Romjoh 2 (1) 2014

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Jurnal dedicat rezidenților, specialiȘtilor și cercetătorilor din domeniul oncologiei, hematologiei, medicinei paliative și terapiei durerii

O n c o l o g y & H e m at o l o g y

R o m a n i a n

Revistă publicată sub egida

Rolul comisiei de tumor board în chirurgia oncologică

www.romjoh.com

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O n c o l o g y & H e m at o l o g y Nr. 1/ Vol. II/ 2014 Revistă publicată sub egida Societatea națională de oncologie medicală din românia; societatea română de hematologie; asociația română pentru studiul durerii; Societatea Română de Cancer “Vasile Păcurar”

Chief Editor Dr. Valentin Rădoi

Senior Editors Prof. Dr. Florin Bădulescu (Universitatea de Medicină şi Farmacie Craiova, Craiova, România) Prof. Dr. Anca Roxana Lupu (Universitatea de Medicină şi Farmacie "Carol Davila", Bucureşti, România) Şef Lucrări Dr. Lucia Stănculeanu (Universitatea de Medicină şi Farmacie "Carol Davila", Bucureşti, România) Şef Lucrări Dr. Simona Mihuţiu (Universitatea de Medicină şi Farmacie Oradea, Oradea, România) Cerc. St. Gr. I. Dr. Grigorescu Alexandru (Institutul oncologic Prof. Dr. Alexandru Trestiorean, Bucureşti, România)

Romanian Editorial Board Prof. Dr. Oltean Galafteon (Universitatea of Medicină şi Farmacie Târgu Mureș, Târgu Mureș, România) Prof. Dr. Ljubomir Petrov (Universitatea of Medicină şi Farmacie „Iuliu Haţieganu”, Cluj-Napoca, România) Prof. Dr. Ioniță Hortensia (Universitatea of Medicină şi Farmacie "Victor Babeș" , Timișoara, România) Prof. Dr. Cătălina Poiană (Universitatea of Medicină şi Farmacie "Carol Davila", Bucureşti, România) Conf. Dr. Monica Dragomir (Universitatea of Medicină şi Farmacie "Carol Davila", Bucureşti, România) Conf. Dr. Coriu Daniel (Universitatea of Medicină şi Farmacie "Carol Davila", Bucureşti, România) Conf. Dr. Anca Coliță (Universitatea of Medicină şi Farmacie "Carol Davila", Bucureşti, România) Conf. Dr. Horia Bumbea (Universitatea of Medicină şi Farmacie "Carol Davila", București, România) Conf. Dr. Elena Copaciu (Universitatea of Medicină şi Farmacie “Carol Davila”, București, România) Șef Lucrări Dr. Laura Mazilu (Facultatea de Medicină, Universitatea Ovidius, Constanţa, România) Șef Lucrări Dr. Coliță Andrei (Universitatea of Medicină şi Farmacie "Carol Davila", Bucureşti, România) Şef Lucrări Dr. Cristian Silviu Voinea (Universitatea of Medicină şi Farmacie "Carol Davila", Bucureşti, România) Asist. Univ. Mircea O. D. Lupusoru (University of Medicine and Pharmacy “Carol Davila”; Director Medical - Spitalul de Psihiatrie Titan “Dr. C-tin Gorgos”) Asist. Univ. Gabriela Elena Lupusoru (University of Medicine and Pharmacy “Carol Davila”) Asist. Univ. Dr. Carsote Mara-Laura (Universitatea of Medicină şi Farmacie "Carol Davila", Bucureşti, România) Asist. Univ. Dr. Victor Gabriel Clătici (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România Asist. Univ. Dr. Trandafir Maria Silvia (Universitatea of Medicină şi Farmacie "Carol Davila", Bucureşti, România) Asist. Univ. Dr. Ioana Soare (Universitatea Titu Maiorescu, Facultatea de Medicină, București, România) Dr. Adrian Udrea (Medisprof, Cluj-Napoca, România) Dr. Radu Niculescu (Institutul Clinic Fundeni, Bucureşti, România) Dr. Ana Maria Boeru (Asociaţia Free of Pain, Bucureşti, România) Dr. Anca Coliţă (Institutul Clinic Fundeni, Bucureşti, România) Dr. Virgil Dincă (Asociația Română pentru Studiul Durerii, Bucureşti, România)

International Editorial Board Prof. Dr. med. Anca-L. Grosu (Klinik für Strahlenheilkunde, Universität Freiburg, Freiburg, Germany) Prof. Dr. Shibo Li (University of Oklahoma Health Sciences Center, Oklahoma City, USA) Prof. Dr. Mariusz Z. Ratajczak (University of Louisville, Louisville, USA) Prof. Dr. Arnold Ganser (Hannover Medical School, Hanover, Germany) Prof. Dr. Saverio Bettuzzi (University of Parma Via Volturno, Parma, Italy) Prof. Dr. Lodovico Balducci (Moffitt Cancer Center, Tampa, USA) Prof. Dr. Leonard Wartofsky (Georgetown University School of Medicine, Washington, USA) Prof. Dr. Robert Amato (Memorial Hermann Cancer Center, Texas, USA) Prof Dr. Kevin R. Loughlin (Harvard University, Cambridge, USA) Prof. Dr. Maureen Markman (Drexel University College of Medicine, Philadelphia, USA) Prof. Dr. Stephen