleading because the data is mostly based on retrospective information, and it is probable that GPs were not recorded in the operation documents because GP is generally believed to be harmless, with no adverse consequences in most instances. Thus, to understand the incidence, risk factors, and consequences of GP, we aimed to analyze compact disc videos of the operations. MATERIALS AND METHODS The Institutional Review Board approved the design and content of the study (Reference number: B104ISM4340029/1009/20). All the patients who underwent an elective cholecystectomy between March 2011 and March 2015 at our department were retrospectively reviewed. The procedures were performed or supervised by one of six surgeons at our department and were performed using a four-trocar technique as described previously [17]. In case of GP during the operation, the management was generally alike: free bile was aspirated, the soiled areas were irrigated with physiological saline until clear, and spilled stones were retrieved whenever possible. These patients continued to receive intravenous and peroral antibiotics for 1 week in most instances. The placement of a drain and conversion to open surgery were decided by the operating surgeon. The patients were generally discharged from the hospital on the next day, but longer hospitalization was sometimes necessary. The primary aims of the present study were to reveal the incidence and risk factors for and outcomes after intraoperative GP during elective laparoscopic surgery. The patients for whom conversion to open surgery was undertaken were excluded from further analyses, but the reasons for conversion were stated. An experienced surgeon (YEA) blinded to the patients, operators, and outcomes of the procedures watched the operation videos taped on compact discs (CD) of all the included patients. The patients were classified into two groups based on the presence of GP at the time of the operation (Perforation or No perforation groups). The patients were excluded

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if the operation CDs were not available or defective. During this inspection, the degree of difficulty was calculated according to Cuschieri’s scale, which defines the complexity of the procedure in four grades [18]. Grade 1 refers to an easy cholecystectomy without any further problems. Grade 2 refers to the presence of light pericholecystitis or adherences or fatty tissue masking the cystic pedicle or mucocele. According to this scale, grade 3 defines severely difficult cholecystectomies in patients with gangrenous cholecystitis; shrunken fibrotic gallbladder; intense pericholecystitis; subhepatic abscesses; or advanced hepatic diseases, such as cirrhosis or portal hypertension. In those patients, the dissections of the cystic pedicle or the body gallbladder from the hepatic bed are hard or sometimes impossible because of the accompanying problem or adherence of Hartman’s pouch over the common bile duct. Patients with grade 4 difficulties were excluded because it refers to conversion to open surgery [18]. The timing of perforation was noted as follows: during traction of the gallbladder, during the dissection of adhesions and bands, during the dissection of Callot’s triangle prior to cystic duct clipsing, during the further dissection of Callot’s triangle after cystic duct clipsing, during the dissection of the gallbladder from the hepatic fossa, and during the extraction of the gallbladder from the abdominal cavity. A chart review was completed for all patients, and computer-based data were scanned for the following information as risk factors for and outcomes of intraoperative GP: demographics; body mass index; the presence/absence of previous hospitalization for acute cholecystitis, biliary pancreatitis, or choloangitis; the American Society of Anesthesiology score; laboratory findings [alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transaminase (GGT), albumin, white blood cell (WBC), hemoglobin, total bilirubin, and amylase]; the necessity and findings of magnetic resonance imaging cholangiography (MRCP) and/or endoscopic retrograde cholangiography (ERCP); ultrasound findings; the presence/absence of previous laparotomy [regional (midline or right subcostal incisions) or others (McBurney or Pfannenstiel)]; previous operations (operations of the gallbladder or gastroduodenal region; or others, including appendectomy, section, or gynecological); the experience of the operator (staff or resident); the degree of difficulty of the operation as described by Cuschieri; operation time; the presence or omission of drain placement; hospitalization period; complications; and re-hospitalization and its causes,

Altuntas et al., Gallbladder perforatıon during elective laparoscopic cholecystectomy

mortality, and pathological findings. Finally, the operation notes were also scanned by two investigators (EG and MH) who were blinded to the patients’ information and operation CDs, and whether or not the perforation was stated in the operation notes was assessed. The patients with a previous hospitalization related to gallbladder stones received an interval cholecystectomy from 6 to 8 weeks after the initial presentation. In our routine practice, if the operation and hospitalization period are uneventful, the patients are seen at day 7 postoperatively. In case of having no complaints, further follow-up is not offered. Statistical Analysis Data were analyzed using SPSS 17.0 for Windows (SPSS Inc., Chicago, IL, USA). Results were given as percentages, mean and standard deviations, or median and ranges. Quantitative and qualitative variables were compared using Student’s t-test and chi-square (Pearson’s or Fischer’s exact) test, respectively. A Mann–Whitney U test was preferred when there was an abnormal distribution of the samples confirmed by the Kolmogorov– Smirnov test. A p value <0.05 was accepted to be significant. RESULTS In total, 737 patients [575 (78.0%) females with a mean (SD) age of 49.1±13.3 years] underwent an elective cholecystectomy at our department during the study period. However, the operation CDs were not available or defective in 60 (8.1%) cases, leaving 677 cases for further analyses. Of these, 13 (1.9%) necessitated conversion to open surgery due to severe adhesions (n=9, 1.3%) not identifying anatomical structures (n=2, 0.3%), severe bleeding (n=1, 0.1%), and injury to the transverse colon (n=1, 0.1%). Thus, current data include a total number of 664 cases [524 (78.9%) females with a mean (SD) age of 49.7±13.4 years]. Of 664 patients, an intraoperative GP was observed in 240 (36.1%) patients (Perforation group) during traction of the gallbladder (n=15, 6.3%), the dissection of adhesions and bands (n=2, 0.8%), the dissection of Callot’s triangle prior to cystic duct clipsing (n=9, 3.8%), the further dissection of Callot’s triangle after cystic duct clipsing (n=6, 2.5%), the dissection of the gallbladder from its bed (n=197, 82.1%), and the extraction of the gallbladder from the abdominal cavity (n=11, 4.6%).

The remaining patients (n=424) were present in the No perforation group. Of 240 patients, GP was not stated in the operation records in 177 (73.8%) cases. The present study evaluated the risk factors; however, almost none of the analyzed parameters were found increase intraoperative GP during elective laparoscopic cholecystectomy, including patient-related aspects, preoperative laboratory or other diagnostic findings, and operative features (Table 1). The only risk factor that increased the risk of GP was preoperative ALT level (p <0.05). Of the 63 patients with elevated ALT levels, 33 (52.4%) had GP, but the sensitivity and specificity of elevated ALT in predicting GP were 14.2% and 7.4%, respectively. There were no differences between the blood tests, apart from ALP. Although some patients required MRCP or ERCP due to elevated bilirubin levels or choledocholithiasis, there were no patients who were in need of intraoperative cholangiography, exploration of the common bile duct, or laparoscopic ultrasonography in the current study. The outcomes after the operations were also analyzed. The results showed no statistically significant differences between the groups regarding postoperative hospitalization period, complications, and re-hospitalizations (Table 2). In addition to the median (range) operation time [32 (10-120) vs 36.5 (11-120)], the rate of drain use was significantly increased in patients with GP (p <0.001 for both). No patients required reoperation as a consequence of the complications. However, the pathological evaluations revealed gallbladder cancer in two patients (0.8%), both in the Perforation group. Subsequent procedures were required for both the patients, and they remained alive 5 and 9 months after the operations without any evident tumor recurrence. DISCUSSION Cholecystectomy is one of the most common indications for surgery worldwide [1]. Besides, GP frequently occurs during laparoscopic cholecystectomy. A recent review on 18.280 patients has revealed that the incidence of GP is 18.3% [19]. In another analysis, the rate of GP in 1059 consecutive laparoscopic cholecystectomies was 29% [20]. However, it is possible that even this higher rate may not be the actual incidence of GP because prospective information has shown that the frequency of GP during laparoscopic cholecystectomy reaches up to 33% [9]. Consequently, it may be more reasonable to consider the highest reported rates in the literature because

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Table 1. The risk factors for gallbladder perforation during elective cholecystectomy

No perforation (n=424)

Perforation (n=240)

Demographics Age 49.8±13.2 49.7±13.8 Gender Females 342 (80.7) 182 (75.8) Males 82 (19.3) 58 (24.2) Body mass index 28.5±5.1 29.6±5.5 Previous hospitalization for 18 (4.2) 8 (3.3) Acute cholecystitis 8 (1.9) 2 (0.8) Biliary pancreatitis 7 (1.7) 5 (2.1) Cholangitis 3 (0.7) 1 (0.4) ASA score I 83 (20.2) 62 (26.7) II 262 (63.9) 129 (55.6) III 63 (15.4) 41 (17.7) IV 2 (0.5) 0 Laboratory Findings ALT 20 (6-548) 18 (7-671) (n=408) (n=232) Elevated ALT 30 (7.4) 33 (14.2) MRCP findings (n=25) (n=12) Cholelithiasis 21 (84.0) 11 (91.7) + Choledocolithiasis 4 (16.0) 1 (8.3) ERCP findings (n=14) (n=4) Sphincterotomy only 9 (64.3) 2 (50.0) + stone extraction ± stent application 5 (35.7) 2 (50.0) USG findings n=338 n=207 Stone 322 (95.3) 200 (96.6) Polyp 8 (2.4) 4 (1.9) Sludge 7 (2.1) 3 (1.4) Residue gallbladder 1 (0.3) 0 Stone size (>1 cm/ < 1cm) 153/169 (63.2/60.4) 89/111 (36.8/39.6) Single/multiple 86/236 (62.8/61.3) 51/149 (37.2/38.7) Previous operation/laparotomy Operations to gallbladder or gastroduodenal region 4 (0.9) 3 (1.3) Regional laparotomy 5 (1.2) 5 (2.1) Overall laparotomy 41 (9.7) 31 (12.9) Experience of the Surgeon Staff/Resident 42 (58.3) / 382 (64.5) 30 (41.7) / 210 (35.5) Degree of difficulty† I 321 (75.7) 165 (68.8) II 57 (13.4) 39 (16.3) III 46 (10.8) 36 (15.0)

0.914 0.143

0.053 0.561 0.343 0.764 0.999

0.104

0.176 0.005 0.999

0.999

0.930

0.502 0.760 0.708 0.508 0.196 0.302 0.136

(Data are presented as either median [range] or mean [±standard deviation]. Information in the parentheses indicates the percentages). *The levels of Hgb are presented separately in male and female patients; †: Data are presented according to Cuschieri’s scale, which defines the complexity of the procedure in 4 grades; however patients with grade 4 difficulties were excluded since it refers to conversion to open surgery [18]. ASA: American Society of Anesthesiology score; AST: Alanine transaminase; ALT: Aspartate transaminase; GGT: Gamma-glutamyl transaminase; WBC: White blood cell; Hbg: Hemoglobin; MRCP: Magnetic resonance imaging cholangiography; ERCP: Endoscopic retrograde cholangiography; USG: Ultrasonography.

Altuntas et al., Gallbladder perforatıon during elective laparoscopic cholecystectomy

Table 2. Outcomes after gallbladder perforation

No perforation Perforation (n=424) (n=240)

Operation time (minutes) 35.4±17.5 41.4±18.7 Drain use 106 (25.0) 110 (45.8) Hospitalization period (days) 1.3±1.0 1.3±0.9 Complications Bile drainage 0 2 (0.8) Evisceration 0 1 (0.4) Abscess 3 (0.7) 3 (1.3) Cholangitis 4 (0.9) 1 (0.4) Respiratory 2 (0.5) 0 Overall 9 (2.1) 7 (2.9) Re-hospitalization 6 (1.4) 5 (2.1)

0.000 0.000 0.664 0.130 0.361 0.673 0.659 0.538 0.522 0.538

most perforations may not be documented in operation records. The controversy probably arises from the fact that some surgeons do not report GP in the operation records, which are the data sources of retrospective studies. A recent analysis on operative notes has revealed that GP with or without bile and stone spillage was not documented in some instances [21]. Thus, we believe that the rate of GP presented in the present study is more realistic because the data were obtained from operation videos. Accordingly, our data shows that GP may be more common than expected and occurs in at least one third of all patients undergoing laparoscopic cholecystectomy. In addition, the present study has also shown that GP is not noted in almost three-fourth of the operation records probably because most surgeons do not consider this problem a major complication in most instances and believe that GP is harmless and thus do not report it. Several studies have evaluated the potential risk factors for GP during laparoscopic cholecystectomy. A multivariant logistic regression analysis has revealed male sex, a history of acute cholecystitic, the use of a laser, and the presence of a grossly inflamed gallbladder as individually significant risk factors for GP [5]. Other studies have underlined some other parameters influencing the frequency of GP, for example, age; preoperative ultrasound findings, including a thickened gallbladder wall and hydrops; the presence of a previous laparotomy; the nature of the stone (pigment stones); and the surgeon’s experience [5, 7, 9, 22]. However, these studies may be criticized to include both groups of patients who underwent emergent and elective procedures, which are proba-

bly different types of operations. Thus, the patients who underwent emergent cholecystectomies were excluded in the present study. In addition, the patients for whom conversion to open surgery was undertaken were also excluded because it was generally impossible to determine whether the adverse consequences in these cases were due to GP or the conversion itself. Thus, the present study focuses on a more specific condition that only includes elective non-problematic laparoscopic cholecystectomy, which is actually the case in most instances. Although the present study has revealed that a preoperatively elevated ALT level may be an indicator for a possible GP at the time of the operation, we are not sure whether it is a significant factor or an incidental finding because the risk for GP was only 52.4% in patients with elevated ALT levels, which was <two-fold of that with normal ALT levels. Consequently, because the sensitivity and specificity were unacceptably low, in our opinion, the preoperative ALT level cannot be considered a predictive factor for GP. Interestingly, a correlation between GP and the difficulty scale of the cholecystectomy was not attained within the framework of the present data. Although the statistical analysis revealed no difference, the p value of 0.136 may suggest a trend. Our data did not reveal any other risk factor that increased the possibility of GP. Thus, we believe that GP may be unpredictable in the case of an elective cholecystectomy. In a recent study, it has been mentioned that 69 of 131 GPs (52.7%) occurred while dissecting the gallbladder from the hepatic fossa [6]. Because we had the same result, we can conclude that the separation of the gallbladder from its bed is probably the most risky stage of cholecystectomy for a possible GP. We believe that this information is significant, and it may warn surgeons about this particular threat. In addition, the above-mentioned point should be emphasized during the training period of surgeons. The consequences of GP have been extensively evaluated previously. In animal models, it has been generally shown that GP and the consequent spillage of bile and/ or stones are harmless and do not cause any infection or mortality during the follow-up period [23, 24]. In contrast, the data derived from human studies remain controversial. Although, at least theoretically, GP leads to the contamination of the peritoneal cavity with bile, calculi, and bacteria, some believe that that the adverse consequences of spillage after GP during laparoscopic cholecystectomy may be minimized by the prompt re-

trieval of as many of the spilled stones as possible, abundant irrigation of the peritoneal cavity, and adequate antibiotic therapy [6]. It has been shown in most studies that GP does not increase the complication risk, reoperations, or hospital stay [6, 25]. A recent prospective study has also advocated that GP and retained gallstones do not adversely affect respiratory mechanics or alter postoperative pain [9]. Besides, other studies have reported adverse consequences of bile spillage due to GP because bile is frequently contaminated in the presence of gallstones [26]. In an analysis of 1059 consecutive laparoscopic cholecystectomies, increased incidences of fever and intraabdominal abscesses have been reported if GP had happened at the time of the operation [20]. In addition, some case reports have advocated that retained gallstones and bile spillage cause infection or abscesses, fibrosis, adhesions, cutaneous sinuses, small-bowel obstructions, or generalized septicemia [27, 28]. Finally, even conversion to open surgery has been recommended in a study in patients with a loss of numerous or large pigment stones that cannot be retrieved by laparoscopy [4]. However, we believe that the adverse consequences of spillage after GP during laparoscopic cholecystectomy may be minimized by the prompt retrieval of as many of the spilled stones as possible, abundant irrigation of the peritoneal cavity, and adequate prophylactic antibiotic therapy [6], as mentioned above. With this approach, we have found that GP and consequent intraabdominal contamination does not increase the risk of complications or alter the outcomes during the early postoperative period. Consequently, the present study reveals that GP increases the incidence of drain use and lengthens the operation time, both of which are probably the consequences of GP because the retrieval of stones and peritoneal irrigation are required in these cases. However, the present study found no other adverse consequence of GP in patients who underwent laparoscopic cholecystectomy. In contrast, similar short-term complications may be related to the treatment strategy followed in patients with GP. In addition, many of the documented complications from split gallstones are long-term, and they often happen after 1 year. Therefore, based on the results of the present study, we cannot comment on any long-term complications. Thus, we believe that GP is something that may be avoided whenever possible, but in the case of GP, the outcomes do not alter if certain rules for limiting the contamination are followed. Finally, it is necessary to detail the outcomes in two patients with gallbladder cancer in the present study. Th-

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ese patients received further operations, including partial hepatic resections and lymph node dissection in the hepatic hilum, because their pathological results denied early T1 tumors. However, the spillage of bile has led to tumor implants over the anterior wall of the stomach in one patient; this patient required a distal gastrectomy. We believe that tumor spillage is the most significant adverse consequence of GP, but it also is a very exceptional problem because incidental gallbladder cancer is rare in patients undergoing elective cholecystectomy. The present study has some limitations mostly due to its retrospective nature. Missing information, namely, the lack of operation CDs of 60 patients, limits the value of the present data. In addition, the findings of the study may be criticized in some standpoints. First, although the difference was statistically significant, we do not know whether a 6-min increase in the operation time reflects an importance in daily practice. In addition, the increased incidence of drain use in the Perforation group may be because there was no clear-cut criteria about the indications to put a drain. This may stem from the retrospective nature of the study. Furthermore, the increase in the operation time and the necessity of drain use may not be caused by GP, but all the three endpoints occurred due to the difficulty of the operation. The present study data may be criticized regarding the experiences of the surgeons because all staff surgeons do not have the same expertise. In addition, because the surgeons know they are being recorded, their performance may be more meticulous, which may have an impact on our results. In conclusion, the present study reveals that GP occurs in 36.1% of the patients undergoing laparoscopic elective cholecystectomy but is less commonly reported in the operation notes. GP is unpredictable because there are probably no risk factors that increase the risk of GP, except a preoperatively assessed elevated ALT level; however, the sensitivity and specificity of this measure are low. The early postoperative outcomes are similar in patients with GP and those without, but the operation time lengthens and the incidence of drain use increases in patients with GP. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – Y.E.A., M.O.; Design – Y.E.A., M.O.; Supervision – Y.E.A., M.O., M.K.; Materials – Y.E.A., M.H., F.C.G.; Data collection &/or processing – Y.E.A., E.G., N.A.; Analysis and/or in-

Altuntas et al., Gallbladder perforatıon during elective laparoscopic cholecystectomy

terpretation – Y.E.A. M.K.; Writing – Y.E.A., M.O.; Critical review – Y.E.A., M.O., M.H.

REFERENCES 1. Schäfer M, Krähenbühl L, Farhadi J, Büchler MW. Cholelithiasis-laparoscopy or laparotomy? Ther Umsch 1998;55:110–5. 2. Chekan EG, Pappas TN, Minimally invasive surgery. In: Townsend CM Jr, editor. Sabiston Textbook of Surgery: The biological basis of modern surgical practice. Philadelphia: WB Saunders; 2001. p. 292– 310. 3. Memon MA, Deeik RK, Maffi TR, Fitzgibbons RJ Jr. The outcome of unretrieved gallstones in the peritoneal cavity during laparoscopic cholecystectomy. A prospective analysis. Surg Endosc 1999;13:848–57. 4. Brockmann JG, Kocher T, Senninger NJ, Schürmann GM. Complications due to gallstones lost during laparoscopic cholecystectomy. Surg Endosc 2002;16:1226–32. 5. Mohiuddin K, Nizami S, Fitzgibbons RJ Jr, Watson P, Memon B, Memon MA. Predicting iatrogenic gall bladder perforation during laparoscopic cholecystectomy: a multivariate logistic regression analysis of risk factors. ANZ J Surg 2006;76:130–2. 6. Sarli L, Pietra N, Costi R, Grattarola M. Gallbladder perforation during laparoscopic cholecystectomy. World J Surg 1999;23:1186–90. 7. De Simone P, Donadio R, Urbano D. The risk of gallbladder perforation at laparoscopic cholecystectomy. Surg Endosc 1999;13:1099–102. 8. Duca S, Bãlã O, Al-Hajjar N, Lancu C, Puia IC, Munteanu D, et al. Laparoscopic cholecystectomy: incidents and complications. A retrospective analysis of 9542 consecutive laparoscopic operations. HPB (Oxford) 2003;5:152–8. 9. Uygar Kalayci M, Veli Akin B, Alis H, Kapan S, Nuray Turhan A, Aygun E. Short-term effects of gallbladder perforations during laparoscopic cholecystectomy on respiratory mechanics and depth of pain. Surg Endosc 2008;22:1317–20. 10. Gallinaro RN, Miller FB. The lost gallstone. Complication after laparoscopic cholecystectomy. Surg Endosc 1994;8:913–4. 11. Golub R, Nwogu C, Cantu R, Stein H. Gallstone shrapnel contamination during laparoscopic cholecystectomy. Surg Endosc 1994;8:898– 900. 12. Jacob H, Rubin KP, Cohen MC, Kahn IJ, Kan P. Gallstones in a retroperitoneal abscess: a late complication of perforation of the gallbladder. Dig Dis Sci 1979;24:964–6. 13. Kakani PR, Bhullar IS. Complications of spilled gallstones during la-

paroscopic cholecystectomy. Contemp Surg 1993;43:357–61. 14. Leland DG, Dawson DL. Adhesions and experimental intraperitoneal gallstones. Contemp Surg 1993;42:273–5. 15. Sax HC, Adams JT. The fate of the spilled gallstone. Arch Surg 1993;128:469. 16. Stewart L, Smith AL, Pellegrini CA, Motson RW, Way LW. Pigment gallstones form as a composite of bacterial microcolonies and pigment solids. Ann Surg 1987;206:242–50. 17. Zucker KA. Surgical Laparoscopy. St. Louis, Missouri: Quality Publishing; 1991. p. 143–82. 18. Cuschieri A, Berci G. Laparoscopic Billiary Surgery. London: Blackwell Scientifıc Publications; 1992. p. 134–42. 19. Woodfield JC, Rodgers M, Windsor JA. Peritoneal gallstones following laparoscopic cholecystectomy: incidence, complications, and management. Surg Endosc 2004;18:1200–7. 20. Rice DC, Memon MA, Jamison RL, Agnessi T, Ilstrup D, Bannon MB, et al. Long-term consequences of intraoperative spillage of bile and gallstones during laparoscopic cholecystectomy. J Gastrointest Surg 1997;1:85–90. 21. Wauben LS, van Grevenstein WM, Goossens RH, van der Meulen FH, Lange JF. Operative notes do not reflect reality in laparoscopic cholecystectomy. Br J Surg 2011;98:1431–6. 22. Kimura T, Goto H, Takeuchi Y, Yoshida M, Kobayashi T, Sakuramachi S, et al. Intraabdominal contamination after gallbladder perforation during laparoscopic cholecystectomy and its complications. Surg Endosc 1996;10:888–91. 23. Welch N, Hinder RA, Fitzgibbons RJ Jr, Rouse JW. Gallstones in the peritoneal cavity. A clinical and experimental study. Surg Laparosc Endosc 1991;1:246–7. 24. Zisman A, Loshkov G, Negri M, Herbert M, Halpern Z, Lin G, et al. The fate of long-standing intraperitoneal gallstone in the rat. Surg Endosc 1995;9:509–11. 25. Barrat C, Champault A, Matthyssens L, Champault G. Iatrogenic perforation of the gallbladder during laparoscopic cholecystectomy does not influence the prognosis. Prospective study. Ann Chir 2004;129:25– 9. 26. Keighley MR. Micro-organisms in the bile. A preventable cause of sepsis after biliary surgery. Ann R Coll Surg Engl 1977;59:328–34. 27. Yamamuro M, Okamoto B, Owens B. Unusual presentations of spilled gallstones. Surg Endosc 2003;17:1498. 28. Zulfikaroglu B, Ozalp N, Mahir Ozmen M, Koc M. What happens to the lost gallstone during laparoscopic cholecystectomy? Surg Endosc 2003;17:158.

Orıgınal Article

EYE DISEASES

North Clin Istanb 2018;5(1):54-57 doi: 10.14744/nci.2017.80958

Effect of trabeculectomy on ocular higher-order aberrations in patients with open angle glaucoma Ali Mahdavi Fard, Rana Daei Sorkhabi, Kamal Nasiri, Arezou Tajlil Department of Ophthalmology, Tabriz University of Medical Sciences, Tabriz, Iran

ABSTRACT OBJECTIVE: The aim of this study was to evaluate the effect of trabeculectomy on ocular higher-order aberrations following surgery in a group of patients with open angle glaucoma. METHODS: In this prospective study, patients with primary open angle glaucoma underwent wavefront aberrometry before trabeculectomy with mitomycin-C. Coma-like, spherical-like, and total ocular higher-order aberrations were measured as root mean square values. The measurements were repeated 1 month and 3 months after the procedure. RESULTS: A total of 20 eyes from 20 patients were examined. There was a significant decrease in intraocular pressure following surgery at 1 month and 3 months postoperatively. However, there was no statistically significant change in the spherical equivalent of the eyes. One month after surgery, a significant change in coma-like, spherical-like, and total higher-order aberrations of the eyes was observed. However, the repeated measurements performed 3 months after procedure revealed no significant difference compared to the baseline values. CONCLUSION: Ocular higher-order aberrations increased 1 month following trabeculectomy surgery. However, this effect seems to be transient, as the values returned to the preoperative measurement 3 months after the procedure. Keywords: Aberrometry; glaucoma; higher-order aberration.

laucoma is a progressive neuropathy of the optic nerve which can lead to irreversible visual impairment. So far, lowering intraocular pressure (IOP), which can be achieved either with medication or surgery, is the most useful approach to protect the optic nerve. One of the most effective procedures for lowering IOP is trabeculectomy, with or without anti-fibrotic agents. On the other hand, many patients report changes in their vision following trabeculectomy surgery, such as choroidal detachment, corneal decompensation, hypotony, maculopathy and infection [1-8], which may be complications of the surgery, or, as in other ocular surgeries, including intraocular lens implantation and cataract extraction [911], scleral buckling [12], or pterygium excision [13], may be the result of changes in refractive state or higherorder aberrations [14-16] of the eye. The present study is an evaluation of the impact of trabeculectomy surgery on ocular higher-order aberrations.

MATERIALS AND METHODS This study was approved by the institutional review board of Tabriz University of Medical Sciences and was conducted in accordance with the Declaration of Helsinki. All study patients gave written informed consent for their participation in this study. Patients with primary open angle glaucoma who had received the maximal nonsurgical treatment, including topical anti-glaucoma medications and laser therapy, and who were candidates for trabeculectomy with mitomycin-C (MMC) surgery and had been referred to the glaucoma clinic were considered for enrollment. Patients were included if they had corrected visual acuity of ≥20/40, were free of significant cataract, had good cooperation for aberrometry, and had a dilated pupil diameter of ≥4 mm. Patients with secondary glaucoma and angle closure glaucoma were excluded from the study. Additionally, patients with a prior

Received: April 30, 2017 Accepted: December 10, 2017 Online: January 26, 2018 Correspondence: Dr. Ali Mahdavi Fard. Tabriz Tip Bilimleri Universitesi Goz Hastaliklari Anabilim Dali, Tabriz, Iran. Tel: +90 89144117328 e-mail: alimahdavifard@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Fard et al., Trabeculectomy and higher-order aberrations

history of ocular surgery or ocular disease other than glaucoma were not considered for participation. Patients underwent a detailed ophthalmic examination of the anterior and posterior segments of the eye with IOP measurement using standard applanation tonometry, as well as aberrometry measurements with I- trace aberrometer and refraction. Trabeculectomy surgery procedures were performed by 2 surgeons (AMF and RDS) using the same technique. After fashioning a fornix base conjunctival flap, a partial thickness scleral flap was created. MMC with a concentration of 0.4% was applied for 2 minutes, and after copious irrigation a paracentesis was performed. Following a sclerostomy, a peripheral iridectomy was performed and the scleral flap was closed with 10/0 nylon sutures. After checking for oozing through the scleral flap, the conjunctiva was sutured with 10/0 nylon. At the end of the procedure, the wound was controlled for leakage and a subconjunctival injection of betamethasone, cefazolin, and atropine was administered. Patients underwent a thorough ophthalmological examination, including the anterior and posterior segments of the eye and IOP measurement the day after surgery and were discharged with topical betamethasone, ciprofloxacin, and homatropin to be administered 4 times a day. One week after surgery, patients underwent an ophthalmological examination with IOP control and conjunctival suture removal. At 1 month and 3 months after surgery the patients again underwent an ophthalmological examination and IOP control, as well as aberrometry with the same aberrometer unit. The wave-front aberrations were measured in a 4-mm pupil area and the data were expanded to Zernike polynomials. The magnitude was demonstrated as root mean square (RMS). The RMS of the third-order Zernike coefficients (the square root of the sum of the squared coefficients of C-33 ,C3-1,C31, and C33 ) was considered a coma-like aberration, and the RMS of the fourth-order Zernike coefficients (the square root of the sum of the squared coefficients of C-44 ,C4-2,C40, C24, and C44) was considered a spherical-like aberration. The total of higher-order aberrations was defined as the RMS of the magnitudes for the third-order and forth-order aberrations. Statistical Analysis The categorical variables are presented as frequencies and percentages, while continuous variables are shown as mean±SD. Preoperative and postoperative values were compared using analysis of variance. The recorded data were analyzed with IBM SPSS Statistics for Windows, Version 22.0. (IBM Corp., Armonk, NY, USA) software

and a p value of less than 0.05 was considered statistically significant. RESULTS Twenty eyes from 20 patients with primary open angle glaucoma were included in the study. In all, 11 (55%) patients were male and 9 (45%) were female. The patients’ age ranged from 46 to 78 years (mean age: 61±9.3 years) and all of them had a Snellen visual acuity of more than 20/40. All the patients underwent trabeculectomy with MMC without any surgery-related complication such as hypotony, poor IOP control, infection, or gross choroidal detachment. During the follow-up period, none of the participants developed a significant cataract or visual loss. The mean preoperative IOP was 29.1±6.4 mmHg, and at postoperative 1 month and 3 months, the mean IOP was 13.98±3.8 and 13.1±3.6 mmHg, respectively. The change in IOP after surgery at all time points was significant in comparison with preoperative measurements (p<0.0001); however, the difference in IOP between 1 month and 3 months after surgery was statistically insignificant (p=0.453). The mean spherical equivalent of refractive errors before surgery was -1.65±1.35 D and for 1 month and 3 months after surgery it was -1.81±1.63 D and -1.97±1.45 D, respectively. Again, there was not a significant change in spherical equivalent before and after surgery (p=0.737; 95% confidence interval [CI] -0.798 to 1.118 and p=0.575; 95% CI -0.646 to 1.146, respectively). Preoperative and 1 month and 3 month postoperative ocular aberrations are reported in Table 1. The mean ocular coma-like RMS value before surgery was 0.23±0.13, and 1 month and 3 months after surgery, it was 0.34±0.15 and 0.31±0.13, respectively. The difference between the preoperative and 1 month postoperative values was statistically significant (p=0.017; 95% CI -0.192 to -0.028); however, 3 months postoperative it was not statistically significant (p=0.059; (95% CI -0.164 to 0.003). The mean ocular spherical-like RMS value before surgery was 0.12±0.07, and 1 month and 3 months after surgery it was 0.19±0.08 and 0.16±0.08, respectively. The difference between the preoperative and 1 month postoperative values was statistically significant (p=0.005; 95% CI -0.117 to-0.023); however, 3 months postoperative it was not statistically significant (p=0.113; 95% CI -0.086 to 0.008). The mean ocular total RMS value before surgery was 0.47±0.26, and 1 month and 3 months after surgery it was 0.70±0.34 and 0.60±0.25, respectively. The difference between the pre-

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Table 1. Mean intraocular pressure, spherical equivalent,

and root mean square of higher-order aberration values measured

preoperatively and at 1 and 3 months postoperatively

Preoperative 1 month 3 months Postoperative Postoperative Mean Mean Mean Mean Mean

IOP (mmHg) spherical equivalent (D) coma-like aberration RMS spherical-like aberration RMS total ocular higher order aberration RMS

29±6.40 -1.65±1.35 0.23±0.13 0.12±0.07 0.47±0.26

13.98±3.8 -1.63±1.81 0.34±0.15 0.19±0.08 0.70±0.34

13.1±3.6 -1.97±1.45 0.31±0.13 0.16±0.08 0.60±0.25

p (preop and 1m post op)

p (preop and 3m post op)

p<0.0001 p=0.737 P=0.017 P=0.005 P=0.023

p<0.0001 P=0.575 P=0.059 P=0.113 P=0.113

IOP: Intraocular pressure; m: Month; preop: Preoperative; postop: Postoperative; RMS: Root mean square; SE: Spherical equivalent.

operative and 1 month postoperative values was statistically significant (p=0.023; 95% CI -0.427 to -0.031); however, 3 months postoperative it was not statistically significant (p=0.113; 95% CI -0.291 to 0.033). DISCUSSION Several studies have demonstrated that ocular surgeries such as intraocular lens implantation and cataract extraction [9-11], scleral buckling [12], and pterygium excision [13] may result in changes in the refractive state or higher-order aberrations [14-16] in the affected eye. In the present study, consistent with previous studies, we report similar changes in ocular higher-order aberrations 1 month postoperatively. However, no significant change was observed 3 months after the surgery. A prospective study found that 1 week after trabeculectomy surgery, 94% and 43% of patients reported a change in their uncorrected and corrected Snellen visual acuity, respectively [17]. Some studies have attributed these alterations in visual acuity to changes in corneal contour, anterior chamber depth, axial length of the globe, and thickness of the crystalline lens [6, 18-23]. Another study demonstrated with vector analysis that the cylinder component of refraction was increased by 1.4 D; however, the vector power of surgically induced refractive change at 1 month postoperatively did not significantly correlate with corneal coma-like, spherical-like, or total RMS, suggesting that changes other than anterior corneal aberration, such as internal optics of the eye, play a role in the changes in higher-order aberrations postoperatively[14]. Francis et al. [23] reported a decrease in the axial length of the globe following trabeculectomy that was more prominent 1 week and 1 month after surgery,

and suggested over-filtration as the explanation for their finding; however, similar to our findings, Fukuoka et al. [14] have shown that despite the stability of IOP from 1 month to 3 months postoperatively, the values of ocular coma-like, spherical-like, and total higher order aberrations changed during this time period and reached values similar to preoperative measures. Accordingly, we can conclude that changes in the internal optics of the eye due to factors such as iridocyclitis, macular edema, retinal hemorrhage, and scleral and choroidal thickness that may occur due to hypotony and surgical manipulation of ocular tissues, independent of IOP, are responsible for the alterations in higher-order aberrations. [24] In a prospective study by Karasheva and et al. [22] it was demonstrated that macular thickness increases 1 month after surgery, but subsides 3 months postoperatively and reaches the preoperative value. Furthermore, there was not a significant correlation between IOP and retinal thickness, and they concluded that even in the absence of ocular hypotony, macular edema may occur following trabeculectomy. In a study conducted by Martinez-Bello [25], 12.5% of the eyes developed suprachoroidal fluid in 3 to 6 months following trabeculectomy, which was detectable with ultrasound biomicroscopy. They hypothesized that it might have resulted from traction of the iris root during peripheral iridectomy and low IOP on the removal of the deep scleral block. Moreover, Sugimoto et al. [26] reported even higher rates of suprachoroidal fluid (33%) following trabeculectomy in the absence of any intraocular inflammation and changes in anterior chamber depth or gross choroidal detachment within 2 weeks after surgery. These findings indicate that suprachoroidal fluid may appear more commonly and at an earlier stage than 3 or 6 months postoperatively and

Fard et al., Trabeculectomy and higher-order aberrations

may dissolve soon after. Crystalline lens position and the thickness and anterior chamber depth can temporarily be changed following ciliary body edema due to surgical manipulation [14]. Limitations The present study is limited by the relatively small number of patients and the lack of a control group. Additionally, we did not evaluate corneal higher-order aberrations along with ocular aberrations. CONCLUSION The results of this study are consistent with previous reports, and demonstrate the effect of trabeculectomy surgery on the optical system of the eye. Furthermore, the data suggest that the observed changes in the optics of the eye are transient and will most probably resolve in 3 months after surgery. Accordingly, any visual changes observed after this period cannot be attributed to the effect of surgery and would mandate comprehensive evaluation. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – A.M.F., R.D.S., K.N., A.T.; Design – A.M.F., R.D.S., K.N., A.T.; Supervision – A.M.F., R.D.S.; Materials – A.M.F., R.D.S., K.N., A.T. Data collection &/or processing – A.M.F., R.D.S., K.N., A.T.; Analysis and/or interpretation – A.M.F., R.D.S., K.N., A.T.; Writing – A.M.F., R.D.S., K.N., A.T.; Critical review – A.M.F., R.D.S.

REFERENCES 1. Zacharia PT, Deppermann SR, Schuman JS. Ocular hypotony after trabeculectomy with mitomycin C. Am J Ophthalmol 1993;116:314–26. 2. Sun X, Dai Y, Chen Y, Yu DY, Cringle SJ, Chen J, et al. Primary angle closure glaucoma: What we know and what we don’t know. Prog Retin Eye Res 2017;57:26–45. 3. Shigeeda T, Tomidokoro A, Chen YN, Shirato S, Araie M. Long-term follow-up of initial trabeculectomy with mitomycin C for primary open-angle glaucoma in Japanese patients. J Glaucoma 2006;15:195–9. 4. Seah SK, Prata JA Jr, Minckler DS, Baerveldt G, Lee PP, Heuer DK. Hypotony following trabeculectomy. J Glaucoma 1995;4:73–9. 5. Reibaldi A, Uva MG, Longo A. Nine-year follow-up of trabeculectomy with or without low-dosage mitomycin-c in primary open-angle glaucoma. Br J Ophthalmol 2008;92:1666–70. 6. Leeungurasatien T, Khunsongkiet P, Pathanapitoon K, Wiwatwongwana D. Incidence of short-term complications and associated factors after primary trabeculectomy in Chiang Mai University Hospital. Indian J Ophthalmol 2016;64:737–42.

57 7. Jongsareejit B, Tomidokoro A, Mimura T, Tomita G, Shirato S, Araie M. Efficacy and complications after trabeculectomy with mitomycin C in normal-tension glaucoma. Jpn J Ophthalmol 2005;49:223–7. 8. Hagiwara Y, Yamamoto T, Kitazawa Y. The effect of mitomycin C trabeculectomy on the progression of visual field defect in normal-tension glaucoma. Graefes Arch Clin Exp Ophthalmol 2000;238:232–6. 9. Mojzis P, Majerova K, Plaza-Puche AB, Hrckova L, Alio JL. Visual outcomes of a new toric trifocal diffractive intraocular lens. J Cataract Refract Surg 2015;41:2695–706. 10. Song IS, Park JH, Park JH, Yoon SY, Kim JY, Kim MJ, et al. Corneal coma and trefoil changes associated with incision location in cataract surgery. J Cataract Refract Surg 2015;41:2145–51. 11. Oshika T, Sugita G, Miyata K, Tokunaga T, Samejima T, Okamoto C, et al. Influence of tilt and decentration of scleral-sutured intraocular lens on ocular higher-order wavefront aberration. Br J Ophthalmol 2007;91:185–8. 12. Okamoto F, Yamane N, Okamoto C, Hiraoka T, Oshika T. Changes in higher-order aberrations after scleral buckling surgery for rhegmatogenous retinal detachment. Ophthalmology 2008;115:1216–21. 13. Gumus K, Topaktas D, Göktaş A, Karakucuk S, Oner A, Mirza GE. The change in ocular higher-order aberrations after pterygium excision with conjunctival autograft: a 1-year prospective clinical trial. Cornea 2012;31:1428–31. 14. Fukuoka S, Amano S, Honda N, Mimura T, Usui T, Araie M. Effect of trabeculectomy on ocular and corneal higher order aberrations. Jpn J Ophthalmol 2011;55:460–6. 15. Dietze PJ, Oram O, Kohnen T, Feldman RM, Koch DD, Gross RL. Visual function following trabeculectomy: effect on corneal topography and contrast sensitivity. J Glaucoma 1997;6:99–103. 16. Claridge KG, Galbraith JK, Karmel V, Bates AK. The effect of trabeculectomy on refraction, keratometry and corneal topography. Eye (Lond) 1995;9:292–8. 17. Shigeeda T, Tomidokoro A, Araie M, Koseki N, Yamamoto S. Longterm follow-up of visual field progression after trabeculectomy in progressive normal-tension glaucoma. Ophthalmology 2002;109:766–70. 18. Rosen WJ, Mannis MJ, Brandt JD. The effect of trabeculectomy on corneal topography. Ophthalmic Surg 1992;23:395–8. 19. Rasooly R, Benjamin L, Casson R. Change in lens thickness after trabeculectomy. Int Ophthalmol 2001;24:25–6. 20. Németh J, Horóczi Z. Changes in the ocular dimensions after trabeculectomy. Int Ophthalmol 1992;16:355–7. 21. Kook MS, Kim HB, Lee SU. Short-term effect of mitomycin-C augmented trabeculectomy on axial length and corneal astigmatism. J Cataract Refract Surg 2001;27:518–23. 22. Karasheva G, Goebel W, Klink T, Haigis W, Grehn F. Changes in macular thickness and depth of anterior chamber in patients after filtration surgery. Graefes Arch Clin Exp Ophthalmol 2003;241:170–5. 23. Francis BA, Wang M, Lei H, Du LT, Minckler DS, Green RL, et al. Changes in axial length following trabeculectomy and glaucoma drainage device surgery. Br J Ophthalmol 2005;89:17–20. 24. Cunliffe IA, Dapling RB, West J, Longstaff S. A prospective study examining the changes in factors that affect visual acuity following trabeculectomy. Eye (Lond) 1992;6:618–22. 25. Martínez-Belló C, Capeáns C, Sánchez-Salorio M. Ultrasound biomicroscopy in the diagnosis of supraciliochoroidal fluid after trabeculectomy. Am J Ophthalmol 1999;128:372–5. 26. Sugimoto K, Ito K, Esaki K, Miyamura M, Sasoh M, Uji Y. Supraciliochoroidal fluid at an early stage after trabeculectomy. Jpn J Ophthalmol 2002;46:548–52.

Original Images

HEMATOLOGY

North Clin Istanb 2018;5(1):58-59 doi: 10.14744/nci.2017.01336

Gaucher disease in an adult: A rare cause of hepatosplenomegaly in adults Volkan Karakus,1 Yelda Dere,2 Ozcan Dere,3 Fahri Sahin,4 Nazan Ozsan5 Department of Hematology, Mugla Sıtkı Kocman University Training and Research Hospital, Mugla, Turkey

Department of Pathology, Mugla Sıtkı Kocman University Faculty of Medicine, Mugla, Turkey

Department of Surgery, Mugla Sıtkı Kocman University Faculty of Medicine, Mugla, Turkey

Department of Hematology, Ege University Faculty of Medicine, Izmir, Turkey

Department of Pathology, Ege University Faculty of Medicine, Izmir, Turkey

19-year-old woman with no significant medical history presented with weakness. Physical examination revealed hepatosplenomegaly with no peripheral lymphadenopathies. Laboratory tests revealed anemia (Hb: 11.9 mg/dL) and thrombocytopenia (platelet: 108000/mm3). Other results were normal. Peripheral blood smear revealed 60% PMNL (polymorphonuclear leukocytes) and 30% lymphocytes, with slightly polychromatic erythrocytes, and 8–9 thrombocytes in every field. Color Doppler ultrasonography (USG) revealed the liver to be 195 mm in size and the spleen to be 175 mm in size, with no paranchymal abnormalities in either. Hematological tests revealed negative gene mutations for JAK2 and t(9;22). Therefore, bone marrow aspiration and biopsy was performed. In bone marrow aspirates, macrophages with abundant sea-blue “crumpled tissue paper” cytoplasm were observed (Fig. 1, arrows). In the bone marrow biopsy, cellularity was 50%, consisting of mostly macrophages (Fig. 2, circle). These cells were positive for CD68, lyzozyme, and TRAP, but negative for S100 and CD1a. Histomorphologic features were reported to be concordant with those of Gaucher disease. After the diagnosis, enzymatic activity and level were investigated and the results were as follows: β-glycosidase, 0.08 nmol/mL/h (normal range for adults: 0.94–5.29) and cytotriosidase, 193 nmol/mL/h

(normal range for adults: 0–1074). In addition, genetic studies showed heterozygous mutations (p. N370S) and (p. L444P) and confirmed the diagnosis. Cerezym® treatment was started. The patient recovered and remained healthy on her first-year follow-up with the following findings: Hb 12.5 mg/dL, platelet 163000/ mm3, liver size 178 mm, and spleen size 137 mm (on her last USG).

Figure 1.

Large histiocytes with crumpled tissue paper cytoplasm. Giemsa stain (×400).

Received: May 16, 2017 Accepted: July 17, 2017 Online: January 09, 2018 Correspondence: Dr. Yelda DERE. Mugla Sitki Kocman Universitesi Tip Fakultesi, Patoloji Anabilim Dali, Mugla, Turkey. Tel: +90 505 465 31 98 e-mail: yeldamorgul@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Karakus et al., Gaucher disease in an adult

Figure 2.

Histiocytes with pink pale cytoplasm in the bone marrow on cell block prepared from the aspirate. H&E stain, Ă&#x2014;400.

Gaucher disease is the most common autosomal recessive lysosomal storage disease worldwide and is generally diagnosed in children with splenomegaly and cytopenias. The diagnosis depends on the demonstration of low enzymatic activity of glucocerebrosidase. Hepatosplenomegaly is the most common finding; Gaucher disease should be kept in mind in patients with unexplained hepatosplenomegaly. Cytopenia secondary to bone marrow infiltration and hypersplenism may be seen. The gold standard for the diagnosis is to measure the enzymatic activity of glucocerebrosidase. Enzymatic replacement is the main treatment modality for these cases. Gaucher disease is a progressive disease and generally diagnosed in childhood. However, in asymptomatic adults, progression may be slow or the disease may regress spontaneously.

Case Report

HEMATOLOGY & ONCOLOGY

North Clin Istanb 2018;5(1):60-63 doi: 10.14744/nci.2017.75537

Renal clear cell sarcoma presenting as a spontaneous renal hematoma: A rare presentation Zeynep Canan Ozdemir,1 Burcu Ayvaci,1 Yeter Duzenli Kar,1 Mehmet Oguzman,2 Mehmet Surhan Arda,3 Mustafa Fuat Acikalin,4 Ozcan Bor1 Department of Pediatric Hematology and Oncology, Eskisehir Osmangazi Universitiy Faculty of Medicine, Eskisehir, Turkey

Department of Pediatrics, Eskisehir Osmangazi Universitiy Faculty of Medicine,Eskisehir, Turkey

Department of Pediatric Surgery, Eskisehir Osmangazi Universitiy Faculty of Medicine, Eskisehir, Turkey

Department of Pathology, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey

ABSTRACT Clear cell sarcoma of the kidney (CCSK) is an uncommon renal neoplasm of childhood. It represents between 2% and 9% of all pediatric renal tumors, and generally arises before the age of 5 years. It often mimics other pediatric renal tumors. Presently described is the case of a 7-year-old girl who presented with complaints of vomiting and abdominal pain. Abdominal ultrasonography revealed a right renal mass, and the patient developed a renal hematoma a few hours after admission. The patient underwent a nephroureterectomy with a provisional diagnosis of Wilms tumor; however, histopathological examination of a specimen revealed CCSK. CCSK is similar to Wilms tumor in terms of the typical age of appearance and clinical and histopathological features, but the treatment method and prognosis are different. Therefore, the differential diagnosis is very important. This case was presented to draw attention to a rare presentation of clear cell sarcoma. CCSK should be kept in mind in the differential diagnosis of a renal mass. Keywords: Clear cell sarcoma; child; hematoma; kidney.

enal tumors are rare in childhood. They constitute 6% to 7% of all pediatric tumors. Wilms tumor is the most frequently seen among them [1]. Clear cell sarcoma of the kidney (CCSK) is the second most frequently seen tumor after Wilms tumor [2, 3]. Renal cell carcinoma and rhabdoid tumor are less frequently seen tumors [1]. Clear cell sarcoma is a unilateral tumor arising from the renal medulla; it is known as pediatric tumor with a propensity to metastasize to bone. It is called clear cell cancer because the cytoplasm contains multi-

ple vesicles. It has a tendency to penetrate the renal and perirenal vascular system [4, 5]. It is an important clinical entity because it can be confused with Wilms tumor, but the treatment is completely different. Presented here is the case of a child with an initial diagnosis of suspected Wilms tumor who developed massive, nontraumatic bleeding. The postoperative histopathological examination of the nephrectomy specimen established the diagnosis of CCSK. This case is presented because of a distinctive presentation.

Received: February 22, 2017 Accepted: May 02, 2017 Online: January 18, 2018 Correspondence: Dr. Zeynep Canan OZDEMIR. Eskisehir Osmangazi Universitesi Tip Fakultesi, Pediatrik Hematoloji ve Onkoloji Bilim DalÄą, Eskisehir, Turkey. Tel: +90 222 239 39 79 e-mail: efecanan@yahoo.com ÂŠ Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Ozdemir et al., Renal clear cell sarcoma presenting as a spontaneous renal hematoma

CASE REPORT A 7-year-old girl presented with complaints of abdominal pain and vomiting that had begun 2 days earlier. Anamnesis revealed that she had persistent pain on the right side of the abdomen, had experienced bilious vomiting 3 to 4 times a day, and there was no weight loss, fever, or history of trauma. Her physical examination findings were a body temperature of 37.2ÂşC, heart rate of 96 bpm, and arterial blood pressure of 110/80 mmHg. There was diffuse abdominal tenderness and a mass 4x5 cm in size was palpated in the right renal bed (Fig. 1). Other systemic examination results were within normal limits. The hematological parameters were reported as hemoglobin: 11.6g/dL, hematocrit: 34%, mean corpuscular volume: 83.3 fL, mean corpuscular hemoglobin: 27.7 pg, mean corpuscular hemoglobin concentration:

Figure 1. The macroscopic appearance of the mass palpated on physical examination.

Figure 2. The abdominal tomography image of right renal mass and hematoma.

33.2 mg/dL, red cell distribution width: %14.3, white blood cell count: 12800/mmÂł, platelet count: 347.000/ mmÂł, and C-reactive protein level: 0.314 mg/dL. Results of hemochemistry and complete urinalysis were within normal limits. On abdominal ultrasound, an 8x6.5-cm mass lesion with predominant vascularization localized on the lower right kidney was detected. Doppler ultrasound did not reveal any thrombus in the renal vein or vena cava inferior. Her peak heart rate ranged between 110 and 120 bpm. In the sixth hour of hospitalization, her hemoglobin level dropped to 6 g/dL. Emergency abdominal computed-tomography was performed for suspected intratumoral bleeding and an erythrocyte suspension was infused. Abdominal tomography revealed a mass arising from the inferolateral end of the right kidney, not crossing the midline, and almost completely filling the perirenal fat capsule and the retroperitoneal region, with a predominant hemorrhagic component with indistinct borders (Fig. 2). The initial diagnosis was Wilms tumor. Emergency surgery was performed. The hematoma was drained and a right nephroureterectomy was performed (Fig. 3). Positron emission tomography and brain magnetic resonance imaging did not detect any evidence suggesting metastasis. The histopathological examination of a bone marrow biopsy specimen was unremarkable. The diagnosis of CCSK was made based on the histopathological result of nephrectomy specimen testing. Radiotherapy was performed on the tumor bed, and a combination chemotherapy consisting of doxorubicin, cyclophosphamide, etoposide, and vincristine was initiated. The chemotherapy treatment was continued for 6 months, and follow-up at 8 months revealed no further problem.

Figure 3. The macroscopic appearance of the mass.

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DISCUSSION Wilms tumor makes up 92% of renal mass lesions. Of other renal tumors, 17% are clear cell sarcoma [2]. In a study of pediatric cases with clear cell sarcoma, it was reported that while the age of the patients ranged between 2 months and 14 years, nearly 50% of the patients were between 2 and 3 years of age at the time of diagnosis. It was also indicated that it is seen more frequently in male children, and has an overall survival rate of 69% [3]. Since there are no clinical or radiological findings specific to clear cell sarcoma, it is frequently confused with Wilms tumor, which complicates decision-making process for treatment [4, 6]. The most frequently seen symptoms include abdominal mass, hematuria, and abdominal pain. Other symptoms defined include vomiting, fever, constipation, loss of appetite, and hypertension [7]. To our knowledge, there has been no prior report of a case of CCSK with a renal hematoma. Wilms tumor typically metastasizes to the lymph nodes, lungs, or liver. Bone metastasis is rare. Clear cell sarcoma generally has a tendency to metastasize to the lymph nodes, bone, lungs, or liver [4]. Wilms tumor tends to invade blood vessels as tumor thrombi. These thrombi may be found in the renal veins, the vena cava inferior, or even the right atrium. In 4% to 10% of cases, tumor thrombi in a renal vein or the vena cava inferior can be seen at the time of diagnosis [8]. The precise incidence of vascular tumor thrombosis is not known. Wilms tumor

Figure 4. The microscopic appearance of clear cell sarcoma composed of epitheloid cells with pale cytoplasm and indistinct nucleoli separated by a clear extracellular matrix (hematoxylin-eosin x400).

is bilateral in approximately 5% of cases, while clear cell sarcoma is almost always unilateral. In some 10% of cases, overgrowth syndromes, isolated anhidrosis, and congenital anomalies, such as trisomy-18, hypospadias, or cryptorchidism may accompany Wilms tumor. No concomitancy between clear cell sarcoma and the abovementioned anomalies has been reported so far [1, 9]. In clear cell sarcoma, the most frequently described anomaly is a loss of the 19 chromosome and a 1p chromosome gain [10, 11]. Other anomalies that have been demonstrated are rearrangements of the YWHAE gene on chromosome 17 and the FAM22 gene on chromosome 10, dysregulation of epidermal growth factor and overproduction of the Ckit protein [12, 13, 14]. Though a series of chromosomal translocations and genetic changes have been described in clear cell tumors, its molecular pathogenesis and cellular origin have not yet been clarified [4]. The results of karyotypic examination in these cases are generally within normal limits [15]. Histopathologically it is very hard to discriminate a CCSK tumor from other renal tumors. It has similarities to blastomal and stromal Wilms tumor. Typical characteristics of the tumor are a large size with mucinous material, the presence of necrotic foci, and a marked cystic formation. [3]. It consists of small, round, uniform cells containing clear cytoplasm, indistinct nucleoli, abundant extracellular matrix, and evenly distributed fine chromatin separated by a delicate vascular network [5, 16]. The microscopic appearance of the histopathology slide of our case is shown in Figure 4. As is the case with Wilms tumor, a widely accepted diagnostic immunohistochemical feature of clear cell sarcoma is not available. Diagnostic clues include clearly separated nuclear cavities, a fine chromatin network, and a relatively younger mean patient age [3]. However, as in the present case, rarely, patients may also be older. In conclusion, the differential diagnosis of clear cell sarcoma and Wilms tumor can be difficult; however, an accurate diagnosis is important for the choice of treatment and prognosis. Clear cell sarcoma should be considered in the differential diagnosis of children with renal masses. It should also not be forgotten that these patients can present with spontaneous bleeding. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support.

Ozdemir et al., Renal clear cell sarcoma presenting as a spontaneous renal hematoma Authorship contributions: Concept – Z.C.O., Y.D.K.; Design – Z.C.O., O.B., Y.D.K.; Supervision – O.B.; Materials – M.O., M.S.A.; Data collection &/or processing – B.A., M.O., M.F.A.; Analysis and/or interpretation – Z.C.O., O.B.; Writing – Z.C.O.; Critical review – O.B.

REFERENCES 1. Malkan AD, Loh A, Bahrami A, Navid F, Coleman J, Green DM, et al. An approach to renal masses in pediatrics. Pediatrics 2015;135:142–58. 2. Zhuge Y, Cheung MC, Yang R, Perez EA, Koniaris LG, Sola JE. Pediatric non-Wilms renal tumors: subtypes, survival, and prognostic indicators. J Surg Res 2010;163:257–63. 3. Argani P, Perlman EJ, Breslow NE, Browning NG, Green DM, D’Angio GJ, et al. Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms Tumor Study Group Pathology Center. Am J Surg Pathol. 2000;24:4–18. 4. Gooskens SL, Furtwängler R, Vujanic GM, Dome JS, Graf N, van den Heuvel-Eibrink MM. Clear cell sarcoma of the kidney: a review. Eur J Cancer 2012;48:2219–26. 5. Short SS, Zmora O, Hunter CJ, Wang L, Siegel S, Ford HR. Large clear cell sarcoma of the kidney mistaken as Wilms tumor. J Ped Surg Case Reports 2013;1:235–8. 6. Vasei M, Moch H, Mousavi A, Kajbafzadeh AM, Sauter G. Immunohistochemical profiling of Wilms tumor: a tissue microarray study. Appl Immunohistochem Mol Morphol 2008;16:128–34. 7. Sebire NJ, Vujanic GM. Paediatric renal tumours: recent developments,

new entities and pathological features. Histopathology 2009;54:516–28. 8. Emir S. Wilms tumor with intravascular tumor thrombus. Transl Pediatr 2014;3:29–33. 9. Mullen E, Graf N. Clinical Presentation. In: Pritchhard-Jones K, Dome JS, editors. Renal tumor of childhood. London: Springer-Verlag Berlin Heidaelberg; 2014. p. 39-51. 10. Schuster AE, Schneider DT, Fritsch MK, Grundy P, Perlman EJ. Genetic and genetic expression analyses of clear cell sarcoma of the kidney. Lab Invest 2003;83:1293–9. 11. Barnard M, Bayani J, Grant R, Zielenska M, Squire J, Thorner P. Comparative genomic hybridization analysis of clear cell sarcoma of the kidney. Med Pediatr Oncol 2000;34:113–6. 12. O’Meara E, Stack D, Lee CH, Garvin AJ, Morris T, Argani P, et al. Characterization of the chromosomal translocation t(10;17)(q22;p13) in clear cell sarcoma of kidney. J Pathol 2012;227:72–80. 13. Little SE, Bax DA, Rodriguez-Pinilla M, Natrajan R, Messahel B, Pritchard-Jones K, et al. Multifaceted dysregulation of the epidermal growth factor receptor pathway in clear cell sarcoma of the kidney. Clin Cancer Res 2007;13:4360–4. 14. Jones C, Rodriguez-Pinilla M, Lambros M, Bax D, Messahel B, Vujanic GM, et al. c-KIT overexpression, without gene amplification and mutation, in paediatric renal tumours. J Clin Pathol 2007;60:1226–31. 15. Hadley GP, Sheik-Gafoor MH. Clear cell sarcoma of the kidney in children: experience in a developing country. Pediatr Surg Int 2010;26:345–8. 16. Boo YJ, Fisher JC, Haley MJ, Cowles RA, Kandel JJ, Yamashiro DJ. Vascular characterization of clear cell sarcoma of the kidney in a child: a case report and review. J Pediatr Surg 2009;44:2031–6.

Case Report

GASTROENTEROLOGY

North Clin Istanb 2018;5(1):64-66 doi: 10.14744/nci.2017.77045

Autoimmune hemolytic anemia associated with infliximab infusion in ulcerative colitis Fazia A. Mir, Alhareth Al Juboori, Jack D. Bragg, Veysel Tahan Department of Gastroenterology and Hepatology, Missouri University, Columbia, Missouri, USA

ABSTRACT Infliximab is a monoclonal antibody that antagonizes the activity of tumor necrosis factor alpha to induce and maintain remission in patients with inflammatory bowel disease. Adverse effects associated with Infliximab infusions include infusion reactions, risk of infections, development of hematological malignancies, and pancytopenia. Autoimmune hemolytic anemia has rarely been reported in ulcerative colitis. Herein we report a case of drug-induced hemolytic anemia after infliximab infusion for treating ulcerative colitis. Keywords: Autoimmune hemolytic anemia; inflammatory bowel disease; infliximab; ulcerative colitis.

umor necrosis factor alpha (TNF-α) is a proinflammatory cytokine found in increased concentrations in the blood, colonic tissue, and stools of patients with inflammatory bowel disease including Crohn’s disease and ulcerative colitis (UC) [1]. Infliximab is a monoclonal antibody that antagonizes the activity of TNF-α to induce and maintain remission in patients with inflammatory bowel disease. Adverse effects associated with infliximab infusions include infusion reactions, risk of infections, and the development of lymphoma [2]. Herein we discuss the case of a patient with autoimmune hemolytic anemia (AIHA) receiving infliximab infusion for the treatment of UC.

CASE REPORT A 42-year-old male with a history of pancolonic UC diagnosed in 2009 with no response to mesalamine, azathioprine, and prednisone presented to a university clinic to receive care. Colonoscopy performed in 2014 showed pancolitis, diffuse erythema, and ulceration. At that time, the patient also had clinically significant symptoms with 10 diarrheal bowel movements a day. The patient was started on 5 mg/kg infliximab every 8 weeks after colonoscopy with concomitant 10 mg prednisone daily for functional treating adrenal insufficiency that developed due to prolonged steroid use.

Received: May 19, 2017 Accepted: July 31, 2017 Online: January 11, 2017 Correspondence: Dr. Veysel TAHAN. Missouri Universitesi, Gastroenteroloji ve Hepatoloji Anabilim Dali, Columbia, Missouri, ABD. Tel: +1 573 884-6044 e-mail: tahanv@health.missouri.edu © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Mir et al., Infliximab infusion in ulcerative colitis

At the 6-month follow-up, the patient reported significant improvement in his diarrheal symptoms and reduction in his bowel movement frequency. A decision was made to continue with infliximab with close followup care. At a routine 2-month follow-up visit after being on infliximab for a year, the patient reported extreme fatigue, while denying the presence of blood in his stool or urine. A physical examination showed conjunctival pallor and scleral icterus. His complete blood count and chemistry panel were indicative of pancytopenia, with a hemoglobin level of 5.7g/dL (baseline 14 g/dL), white blood cell count of 1550/mcL, platelet count of 121000/mcL, total bilirubin level of 2.88 mg/dL, and direct bilirubin level of 0.6 mg/dL. His peripheral smear showed macrocytosis, anisocytosis, poikilocytosis, tear drop cells, and spherocytosis. The patient was then referred to the Hematology Department for undergoing a further evaluation. His direct Coombs test result was positive. Given the findings of his direct Coombs test, AIHA was diagnosed, and it was concluded that his anemia was secondary to drug-induced hemolysis from infliximab infusion. A decision was made to discontinue infliximab treatment and monitor serial hemoglobin levels and hematocrit. In his follow-up visit, his hemoglobin levels improved to 13.2 g/dL. He was then started on vedolizumab as a maintenance biologic for his UC. DISCUSSION AIHA is a blood disorder in which immunoglobulin G and/or immunoglobulin M attach to red cell surface antigens and start red cell destruction by activating the complement system and the reticuloendothelial system [3]. Immune hemolytic anemia is classified as either autoimmune, alloimmune, or drug induced depending on the immunological response triggered by antigen stimulation [3]. Drug-induced antibodies can recognize either intrinsic red cell antigens or red cell-bound drugs, and antibodies that react with the red cell-bound drug require the drug for hemolysis [4]. A presumptive diagnosis can be made only if patients respond to withdrawal of the drug, as was witnessed in our patient. AIHA can occur in patients with UC. It can simultaneously present with a flare-up of UC but remits with control of the disease [5, 6]. Drug-induced hemolytic anemia has been well documented with high dose penicillin, methyldopa, and certain third-generation cephalosporins [2]. There have

been three cases of AIHA reported in the literature to be caused by infliximab [7-9]. In a study conducted by Vermeire et al. [7] who investigated the occurrence of antinuclear antibodies in 125 consecutive Crohn’s disease patients, it was noted that one patient had developed sudden-onset anemia with icterus and was diagnosed with Coombs negative AIHA 6 months after the first infusion. In this study, the prevalence of hemolytic anemia in patients with infliximab infusion was 0.8% at the follow-up. A study conducted by Fidder et al. [8] evaluated the long-term safety of infliximab by reviewing the records of 734 patients treated with the drug and showed that one patient developed Coombs negative AIHA 6 months after the single administration of infliximab. Vermerie et al. [9] identified predictive factors of the response to infliximab and noted that three patients developed hematological problems, with one patient developing AIHA. Leo-Carnerero et al. [10, 11] presented two interesting cases of UC with documented severe anemia secondary to AIHA that responded well to infliximab treatment in both conditions. Their 26-year-old female patient had left-sided colitis and 35-year old female patient had pancolitis. Infliximab treatment improved not only colitis but also AIHA after the second induction dose in both patients. In the absence of data supportive to their findings, they speculated that depending on the physiopathology, if AIHA develops as a result of the cross-reactivity of erythrocytes and autoantibodies against antigens in the colon, such UC patients with AIHA can improve in both conditions with infliximab treatment. In our case, the patient did not have anemia before treatment and AIHA developed after infliximab treatment, similar to the previous three cases in the literature [7-9]. It is important to closely follow-up patients on infliximab treatment and withdraw the biologic when side effects arise. Despite the limited number of patients with hemolytic anemia secondary to infliximab infusion, providers need to be aware of such adverse effects of therapy an increasing number of patients are started on infliximab for treating inflammatory bowel disease. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – F.A.M., A.A.J., J.D.B., V.T.; Design – F.A.M., A.A.J., J.D.B., V.T.; Supervision – J.D.B., V.T.; Materials – F.A.M., A.A.J., J.D.B., V.T.; Data collection &/or processing – F.A.M., A.A.J., J.D.B., V.T.; Analysis and/or interpretation – F.A.M., A.A.J., J.D.B., V.T.; Writing – F.A.M., A.A.J., J.D.B., V.T.; Critical review – J.D.B., V.T.

Mir et al., Infliximab infusion in ulcerative colitis

REFERENCES 1. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76. 2. Aronson JK. Meyler’s Side Effects of Analgesics and Anti-inflammatory Drugs. 1st ed. Elsevier; 2009. 3. Chaudhary RK, Das SS. Autoimmune hemolytic anemia: From lab to bedside. Asian J Transfus Sci 2014;8:5–12. 4. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol 2002;69:258–71. 5. Leo Carnerero E, Aoufi S, Montero Cuadrado I, Herrera Martin P, Herrera Justiniano JM. Autoimmune hemolytic anemia associated with ulcerative colitis: response to infliximab. Am J Gastroenterol 2009;104:2370–1. 6. Molnár T, Farkas K, Szepes Z, Nagy F, Wittmann T. Autoimmune hemolytic anemia associated with ulcerative colitis: the most important step is to induce complete remission. Am J Gastroenterol 2010;105:1203–4.

66 7. Vermeire S, Noman M, Van Assche G, Baert F, Van Steen K, Esters N, et al. Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn’s disease: a prospective cohort study. Gastroenterology 2003;125:32–9. 8. Fidder H, Schnitzler F, Ferrante M, Noman M, Katsanos K, Segaert S, et al. Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-centre cohort study. Gut 2009;58:501–8. 9. Vermeire S, Louis E, Carbonez A, Van Assche G, Noman M, Belaiche J, et al. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn’s disease. Am J Gastroenterol 2002;97:2357–63. 10. Leo Carnerero E, Aoufi S, Montero Cuadrado I, Herrera Martin P, Herrera Justiniano JM. Autoimmune hemolytic anemia associated with ulcerative colitis: response to infliximab. Am J Gastroenterol 2009;104:2370–1. 11. Leo-Carnerero E, Araujo-Míguez A, Trigo-Salado C, De-la-CruzRamírez MD, Herrera-Justiniano JM, Márquez-Galán JL. The effect of controlling inflammatory activity in the colon on the response to infliximab of autoimmune haemolytic anaemia associated with ulcerative colitis. Rev Esp Enferm Dig 2014;106:295–6.

Case Report

PATHOLOGY

North Clin Istanb 2018;5(1):67-71 doi: 10.14744/nci.2017.27147

Diagnosing between papillary carcinoma and reactive papillary changes in an infarcted thyroid nodule after fine needle aspiration and accompanied by a synchronous brain stem astrocytoma Ceren Canbey Goret,1 Nuri Emrah Goret,2 Omer Faruk Ozkan,3 Muammer Karaayvaz3 Department of Surgical Pathology, Onsekiz Mart University Faculty of Medicine, Canakkale, Turkey

Department of General Surgery, Canakkale State Hospital, Canakkale, Turkey

Department of General Surgery, Onsekiz Mart University Faculty of Medicine, Canakkale, Turkey

ABSTRACT A 22-year-old patient underwent fine needle aspiration of a nodule at the outer center of the right lobe of the thyroid, and it was reported to be Bethesda system category IV, Hurthle cell follicular neoplasia. The patient, who persented to Onsekiz Mart University Research and Application Hospital, underwent surgery. During right total thyroidectomy, an almost totally infarcted nodule and papillary structures around these infarcted areas were detected. Herein, we report on diagnostic challenges faced in confirming whether the infarcted nodule was a case of reactive papillary changes or an underdiagnosed papillary carcinoma and how the challenges were overcome using immunohistochemistry analysis and molecular genetic testing. In addition, we examined the case along with a literature review because an accompanying synchronous brain stem astrocytoma was detected in the patient after thyroidectomy. Keywords: Infarction after biopsi; synchronous tumor; thyroid papillary carcinoma.

hyroid nodules are very common in clinical practice and mostly benign. Although malignancy rates are low, it is absolutely necessary to cytologically exclude malignancy in nodules with some radiological features. In clinical practice, fine needle aspiration (FNA) has currently replaced radionuclide thyroid screening. FNA cytology is known to be a reliable method in terms of malignant and benign nodule differentiation before making a decision on surgical treatment of the thyroid [1, 2]. It was reported that sensitivity of FNA varies between 65% and 99%, and its specificity varies between 72% and 100% [1, 2]. Local pain and minor bleeding are among the most common post-FNA complications [4]. Serious postFNA complications occur more rarely. Infarction in the thy-

roid nodule is one of the serious complications and a rare condition. Infarction is reported to occur more frequently in thyroid nodules of oncocytic morphology [9-10]. If cytologic findings by FNA are not correctly evaluated, it can be very difficult to correctly diagnose the resection episode in such cases because of the infarct. In this case report, we aimed to present difficulties experienced in histopathologic evaluation of an almost totally infarcted thyroid nodule whose cytologic diagnoses was Hurthle cell follicular neoplasia and in deciding whether these papillary structures observed in the focal area were reactive or associated with a papillary carcinoma and to introduce it in the literature because an astrocytoma was detected in the 2nd synchronous primary brain stem.

Received: February 09, 2017 Accepted: June 18, 2017 Online: January 10, 2018 Correspondence: Dr. Ceren CANBEY GORET. Onsekiz Mart Universitesi Tip Fakultesi Cerrahi Patoloji Anabilim Dali, Canakkale, Turkey. Tel: +90 507 950 02 12 e-mail: drcerencanbey@hotmail.com ÂŠ Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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CASE REPORT A 22-year-old patient underwent FNA as a nodule was detected on the outer center of the right lobe of the thyroid, and it was reported to be a Bethesda system [22] category IV, Hurthle cell follicular neoplasia. A right total thyroidectomy was performed on the patient who presented to our hospital, and a frozen section was requested. In the right total, 3.5×2-cm thyroidectomy material section, a 1.7×1.2-cm nodule, including necrotic and focal hyalinized areas, located 0.3 cm from the thyroid capsule, was observed. The frozen section

Figure 1. A nodule with large localized areas of necrosis under the thyroid capsule (H&E, ×40).

Figure 2. Focal papillary proliferations around large necrosis areas (H&E, ×100).

analysis was reported as “necrosis, focal papillary structures in some places around the hyalinized areas, malignant-benign differentiation was not clear, and paraffin sections were to be examined,” and a total thyroidectomy was prevented. In the center of the paraffin sections, papillary structures composed of large oncocytic cytoplasmic thyrocytes in the focal area around intense infarct were noticed (Figs. 1, 2, 3). These papillary structures were observed in the focal areas, and because of the previous FNA diagnosis of follicular neoplasia, these structures were initially considered to be “reactive papillary hyperplasia.” However, when examined in detail, these papillary structures were found to be infiltrative in places in spite of being in a focal area, and their cytological evaluation suggested papillary carcinoma. Immunohistochemical analysis of the papillary structures showed diffuse, strong positivity with cytokeratin 19 and focal, weak positivity with HBME-1, whereas the external control was positive with galectin-3 and no staining was observed in the case (Figs. 4, 5, 6). On this basis, BRAF V600E was studied in terms of molecular genetics, and the patient was diagnosed with a “thyroid papillary carcinoma” because of a positive result. FNA preparations of the patient that had been previously analyzed in the external center were made available for a re-evaluation to determine the extent to which the cytology would contribute in such cases, and FNA preparations were re-evaluated.

Figure 3.

Thyrocytes of papillary carcinoma with a large oncocytic cytoplasm aligned around the fibrovascular core (H&E, ×400).

Canbey Goret et al., Synchronous brain stem astrocytoma

Figure 4. Extensive strong positivity with cytokeratin 19 and papillary structures (Immunohistochemistry, ×400).

Figure 6. No staining with galectin-3 was observed (Immunohistochemistry, ×400). Cytological evaluation revealed focal groove structures with large oncocytic cytoplasm in hypercellular spreads, mostly in a microfollicular pattern; some of the structures were standing alone or in groups similar to focal papillary structures, overlapping in places, and also showed thyrocytes with intranuclear inclusion (Fig. 7). It was considered that an underdiagnosis was made in the FNA analysis, and it could be evaluated as at least category V (suspicious for malignancy) or category VI (malign aspirate). The patient presented to our hospital again with a complaint of dizziness and nausea after thyroidectomy.

Figure 5.

Focal weak positive staining with HBME 1 (Immunohistochemistry, ×400).

Figure 7.

Cytologic examination revealed presence of mild hypochromia with large oncocytic morphology, focal overlapping, and infrequent intranuclear inclusion (PAP EA 50, ×400).

During MRI at our center (Fig. 8), a mass was detected in the brain stem. “Astrocytoma,” as a 2nd synchronous primary tumor, was detected in the patient who underwent surgery at an external center at the patient’s request. DISCUSSION Papillary carcinoma is the most common malignancy of the thyroid and has very good prognosis with early diagnosis. Thyroid FNA is a widely accepted and important method in terms of nodule evaluation and follow-up [2, 11]. The FNA procedure is easy, nominally invasive, and

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Figure 8.

Magnetic Resonance Imaging (MRI) showed a 2.5×1.5-cm mass lesion in the right superior mesencephalon.

advantageous as it can be repeated several times. These repetitions may lead to a decrease in insufficiency rates. When an FNA procedure is performed, the preparation should be spread on the slide without waiting and should be fixed immediately. Otherwise, a fixation artifact may occur and cause problems in cytological evaluation. To avoid such problems, it may be preferable to have a pathologist accompanying the patient when performing FNA to ensure that the pathologist performs spreading and fixation procedures and confirms by staining the material immediately that the number of cells is sufficiently high to ensure lower insufficiency rates. Local pain and minor bleeding are among the most common post-FNA complications [4]. Serious postFNA complications occur rarely [2]. The literature contains a few studies on tissue changes post FNA. According to Mukunyadzi et al., [12] the use of 23 gauge needles has been reported to cause less bleeding and tissue damage. In a report published by Pandit and Phulpagar, histopathological changes that may occur in the acute and chronic stages post FNA were discussed. Acute lesions were reported to include granulation tissue, siderophages, nuclear atypia, irregularly shaped granulomas, deterioration and infarct in the capsule, and thrombosis, and chronic lesions were reported to include

bleeding, granulation tissue, linear fibrosis, nuclear atypia, vascular changes, papillary changes, thrombosis, capsular pseudoinvasion, infarction, necrosis, metaplasia, and calcification [13]. Diffuse infarcts and macrophages were noticed in our case. In addition, although existing papillary structures have been initially considered as post-FNA reactive changes, the case was interpreted as malignant because these papillary structures exhibited a focal invasive characteristic; their immunohistochemical analysis with cytokeratin 19 demonstrated diffuse, strong positivity; and the result of the BRAF V600E molecular genetic test was positive. It has been reported that necrosis has been detected in various tumors and organs post FNA. Acinic cell carcinoma, pleomorphic adenoma, and Warthin’s tumor in salivary glands; fibroadenoma in the breasts; and renal cell carcinoma in the kidneys are some of the cases reported in the literature [11, 14]. Infarctions of thyroid Hurthle cell neoplasms and papillary carcinomas post FNA have also been reported [3, 6]. Our patient had an oncocytic morphology. Batsakis et al. classified post-FNA tissue effects into three categories: [1] micronecrosis and hemorrhage, where diagnostic properties can be recognized; [2] macronecrosis without diagnostic properties; and [3] reactive proliferative areas with macronecrosis and micronecrosis and stromal cells [15]. Us-Krasovec et al. reported that factors responsible for tissue damage post FNA included interruption of microvascular perfusion, traumatic venous thrombosis, and vascular leakage [16]. As stated in some publications, molecular genetic analyses are currently performed for thyroid malignancies. BRAF mutation exists in 29%–69% papillary thyroid carcinomas, most of which occurs at the V600E codon. In addition, it was detected in 13% differentiated thyroid carcinomas and 10% anaplastic carcinomas. These publications also reported that papillary thyroid carcinomas with a BRAF V600E mutation clinically follow a more aggressive course [5, 17-19]. In our patient, in addition to all of these, a second primary synchronous malignancy was detected in the brain stem and a diagnosis of “astrocytoma” was present. Similar to the case presented here, Pulivarthi et al. have reported a case where synchronous glioblastoma and associated thyroid papillary carcinoma are present [20].

Canbey Goret et al., Synchronous brain stem astrocytoma

Although two primary synchronous malignancies are rarely observed simultaneously, it is reported that the presence of multiple primary malignancies have been observed more frequently than before and the incidence of second primary cancer varies from 1% to 16% depending on the index primary cancer [21]. Numerous synchronous and metachronous tumors have been reported in the literature. These include many synchronous tumor cases, such as small cell lung carcinoma after surgery for lung carcinoid [23], synchronous pancreatic clear cell carcinoma and gastrointestinal stromal tumor [24], synchronous stomach and rectum adenocarcinoma [25], and synchronous papillary and medullary carcinoma in the thyroid [26]. As a conclusion, we should be aware of post-FNA tissue changes, and we should remember that such changes may lead pathologists to misdiagnosis. In addition, in cases with this type of diffuse necrosis, cytologic findings should certainly be correlated with histopathological findings, and even if a small area exists that can be evaluated histopathologically, further immunohistochemical analyses and molecular genetic examinations, if necessary, should be conducted. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – C.C.G.; Design – N.E.G.; Supervision – N.E.G.; Materials – C.C.G., O.F.O.; Data collection &/or processing – C.C.G., O.F.O.; Analysis and/or interpretation – O.F.O., M.K.; Writing – C.C.G.; Critical review – O.F.O., M.K.

REFERENCES 1. Liu YF, Ahmed S, Bhuta S, Sercarz JA. Infarction of papillary thyroid carcinoma after fine-needle aspiration: case series and review of literature. JAMA Otolaryngol Head Neck Surg 2014;140:52–7. 2. Usha M, Rashmi K, Sridhar M, Aarathi RR. Infarcted papillary carcinoma of thyroid following fine needle aspiration. Thyroid Research and Practice 2014;11:124–6. 3. Das DK, Janardan C, Pathan SK, George SS, Sheikh ZA. Infarction in a thyroid nodule after fine needle aspiration: report of 2 cases with a discussion of the cause of pitfalls in the histopathologic diagnosis of papillary thyroid carcinoma. Acta Cytol 2009;53:571–5. 4. Polyzos SA, Anastasilakis AD. Clinical complications following thyroid fine-needle biopsy: a systematic review. Clin Endocrinol (Oxf ) 2009;71:157–65. 5. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66. 6. Pinto RG, Couto F, Mandreker S. Infarction after fine needle aspira-

71 tion. A report of four cases. Acta Cytol 1996;40:739–41. 7. Akerman M, Tennvall J, Biörklund A, Mårtensson H, Möller T. Sensitivity and specificity of fine needle aspiration cytology in the diagnosis of tumors of the thyroid gland. Acta Cytol 1985;29:850–5. 8. Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: an appraisal. Ann Intern Med 1993;118:282–9. 9. Ramp U, Pfitzer P, Gabbert HE. Fine needle aspiration (FNA)-induced necrosis of tumours of the thyroid. Cytopathology 1995;6:248–54. 10. Alejo M, Matias-Cruiu X, de las Heras Duran P. Infarction of a papillary thyroid carcinoma after fine needle aspiration. Acta Cytol 1991;35:478–9. 11. Cobanoglu U, Ersoz S, Adamhasan F, Ozoran Y. Infarction of parotid pleomorphic adenoma following fine needle aspiration biopsy. Aegean Path J 2005;54–7. 12. Mukunyadzi P, Bardales RH, Palmer HE, Stanley MW. Tissue effects of salivary gland fine-needle aspiration. Does this procedure preclude accurate histologic diagnosis? Am J Clin Pathol 2000;114:741–5. 13. Pandit AA, Phulpagar MD. Worrisome histologic alterations following fine needle aspiration of the thyroid. Acta Cytol 2001;45:173–9. 14. Rau AR, Pai RR, Nayak S. Infarction of acinic cell carcinoma in a patient infected with HIV: a complication of fine-needle aspiration cytology obscuring definitive diagnosis. Diagn Cytopathol 2003;29:222–4. 15. Batsakis JG, Sneige N, el-Naggar AK. Fine-needle aspiration of salivary glands: its utility and tissue effects. Ann Otol Rhinol Laryngol 1992;101:185–8. 16. Us-Krasovec M, Golouh R, Auesperg M, Pogacnik A. Tissue damage after fine needle aspiration biopsy. Acta Cytol 1992;36:456–7. 17. Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 2005;90:6373–9. 18. Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 2003;95:625– 7. 19. Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, et al. BRAF mutations in papillary carcinomas of the thyroid. Oncogene 2003;22:6455–7. 20. Pulivarthi S, Haglind E, McGary CT, Gurram MK. Glioblastoma multiforme and papillary thyroid carcinoma - A rare combination of multiple primary malignancies. J Neurosci Rural Pract 2015;6:241–4. 21. Hayat MJ, Howlader N, Reichman ME, Edwards BK. Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 2007;12:20–37. 22. Cibas ES, Ali SZ; NCI Thyroid FNA State of the Science Conference. The Bethesda System For Reporting Thyroid Cytopathology. Am J Clin Pathol 2009;132:658–65. 23. Çeldir Emre J, Baysak A, Çok G, Nart D, Çağırıcı U. Second Primary Neuroendocrine Tumor in a Patient Operated Because of Lung Carcinoid Tumor: Small Cell Lung Cancer. J Clin Anal Med 2013;4:178–80. 24. Kilic MO, Turkan A, Bozer M, Arslan N, Koktener A. Synchronous tumors: clear cell carcinoma of pancreas and gastointestinal stromal tumor of stomach. J Turgut Ozal Med Cent 2016;1–3. 25. Tavusbay C, Sarı E, Kar H, Gür EÖ, Hacıyanlı M, Ekinci N. Synchronous Gastric and Rectal Cancer: Case Report. Kolon Rektum Hast Derg 2015;25:38–42. 26. Olgen U, Dilek G, Özaslan C. Concurrent Thyroid Papillary Carcinoma and Medullary Carcinoma in The Thyroid. Acta Oncologica Turcica 2015;39–42.

Case Report

CARDIAC SURGERY

North Clin Istanb 2018;5(1):72-73 doi: 10.14744/nci.2017.98700

Reconstructive surgery of true aneurysm of the radial artery: A case report Sevinc Bayer Erdogan, Serdar Akansel, Nehir Tandogar Selcuk, Serap Aykut Aka Department of Cardiovascular Surgery, Siyami Ersek Hospital, Istanbul, Turkey

ABSTRACT True radial artery aneurysms are uncommon pathologies and have an organic cause, unlike trauma-induced false aneurysms. A 52-year-old man presented with a pulsatile mass at the anatomical snuff box area of his left hand. The aneurysm was repaired with reconstructive procedure. Although many posttraumatic and iatrogenic cases of false aneurysm of the radial artery have been reported; there are a few reported cases of a true idiopathic aneurysm. A case of reconstructive surgery for true idiopathic radial artery aneurysm is reported in this paper. Keywords: Radial artery aneurysm; reconstructive surgery; true aneurysm.

pper extremity arterial aneurysms are uncommon pathologies with true radial artery aneurysm being the rarest among this group [1]. A true aneurysm is caused by degenerative, congenital, metabolic disorders or can be part of a systemic disease [2]. It is caused by structural deterioration of the vessel wall. All three layers of the arterial wall can be seen under histologic examination. A delay in surgical intervention is not recommended in these cases because of the risk for thromboembolism or rupture [3]. A case of reconstructive surgery for true idiopathic radial artery aneurysm is presented in this paper. CASE REPORT A 52-year-old, left-hand-dominant man presented to our outpatient clinic with a pulsatile and painful mass at the anatomical snuff box area of his left hand. The mass had been present for 1 year and had gradually enlarged. The patient denied history of trauma; there was no family history of aneurysms.

On physical examination, a spherical mass of size 1.5×2 cm was found at the anatomical snuffbox area of the patient’s left hand without any scars hinting at previous trauma (Fig. 1). There were no signs of other arterial aneurysms on examination. Computed tomography (CT) angiography showed a saccular aneurysm with a size of 14 mm at the distal part of the radial artery localized on the dorsal aspect of the first carpometacarpal joint (Fig. 2). Because of abnormal preoperative Allen’s test, revascularization was planned with primary or graft interposition based on anatomy of the radial artery. Under local anesthesia, the skin was incised over the aneurysm site. Proximal and distal arterial segments of the aneurysm were encircled with vessel loops. The aneurysm sac was dissected from the surrounding tissue (Fig. 3a). After heparinization and arterial clamping, the aneurysm sac was resected. Then, the reconstruction was performed with primary end-to-end anastomosis following distal and proximal liberalization from the surround-

Received: March 17, 2017 Accepted: May 23, 2017 Online: January 16, 2018 Correspondence: Dr. Serdar AKANSEL. Dr. Siyami Ersek Hastanesi, Kalp ve Damar Cerrahisi Bolumu, Istanbul, Turkey. Tel: +90 216 542 44 44 e-mail: mdakanselserdar@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Bayer Erdogan et al., Radial artery aneurysm

Figure 1. A mass at the snuff box area of the left hand.

Figure 2. Reconstructed three-dimensional image of the left

as they require higher pressures to enlarge. This is the reason for uncommon occurrence of aneurysms in small vessels, such as the radial, ulnar, and digital arteries [4]. The diagnosis is initially clinical, but is afterwards confirmed using various imaging modalities such as duplex ultrasonography and CT angiography. Duplex ultrasonography is traditionally used first to help diagnosis as it is inexpensive and easy to access. CT angiography is ideal for whole-body scans to exclude other aneurysms. Magnetic resonance angiography or conventional angiography has also been reported to be used in diagnosis. Igari et al. [5] reported five patients with upper extremity aneurysms including two brachial, two ulnar, and one radial aneurysm treated with surgical resection. They performed reconstruction for two brachial aneurysms and ligation for the others. The surgical treatment options in the radial and ulnar artery aneurysms depend on whether they dominantly supply blood to the hand. Many options for evaluation of dominance are available with variable sensitivity and specificity: Allen’s test, modified Allen’s test, digital plethysmography, digital Doppler waveforms and pressures, and duplex ultrasonography [6]. The surgeon can perform a simple resection and ligation on the basis of physical findings and radiographic results. In contrast, a reconstructive surgery can be performed with A

hand shows a saccular aneurysm on the radial artery.

ing tissues to allow for a tension-free anastomosis. Blood flow was successfully re-established to the distal segment (Fig. 3b). The histology of the resected aneurysm showed thrombus formation, fibromyxoid degeneration of the vessel wall, atrophy of the medial layer, and destruction of the elastic lamina. The patient was uneventfully discharged from the hospital on postoperative day 3. No lesion was detected in CT angiography performed 3 months after surgical treatment.

DISCUSSION The upper extremity arterial aneurysms are extremely rare entities, and radial artery aneurysm is the rarest form of upper extremity aneurysms [1]. Vessels with a small lumen, such as the radial artery, have a low possibility of aneurysm formation according to Laplace’s law

Figure 3. Exploration of the aneurysm controlled with vessel loops proximally and distally (a), reconstruction of the radial artery with a primary end-to-end anastomosis (b).

a primary end-to-end anastomosis if there is no tension, or with graft interposition in case the defect is lengthy. A less invasive endovascular intervention using stent grafts is an alternative treatment option for radial artery aneurysms is, but not many cases of radial artery aneurysms treated with stent grafts have been reported [7]; furthermore, it remains a controversial option. The present patient had degenerative true radial artery aneurysm. He denied history of trauma and had no family history of aneurysm. First, we performed duplex ultrasonography to confirm the final diagnosis and then CT angiography to exclude other aneurysms. The patient was treated with a reconstructive procedure. Primary end-to-end anastomosis was performed without tension; histologic examination showed fibromyxoid degeneration of the vessel wall. Although there are alternative treatment options such as simple resection and ligation or endovascular intervention for radial artery aneurysms, this paper favors that reconstructive surgery of the radial artery aneurysms can be safely performed and should be the preferred option, especially in young patients.

North Clin Istanb Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – S.A., S.B.E.; Design – S.A.; Supervision – S.A.A.; Materials – S.A.; Data collection &/or processing – S.A., N.T.; Analysis and/or interpretation – S.A.; Writing – S.A., S.B.E.; Critical review – S.A., S.A.A.

REFERENCES 1. Ho PK, Weiland AJ, McClinton MA, Wilgis EF. Aneurysms of the upper extremity. J Hand Surg Am 1987;12:39–46. 2. Rasouli MR, Moini M, Khaji A. Civilian traumatic vascular injuries of the upper extremity:report of the Iranian national trauma project. Ann Thorac Cardiovasc Surg 2009;15:389–93. 3. Tsutsumi K, Saito H, Ohkura M. Traumatic pseudoaneurysm of the subclavian artery following anterior dislocation of the shoulder: a report of a surgical case. Ann Thorac Cardiovasc Surg 2006;12:74–6. 4. Turner S, Howard CB, Dallimore NS. A case report of a true aneurysm of a digital artery. J Hand Surg Br 1984;9:205–6. 5. Igari K, Kudo T, Toyofuku T, Jibiki M, Inoue Y. Surgical treatment of aneurysms in the upper limbs. Ann Vasc Dis 2013;6:637–41. 6. Habib J, Baetz L, Satiani B. Assessment of collateral circulation to the hand prior to radial artery harvest. Vasc Med 2012;17:352–61. 7. Carrafiello G, Laganà D, Mangini M, Fontana F, Recaldini C, Piacentino F, et al. Percutaneous treatment of traumatic upper-extremity arterial injuries: a single-center experience. J Vasc Interv Radiol 2011;22:34–9.

Case Report

CHILD SURGERY

North Clin Istanb 2018;5(1):75-78 doi: 10.14744/nci.2017.75508

Penetrating injury caused by a long iron bar: A case report Seyithan Ozaydin,1 Aykan Gulleroglu,2 Birgul Karaaslan,1 Suleyman Celebi,1 Cemile Besik,1 Melike Korkmaz Toker,2 Serdar Sander1 Department of Pediatric Surgery, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey

Department of Anesthesiology and Reanimation, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey

ABSTRACT Foreign bodies that strike the body with their long edges can cause severe problems. From the hospitalization of the patients to the removal of the foreign body and from surgery to follow-up, working as a team in a well-organized manner is necessary. In the present research, we present our experience, including the hospitalization, initial assessment by the emergency team, examination, and treatment plan, of a pediatric patient who had a 12-m long iron bar that traversed from the right side of the anus to the loin; this impalement happened while the patient was sliding through a snow-covered street, and the patient had to wait on the snow until the fire department arrived and cut the iron bar. Keywords: Iron bar; perineal impalement injuries; pediatric patient.

mpalement and anorectal injuries in children are rarely observed, but they have high mortality and morbidity rates [1, 2]. While it is advantageous for the patient who had a foreign body, such as iron bar, which traverses a long distance within the body does not injure vital organs, it is disadvantageous that both the hospital and the fire department that are called for help do not have appropriate tools, which do not do harm to the patient and operating room, to cut the bar within safety measures. Herein we present our experience including the examination, treatment, and follow-up of a pediatric patient who was admitted with a construction iron bar traversing from the perineum to the loin through the sacrum.

CASE REPORT An 11-year-old boy was sliding in the supine position when an 18-mm wide, 12-m long construction iron bar entered his body from the right site of the anus and exited from the loin; he had to wait for an hour until the fire department arrived and cut the iron bar into a 140 cm piece. He was taken to the nearest state hospital and was then transferred to the emergency service of our hospital (Fig. 1). The patient was met by a team already present in the emergency service as they were informed by the 112 emergency services operator. He was slightly hypothermic and had an intermediate overall condition, with no

Received: April 04, 2017 Accepted: April 28, 2017 Online: January 11, 2018 Correspondence: Dr. Seyithan OZAYDIN. Kanuni Sultan Suleyman Egitim ve Arastirma Hastanesi, Cocuk Cerrahisi Klinigi, Istanbul Turkey. Tel: +90 212 - 404 15 00 - 13 69 e-mail: seyithanozaydin@gmail.com ÂŠ Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

North Clin Istanb

active hemorrhaging and a normal abdomen; however, he had difficulty in breathing. Chest and abdominal x-ray examinations were performed under the supervision of Pediatric Surgery, Orthopedics, Brain Surgery, Anesthesiology, and Radiology departments. Later, because the patientsâ&#x20AC;&#x2122; pain and breathing difficulty increased, the patient was successfully intubated on a stretcher he was lying in the supine position; computed tomography (CT) was performed afterward (Figs. 2). No abdominal or chest injury was detected in the CT image, and considering the possibility of rectosigmoid/ retroperitoneal injury, laparotomy was performed to remove the construction iron bar in a controlled manner. Meanwhile, tetanus vaccination was performed and antibiotic (ampicillin/sulbactam, amikacin, ornidazole) treatment was started. The patient was very carefully placed in the supine position, and his abdominal re-

gion was opened. No pathological findings other than a hematoma that was 5â&#x20AC;&#x201C;6 cm in diameter at the sigmoid colon mesentery were detected; his abdominal skin was then closed, and he was carefully placed in the face-down position. The main goal of the intervention was to shorten the iron bar to avoid more injuries to the tissues while removing the 18-mm wide ribbed construction iron bar; however, as appropriate tools to cut an iron bar was not available at our hospital, the fire department was urgently called. The fire department reported that they had three types of bar cutters: the scissor-type cutter would cause more injuries to the patient and the other was a spiral cutter that cannot cut such a bar; therefore, these two cutters were not suitable for this task. The third type was a spiral-type cutter that can cut the iron by transmitting heat. Inevitably, this cutter was used, and cold water was

Figure 1. Penetrating injury caused by construction iron.

Figures 2. Computed tomography images in supine position.

Figures 3. The shortened 140-cm iron bar was pulled in a controlled manner and removed.

Ozaydın et al., Penetrating injury

continuously poured to prevent the tissues from burning. The shortened iron bar was pulled out in a controlled manner and removed (Figs. 3). However, we later realized that oxygen and nitrous oxide container tubes for administering anesthesia should not be around while working with these cutters as they require high heat and pressure and that their presence almost caused an explosion. After removing the shortened iron bar, a light exudate containing bone pieces came from the wound in the shape of a long tunnel, and specialists from the Orthopedics and Brain Surgery departments stated that it did not require intervention. Afterward, the wound was washed and cleaned and a lumbar exit hole was closed with a suture; a long Penrose drain was placed into the entry hole. The patient was placed in the supine position, and his abdominal cavity was examined once more and then cavity was closed. The patient remained in the intensive care unit for two days following the operation and was discharged with full recovery on the 11th day of his follow-up . In his control lumbar spinal magnetic resonance image, there were subcutaneous degenerative changes at L4-L5 levels, and there were degenerative changes in the nerve roots at S2–S5 levels. His electromyography findings were normal. The patient did not have any problems while walking, defecating, and urinating and still continues to have no such problems after the 14th postoperative month. DISCUSSION Impalement and anorectal injuries are rarely observed during childhood. Nevertheless, they can have high mortality and morbidity rates [3-5]. While falling from construction sites is usually seen in adults, in children, anorectal injuries occur due to sliding down from trees, falling on sharp objects in the sitting position while playing, or sexual assault [4, 6, 7]. These injuries can very rarely be iatrogenic [8]. These traumas are not limited to the anorectal region but can cause serious problems in every region that the foreign body passes through. Sometimes, a very careful examination should be performed on the patients from whom foreign bodies are removed, and extraperitoneal bladder rupture should not be missed even if the anorectal examination appears to be normal [9]. In our case, the entry site of the construction iron bar was 1 cm to the side of the anus; the bar scraped the rectum, went through the sacrum, affected the spinous

process of the vertebrae, and exited through the loin. Although more severe problems are expected with the injury of intra-abdominal organs, early surgery has been reported to be very critical in such cases [10]. There is emphasis on the importance of intervention within 6 h, particularly for improving sepsis and wound recovery [8]. Our patient waited for approximately 1 h for the removal of 12-m long foreign body by the fire department and was taken to the nearest hospital; he was later transferred to our hospital. The delay caused by these events was somewhat compensated as our team was well organized and ready after being informed by the 112 emergency services operator. Although an unexpected problem caused by the cutter type extended the shortening and removal duration, surgery was finally performed at 4 h. Although sphincter and urinary system problems are more frequently observed in cases accompanied by severe and vital organ injuries, perianal injuries also require long-term follow-up due to these problems [2]. After regular follow-ups for 14 months, our patient does not have any problems in walking, urinating, and defecating; follow-ups still continue and he still has no such problems. In conclusion, surgical teams working in co-ordination have to share wisdom in order to have successful outcomes in similar cases. We believe that sharing our experiences and revealing their shortcomings and developing novel, solution-oriented guidelines will take us forward in similar cases in the future. Acknowledgment: We would like to specially thank Istanbul Sefakoy Fire Department for their help and careful work. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – S.O., A.G., B.K., S.C., C.B., M.K.T., S.S.; Design – S.O., A.G., B.K., S.C., C.B., M.K.T., S.S.; Supervision – S.O., A.G., B.K., S.C., C.B., M.K.T., S.S.; Materials – S.O., A.G., B.K., S.C., C.B., M.K.T., S.S.; Data collection &/or processing – S.O., A.G., B.K., S.C., C.B., M.K.T., S.S.; Analysis and/or interpretation – S.O., A.G., B.K., S.C., C.B., M.K.T., S.S.; Writing – S.O., A.G., B.K., S.C., C.B., M.K.T., S.S.; Critical review – S.O., A.G., B.K., S.C., C.B., M.K.T., S.S.

REFERENCES 1. Beiler HA, Zachariou Z, Daum R. Impalement and anorectal injuries in childhood: a retrospective study of 12 cases. J Pediatr Surg 1998;33:1287–91.

78 2. Russell KW, Soukup ES, Metzger RR, Zobell S, Scaife ER, Barnhart DC, et al. Fecal continence following complex anorectal trauma in children. J Pediatr Surg 2014;49:349–52. 3. Dar Rawat J, Goel P, S Kunnur V, Kushwaha B, Kushwaha R. Penetrating injury of pelvis, abdomen and thorax in a child with a trident (trishula). APSP J Case Rep 2013;4:3. 4. Vincent MV, Abel C, Duncan ND. Penetrating anorectal injuries in Jamaican children. Pediatr Surg Int 2012;28:1101–7. 5. Grisoni ER, Hahn E, Marsh E, Volsko T, Dudgeon D. Pediatric perineal impalement injuries. J Pediatr Surg 2000;35:702–4. 6. Kolahdouzan M, Rezaee MT, Shahabi S. Impalement Thoracoabdominal Trauma Secondary to Falling on Metallic (Iron) Bars: An Extremely

North Clin Istanb Rare and Unique Case. Arch Trauma Res 2016;5:e18330. 7. Malla G, Basnet B, Vohra R, Herrforth C, Adhikari S, Bhandari A. Thoraco- abdominal impalement injury: a case report. BMC Emerg Med 2014;14:7. 8. Shatnawi NJ, Bani-Hani KE. Management of civilian extraperitoneal rectal injuries. Asian J Surg 2006;29:11–6. 9. Kim S, Linden B, Cendron M, Puder M. Pediatric anorectal impalement with bladder rupture: case report and review of the literature. J Pediatr Surg 2006;41:E1–3. 10. Zuccon W, Paternollo R, Del Re L, Cordovana A, De Murtas G, Gaverini G, et al. Emergency treatment of violent trauma: clinical cases and surgical treatment of penetrating thoracoabdominal, perineal and anorectal trauma. Ann Ital Chir 2013;84:11–8.

Invıted Review

GASTROENTEROLOGY

North Clin Istanb 2018;5(1):79–88 doi: 10.14744/nci.2017.10692

Fecal microbiota transplantation and its potential therapeutic uses in gastrointestinal disorders Ryan D. Heath,1 Courtney Cockerell,1 Ravinder Mankoo,2 Jamal A. Ibdah,1 Veysel Tahan1 Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri, USA

Department of Internal Medicine, University of Missouri-Columbia 1 Hospital Drive, Columbia, Missouri, USA

ABSTRACT Typical human gut flora has been well characterized in previous studies and has been noted to have significant differences when compared with the typical microbiome of various disease states involving the gastrointestinal tract. Such diseases include Clostridium difficile colitis, inflammatory bowel disease, functional bowel syndromes, and various states of liver disease. A growing number of studies have investigated the use of a fecal microbiota transplant as a potential therapy for these disease states. Keywords: Disease; fecal microbiota; fecal transplantation; gastrointestinal; stool; therapy; treatment.

Typical human gut microbiome The human gastrointestinal (GI) tract is estimated to be colonized by hundreds of bacterial species: microbiota associated with facilitating digestion, aiding in the provision of nutrition, defense against pathogens, and the development and maturation of the colonic epithelium [1-3]. The typical microbiota appear to vary mildly in composition for each individual; however, some generalizations have been noted. Various phyla of Firmicutes make up the majority of the microbiota in the human gut, observed to be about 40% to 70% [1-5]. These bacteria are a collective, largely composed of various Clostridium strains, Fusobaceterium strains, fecal bacterial strains, and other various genera [1-5]. Also common, though seen less frequently than the Firmicutes, are the Bacteroidetes phyla, with an estimated prevalence of approximately 25% [1-6]. It is worth noting that there does appear to be some variability of microbiota among different ethnic groups. A Tanzanian population was observed to have significantly lower Bifidobac-

terium and enrichment in genera such as Prevotella and Treponema when compared with an Italian population [7]. A similar paper demonstrating microbiota variability between Western and Eastern populations reported significantly different population size and prevalence of Bacteroidetes in a Belgian population compared with Japanese [8]. Other studies have demonstrated differences between countries within the same continent, such as a 2015 study demonstrating significant variability in Bacteroidetes species in groups of Asian schoolchildren of different nationalities, and noted similar profiles between groups with comparable dietary profiles [9]. The varied response to fecal microbiota transplantation (FMT) may in part be explained by ethnic heritage and diet. Overall, however, alterations in the ratio of these groups appear to be associated with various disease states [1-3]. There is an observed “healthy” or “normal” balance between these majority phyla, changes in which are associated with pathological states in a variety of disorders including C. difficile colitis, inflammatory bowel disease (IBD),

Received: September 15, 2017 Accepted: November 09, 2017 Online: February 12, 2018 Correspondence: Dr. Veysel Tahan. Gastroenteroloji ve Hepatoloji Anabilim Dali, Missouri Universitesi, Columbia, Missouri, ABD. Tel: 00 1 412 245 71 63 e-mail: tahanv@health.missouri.edu © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

North Clin Istanb

functional bowel disorders, and several liver diseases [16, 10]. Changes in the microbiome may be induced by a variety of factors. A 2015 study utilized pyrosequencing to quantify changes in the microbiota of healthy patients receiving clindamycin, ciprofloxacin, and a placebo over 12 months [2]. Overall species diversity decreased in groups receiving either antibiotic, though not in the placebo group. It warrants notice that microbiota appear to remain stable over time in healthy patients, suggesting that changes in the microbiome observed in the disease states to be discussed may be influenced by interventions undertaken by clinicians for those pathological states. A growing number of studies have been conducted utilizing FMT from a healthy human donor in the treatment of several gastrointestinal disorders, and assessing the clinical response and potential therapeutic use in those disease states.

Clostridium difficile colitis The incidence of Clostridium difficile (C. difficile) infection (CDI) has been on the rise, with populations at higher risk including patients receiving chemotherapy, those with a history of solid organ transplant, and patients with IBD [11]. Beyond the rising prevalence, its marked recurrence rate necessitates consideration of alternate treatment modalities, particularly in the aforementioned higher risk populations. Studies have demonstrated that anywhere from 10% to 20% develop recurrence within 8 weeks of receiving treatment, and further recurrence in 40% to 65%, suggesting that repeat episodes become more likely with each recurrence [12, 13]. While fidaxomicin, an antibiotic with essentially no absorption from the GI tract and demonstrated to disturb the normal gut flora less than vancomycin has been utilized with success in cases of recurrent CDI, its effectiveness has been noted to decrease dramatically with further recurrences [14]. FMT is hypothesized to treat CDI by

restoring normal gut flora, which compete with C. difficile for nutrients [15]. Multiple studies have demonstrated remarkable effectiveness of FMT in cases of recurrent CDI, perhaps due to the observed sustained restoration of the normal microbiota [16, 17]. The loss of normal flora appears to modulate normal bile salt metabolism, which has an effect on the germination of C. difficile spores [18-24]. One study involving FMT and CDI utilized nasoduodenal (ND) delivery of FMT, and 81% of patients with recurrent CDI experienced resolution of symptoms, compared with 31% who received oral vancomycin [25]. Since that time, endoscopic delivery of FMT has been utilized with similar rates of success; however, a more efficient delivery of FMT has since been explored [26, 27]. Oral capsules have been formulated that demonstrate a similar efficacy. One study assessing capsules used in 20 patients with recurrent CDI observed that 70% of the patients experienced resolution of symptoms, and another 4 patients (20%) experienced resolution after a second round of treatment [28]. A significant number of studies over time have demonstrated the reproducibility of these studies, with a 2015 meta-analysis noting 34 case studies of FMT demonstrated 90% to 97.8% resolution of diarrhea after treatment [29] (Table 1). A total of 21 of the 34 studies performed follow-up to evaluate relapse of disease and it was determined that 80.9% demonstrated no recurrence of symptoms, though the range of 46% to 100% demonstrates some variability in findings, likely attributable to variations in the mode of delivery and patient characteristics, such as age and severity of disease at presentation. Given that professional society guidelines already indicate FMT is an option in patients with refractory CDI, further studies are needed to assess the relative safety and cost effectiveness of each FMT mode of delivery to determine the optimum medium of administration and to potentially avoid the necessity of surgical intervention and improve mortality rates [30, 31].

Table 1. Summary of studies involving fecal microbiota transplantation and Clostridium difficile colitis Author, year Van Nood et al., 2013 [25] Cammarota et al., 2015 [26] Kelly et al., 2016 [27] Youngster et al., 2014 [28] Rossen et al., 2015 [29]

Method

Mode of FMT Delivery

Outcome

RCT RCT RCT RCT Meta-analysis

Nasoduodenal tube Colonoscopy Colonoscopy Oral capsule Various

43 20 46 20 1029

81% resolution of symptoms 90% resolution 90.9% resolution 70% resolution of symptoms 90-97.8% resolution

FMT: Fecal microbiota transplantation; RCT: Randomized controlled trial.

Heath et al., Fecal Microbiota Transplantation in Gastroenterology

Inflammatory bowel disease Studies have demonstrated evidence of dysbiosis in both Crohnâ&#x20AC;&#x2122;s disease (CD) and ulcerative colitis (UC), particularly with a noted decrease of Bacteroidetes and Firmicutes in association with relative increases in Proteobacteria, Campylobacter, Escherichia coli, Mycobacterium, and Actinobaceria [32-35]. Another observation study reported that individuals with an NOD2 gene mutation, predisposing individuals to developing IBD, have a similar dysbiosis [36]. In 1989, UC patients with symptoms refractory to steroid and sulfasalazine therapy were administered FMT enemas with a resultant improvement in active inflammation and symptoms, though chronic inflammation remained on mucosal biopsy [37]. Subsequent studies of patients with IBD refractory to 5-aminosalicylic acid, steroids, and azathioprine demonstrated similar results with clinical remission ranging from 3 months to 13 years [38, 39]. One 2014 meta-analysis of 122 patients across multiple observation studies noted a potential disparate impact of FMT in different types of IBD, with pooled results from 18 studies demonstrating clinical remission of 36.2% in UC patients versus 60.5% in CD patients [40]. Another 2015 meta-analysis, however, found a significantly greater response in UC patients versus CD patients [29]. The variability in response to FMT in UC patients was wide, however, ranging from 0% to 68%. Furthermore, it appears that only 6 patients with CD were included in this meta-analysis, suggesting insufficient evidence in this particular analysis to comment on the response to FMT in CD patients. More recent studies demonstrate similarly mixed results, with a generally more positive outlook regarding FMT in IBD. One 2015 randomized control trial (RCT), the first published regarding FMT and IBD involving UC patients, demonstrated that 9 of 38 patients (24%) experienced clinical remission with the use of an FMT enema, compared with 2 of 37 who were given a water enema placebo. A positive outcome was defined as a Mayo score of less than 3 and an endoscopic Mayo score of 0 at 7 weeks following 6 once weekly enemas [41]. Some interesting observations among the group of FMT recipients with positive outcomes were noted. The first was an inverse association between disease length and positive outcome, with 3 out of the 4 patients in the experimental arm who had the disease for only 1 year entering into clinical remission. In addition, greater microbiota diversity was observed in the FMT group compared with the control group. Also of interest, the microbiota of patients in the experimental

group with a positive outcome had shifted toward greater similarity to that of the donor stool. Another RCT published in 2015 utilized 2 ND infusions of FMT 3 weeks apart versus autologous stool infusion in 48 UC patients with mild to moderately active disease and no significant difference between the groups was found when assessing clinical remission over a 12-week period [42]. Consistency with the aforementioned 2015 study is observed, however, as the microbiota of the responders did shift to more closely resemble donor microbiota in that arm of the trial. A third RCT, the Faecal Microbiota Transplantation in Ulcerative Colitis (FOCUS) trial, included 85 UC patients with active UC and assessed clinical and endoscopic remission in a comparison of FMT by colonoscopy followed by FMT enema 5 days per week for a total of 8 weeks and a placebo. A remission rate of 27% (11/41) was observed in the FMT group versus 8% remission in the placebo group [43]. Patients from the control group later received the FMT regimen as an extension of the study, and 27% (10/37) experienced clinical remission. Of interest, each FMT was prepared with stool from 3 to 7 unrelated donors. These results suggest some promise regarding the use of FMT for the treatment of IBD, although further research assessing various delivery modalities in both CD and UC appears warranted. The disparity of results among the aforementioned cases may be explained by the route of FMT administration in the second 2015 study, suggesting that perhaps ND infusion is an inferior method of delivery in patients with UC when compared with endoscopic delivery or enema in this population. Furthermore, as more data are gathered regarding an appropriate donor profile, studies like the second 2015 RCT may yield more positive data with a different donor source. What is striking regarding reviewing these studies is the lack of any RCT evaluating CD, which is underrepresented in FMT literature. Recent publications, including case series and prospective cohort studies, reviewing the utility of FMT in IBD patients unresponsive to immunosuppressive therapy included CD and offer some promise in this regard. These studies, as well as the RCTs mentioned, are summarized in Table 2. Case reports from 2013 and 2014 detailed individual patients with refractory CD who underwent FMT with subsequent clinical remission [44, 45]. A 2015 prospective study assessed 9 patients with a mild to moderate Crohnâ&#x20AC;&#x2122;s Disease Activity Index score who received FMT via nasogastric tube (NGT) and were followed for 12 weeks [46]. Seven of the 9 patients had an improved Pediatric Crohnâ&#x20AC;&#x2122;s Disease

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Table 2. Summary of studies involving fecal microbiota transplantation and inflammatory bowel disease Author, year

Method

Mode of FMT Delivery

Outcome

Borody et al., 1989 [38] Case series Not reported 2 Positive Borody et al., 2003 [39] Case series Enema 6 Clinical & endoscopic remission at 1 year Angelberger et al., 2013 [50] Cohort study Nasojejunal infusion & enema 5 Positive Kump et al., 2013 [51] Cohort study Colonoscopy 6 Positive Kunde et al., 2013 [52] Cohort study Enema 10 33% clinical response at 1 month Danman et al., 2014 [53] Cohort study Colonoscopy 5 20% clinical response Cui et al., 2015 [47] Cohort study Nasogastric infusion 14 57% clinical improvement Cui et al., 2015 [49] Cohort study Nasogastric infusion 30 86.6% clinical remission at 30 days Moayyedi et al., 2015 [39] RCT Enema 65 24% achieved remission Rossen et al., 2015 [78] RCT Autologous stool 48 No significant effect Suskind et al., 2015 [46] Cohort study Nasogastric infusion 9 78% clinical remission Wei et al., 2015 [54] Cohort study Colonoscopy (ulcerative colitis), 14 Clinical improvement nasojejunal infusion (Crohnâ&#x20AC;&#x2122;s disease) Paramsothy et al., 2016 [43] RCT Enema 81 30% remission achieved Uygun et al., 2017 [48] Cohort study Colonoscopy 30 70% improved symptoms, 43.3% clinical&endoscopic remission FMT: Fecal microbiota transplantation; RCT: Randomized controlled trial.

Activity score at 2 weeks, and 5 remained in remission at 12 weeks. Levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fecal calprotectin decreased over the measured 12 weeks. Another prospective, uncontrolled study followed 30 Crohnâ&#x20AC;&#x2122;s patients with a Harvey-Bradshaw Index score of >7, indicating severe disease, treated with a single NGT-administered FMT [47]. Twenty-six of the 30 patients were observed to be in clinical remission 1 month after receiving FMT. Furthermore, 30 patients with refractory UC who received endoscopically delivered FMT to the proximal ileum were followed in a recent prospective, uncontrolled study. A colonoscopy was repeated 12 weeks later, and Mayo scores calculated pre and post treatment were compared. A total of 21 patients experienced improved clinical symptoms, and 13 experienced clinical and endoscopic remission [48]. In addition, a recent prospective study assessed 14 patients with steroid-dependent UC who received FMT via NGT administration. Mesalamine was continued in these patients. Eight patients demonstrated clinical improvement and at least temporarily discontinued prednisone. Five of these patients received FMT once, 1 received FMT twice, and the other 2 patients followed a prednisone dose tapering regime in addition to a

second FMT. At 18 months, 4 patients had maintained clinical remission. Microbiota analysis was performed on all patients pre and post FMT. It was noted that the best response was seen among patients whose microbiota appeared to be restructured most similarly to that of the donor FMT [49]. As mentioned above, donor selection appears to be an important factor in inducing remission. Also noted was the great diversity of modes of delivery of FMT in IBD. More research in this area is needed to determine the optimal delivery modality. Functional bowel syndromes Functional bowel syndromes are broadly defined disorders with variably characterized abdominal pain and altered bowel frequencies; the prevalence is estimated to be about 15% [55]. The etiologies of disorders such as irritable bowel syndrome (IBS), are not completely understood, though there is evidence that alterations in gut microbiota may be at least partially responsible for the symptoms. Genomic sequencing studies in patients meeting the Rome III criteria for IBS have demonstrated significantly lower concentrations of Lactobacilli and Bifidobacteria, as well as general increases in Firmicutes,

Heath et al., Fecal Microbiota Transplantation in Gastroenterology

Table 3. Studies involving use of fecal microbiota transplantation and functional bowel disorders Author

Method

Mode of FMT Delivery

Borody et al., 1989 [38] Prospective cohort study Enema 55 Andrews et al., 1995 [63] Prospective cohort study Colonoscopy & enema 45 Hoyeda et al., 2009 [62] Meta-analysis Probiotics 895 Ford et al., 2009 [64] Meta-analysis Various 1921 Tian et al., 2016 [65] Prospective cohort Nasojejunal tube 24

Outcome 36% reported improved symptoms 89% improved symptoms Positive trend with various formulation 70% reported improvement Improvement in number of bowel movements

FMT: Fecal microbiota transplantation.

Lachnospiraceae, and Enterobacteriaceae [56-61]. A 1989 prospective cohort study evaluated 55 patients receiving FMT via enema and 36% achieved resolution of symptoms, 6 patients reported partial relief, and the remaining 60% noted no change in symptoms [38]. As the study did not attempt to exclude existing C. difficile infection nor patients with IBD, it is unclear to what extent FMT alleviated symptoms for patients with properly defined functional bowel disorders. A 2009 metaanalysis of 23 trials utilizing probiotics in patients with established IBS demonstrated a significant improvement in symptoms, prompting further investigation of altering gut microbiome to alleviate IBS symptoms [62]. A 1995 cohort study involving 45 patients with chronic constipation symptoms underwent FMT via colonoscopy and subsequent FMT via enema and 89% reported relief of pain and frequency in defecation [63]. A prospective cohort study conducted the same year evaluated patients with IBS with constipation and found overall improvement in mean bowel movements per week in 24 patients who received FMT via nasojejunal tube (NJT) followed for 12 weeks [64]. A more recent 2016 prospective cohort study followed 24 patients with chronic constipation receiving FMT via NJT for up to 12 weeks and determined that there was an improvement in the mean number of stools per week from 1.8 to 4.3 [65]. A 2017 study of mice receiving FMT from IBS with diarrhea patients demonstrated faster gastrointestinal transit, intestinal barrier dysfunction, innate immune activation, and anxiety-like behavior when compared with controls, suggesting that oneâ&#x20AC;&#x2122;s microbiota may impact bowel habits, as well as suggesting a potential side effect of FMT [66]. Given these observations, FMT appears promising as a potential therapy for functional bowel disorders (Table 3).

Cirrhosis, hyperammonemia, and chronic hepatitis Hyperammonemia and hepatic encephalopathy have long been associated with each other and with a worsening prognosis in cirrhosis. Recent evidence demonstrates FMT may be capable of replacing urease-producing bacteria in human gastrointestinal tracts with a metabolically different population and mitigating the symptoms of altered mentation. It is worth noting early that mammalian genes do not encode for urease; ammonia is a result of metabolism via bacterial urease. Ammonia is then either reabsorbed or excreted fecally [67]. In a 2014 randomized control study, FMT with low urease activity was administered to mice via a bacterial slurry [68]. Significantly reduced fecal ammonia levels were observed in the experimental group after FMT. Also, no urease activity was observed in pellets from mice colonized from the FMT group, a response that was sustained for at least 80 days. Fecal ammonia levels were lower in FMT mice than in control mice treated with a low protein diet alone. After documentation of the above measurements and completion of this arm of the study, hepatic injury was then induced in the same groups using thioacetamide (TAA). The mice that had undergone FMT had lower fecal ammonia levels as well as reduced mortality after infusion of TAA. To assess dose response, lower concentrations of TAA were also introduced in progressively increasing doses over 7 weeks at a point 3 weeks from initial FMT. The mice in the FMT group were observed to have a lower mortality rate during this period, though fibrosis was observed in both arms, suggesting a potential hepatoprotective effect of FMT. A 2015 case report reinforced this conclusion [69]. This case report described a 57-year-old male with cirrhosis secondary to both al-

cohol and the hepatitis C (HCV) virus, decompensated by grade 2 portal systemic encephalopathy. The patient had previously responded to a regimen of lactulose and rifaximin, however, for financial reasons was unable to continue the rifaximin. Consequently, his clinical course declined. Via a universal stool donor, this patient underwent FMT with a reduction observed in serum ammonia levels as well as improved cognition. Analysis of his stool microbial diversity demonstrated shifts in his own microbiota toward that of the donor. This composition shift correlated with improvement in his encephalopathy. Regrettably, 10 weeks after his final FMT, his cognitive status declined to the previously observed encephalopathy. Repeat analysis of his microbiota was not performed at this point. While a suspected shift back toward his original composition was not documented, this case suggests an opportunity for research with a larger number of participants and more frequent observation of shifts in microbial diversity related to FMT over time, and particularly changing the physical exam. In this regard, recent hepatitis B (HBV) research suggests an opportunity for the use of FMT to clear viral hepatitis and consequently avoid later complications such as encephalopathy. Mice aged 6 to 12 weeks and inoculated with HBV did not clear the virus in the youngest group after administration of antibiotics intended to sterilize the GI tract [70]. Mice of equivalent age with mutations rendering them unable to respond to these same antibiotics, however, cleared the virus rapidly. A 2015 prospective cohort trial analyzed 5 patients with chronic HBV and the serum hepatitis B virus e antigen (HBeAg) who received endoscopically administered FMT for a period of up to 7 weeks [71]. The recipients’ microbiota were analyzed after each treatment and became increasingly similar to that of the donor. A reduction in HBeAg titers was noted after each treatment. Two patients achieved clearance after 1 treatment, another achieved clearance after a second treatment. A fifth patient left the trial after the first 4 treatments. Thirteen control patients were included, none of whom demonstrated any change in microbiota composition or reduction of serum HBeAg. Therefore, FMT may function as a potential immunomodulator and may perhaps be used to treat chronic HBV. Further trials are needed to evaluate the potential role of FMT for etiologies of viral hepatitis. Primary sclerosing cholangitis FMT also may be useful for treating primary sclerosing cholangitis (PSC). Chronic cholangitis has been hypoth-

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esized to develop secondary to endotoxin production or secondary to microbial metabolites, progressing in time to clinically evident PSC [72-74]. Consequently, altered microbial diversity or metabolism is hypothesized to produce a pathological cholangiocyte response, resulting in inflammation or apoptosis, and perhaps affecting the cell’s ability to respond appropriately to injury over time [4, 6, 74]. Metabolites, such as lipopolysaccharide, lipoteichoic acid, and various DNA fragments of bacterial organisms have been observed in the bile, cholangiocytes, and portal tracts of patients with cholestatic liver disease [4, 5, 72]. Evaluation of the relative microbiome diversity of patients with PSC, PSC and concomitant IBD, as well as healthy control patients yielded generally complementary results, demonstrating significantly reduced Clostridium strains in patients with PSC [75, 76]. Also observed in patients with PSC who lacked markers for IBD was an overall decreased diversity of microbiota and an increased presence of Lactobacillus, Enterococcus, and Fusobacterium compared with controls [77, 78]. Given this information regarding an altered microbiome in PSC patients, FMT may have a therapeutic role in this disease state. Two publications lay additional groundwork for such a hypothesis. One prospective study documented improved alkaline phosphatase (ALP) levels in PSC patients treated with a low dose of vancomycin, thought to be secondary to subsequent alterations in these patients’ microbiota [74]. There is also a case report of 1 PSC patient who had previously undergone liver transplantation who had an improvement in ALP after administration of vancomycin [80]. While this is a small group of patients from which to draw conclusions, FMT appears to be an alternative means to achieve a shift in fecal microbiota. It has previously been hypothesized that probiotics may be able to play a similar role in PSC, though a variety of studies suggest no consistent and clear consequence of their use, likely secondary to a variety of treatment durations and varying compositions of probiotics [81]. FMT may more easily and directly affect microbiota than probiotics in PSC. A recent clinical trial at Brigham and Women’s Hospital in the USA evaluated the impact of FMT in PSC patients. The study’s primary outcome measures include genotyping and a comparison of recipient microbiota before and after FMT in addition comparison with the donor’s microbiota. Liver chemistry was measured over 3 months, with success defined as a 50% reduction in the levels of ALP, alanine transaminase, aspartate aminotransferase, and total bilirubin. This study concluded in April 2017 [82].

Heath et al., Fecal Microbiota Transplantation in Gastroenterology

Safety considerations in fecal transplantation and thoughts on future application The aforementioned meta-analyses, especially regarding CDI and IBD, do note infrequent cases of flares requiring hospitalization and, in 1 case, colectomy [83, 84]. Given the altered microbiota in various disease states, it is worth noting that FMT donor stool is tested for multiple infectious diseases, including HIV and HCV, as well as screened for recent use of antibiotics, immunosuppressant medication, or the presence of metabolic or malignant disease [29, 83]. In the future, the sequencing of donor stool before transplantation may be considered, as further data are collected demonstrating the “typical” microbiota of previously successful FMTs. A legitimate concern cited by many authors has been inducing systemic infection with the introduction of a foreign microbiome into the GI tract of patients, and particularly immunosuppressed patients [29, 8387]. Based on the previously discussed studies utilizing FMT in patients taking immunosuppressive drugs, such as IBD patients, a potential future use of FMT involves graft versus host disease (GVHD) of the lower GI tract. Given the previously noted dysbiosis associated with GVHD with lower GI tract involvement, 1 observation study of the use of FMT in such cases noted 2 trials of FMT in refractory CDI patients with a history of solid organ transplant who experienced no post-transplantation-related infection, though cases of aspiration were noted [88, 89]. In this study, 3 patients with GI-involved GVHD and dysbiosis demonstrated by fecal genotyping received endoscopic FMT on a weekly basis, and 2 patients demonstrated reconstituted microbiota and improved symptoms at 8 and 9 weeks [85]. The third patient did not achieve remission, though this patient’s microbiota did appear to be briefly reconstituted and there was improvement in diarrhea before relapse. A separate 2016 case series involving 4 patients with steroid-refractory or steroid-dependent gut-involved GVHD also observed clinical remission in 3 of the 4 cases after use of FMT [89]. Cumulatively, while only 7 patients have been reported on, this is yet another disease that appears to be amenable to FMT. A review of the data regarding FMT suggests that earlier application of FMT may potentially lead to more successful interventions. For instance, the aforementioned GVHD cases were all steroid-dependent or refractory cases. Studies involving GVHD at the time of diagnosis may provide more insight on the ability of

FMT to be a successful intervention. Similarly, as discussed earlier, patients with a more recent IBD diagnosis who underwent treatment with FMT appeared to generally have a relatively greater chance of a positive outcome. Regarding the safety profile, known adverse effects of FMT are cramping and nausea [29, 83, 84]. In terms of serious adverse effects, there have been instances of IBD flares reported in patients with IBD and CDI treated with FMT. While these studies document overall improvement in patients’ clinical status following FMT, a minority of patients has experienced this complication. One 2014 retrospective uncontrolled study utilizing endoscopically delivered FMT resulted in an overall cure rate of 89%; however, 5 patients experienced disease flare [88]. Another 2016 cohort study followed 67 IBD patients with CDI, and 2 experienced IBD flare after FMT [90]. One 2016 case report documented what appears to be the first case of flare of extra-intestinal CD manifestations after endoscopically delivered FMT for CDI [91]. It is unclear why IBD patients may be at risk for flares after FMT, although a 2014 case report demonstrated documented bacteremia after FMT, leading to the hypothesis that transient bacteremia may result in altered intestinal permeability resulting in a flare [92]. One 2013 case report documented the case of a UC patient in clinical remission for 20 years who developed a flare of the disease after successful treatment of CDI with FMT [93]. Development of diffuse arthralgia with photographed erythema nodosum, as well as a concurrent increase in ESR and CRP levels, was successfully treated with prednisone. A great deal of heterogeneity is seen regarding the delivery modality of FMT. Given that oral medications are cheaper than endoscopic intervention, it appears sensible that treatment utilizing this mode of delivery has historically been the initial approach. As we have demonstrated in this review, there are oral formulations of FMT which can be used safely in conjunction with the classic firstline treatments for the previously discussed disorders, and possibly augment the effectiveness of those treatments. Furthermore, a direct comparison of the different modes of delivery of FMT has not been performed in a single clinical trial. While oral formulations may be cheaper, it may ultimately be more cost effective to utilize nasoenteral or endoscopically delivered FMT should the initial response to these relatively higher risk modalities be sufficiently greater. Nasoenteric administration is minimally invasive; however, it comes with an increased risk of aspiration and emesis. Endoscopic administration

has the advantages of direct visualization of the GI tract; however, there are the standard risks of sedation and procedural intervention, in addition to the higher cost of performing the procedure. Oral capsules prepared from stool are the least invasive; however, less evidence is available regarding effectiveness. Previously, fresh stool was thought to be necessary for successful transfer, but recent studies demonstrate no loss of efficacy using capsules prepared from frozen stool when compared with those prepared with fresh stool [25, 94, 95]. The relative safety profile of fresh versus frozen FMT oral capsules has not been thoroughly characterized. In any case, standardization of FMT practices will certainly be necessary. As such, the American Gastroenterology Association is creating a national FMT registry, a consortium of case reports and studies with the goals of serving as an efficient and comprehensive database of current research on FMT and providing the ability to discuss areas in which further research is warranted [96]. Ultimately, further investigation regarding the effectiveness and appropriate timing of FMT for the disorders discussed appears not only justified, but promising, as well. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – R.D.H., C.C., R.M., J.A.I., V.T.; Design – R.D.H., C.C., R.M., J.A.I., V.T.; Supervision – R.D.H., C.C., R.M., J.A.I., V.T.; Materials – R.D.H., C.C., R.M., J.A.I., V.T.; Data collection &/or processing – R.D.H., C.C., R.M., J.A.I., V.T.; Analysis and/or interpretation – R.D.H., C.C., R.M., J.A.I., V.T.; Writing – R.D.H., C.C., R.M., J.A.I., V.T.; Critical review – R.D.H., C.C., R.M., J.A.I., V.T.

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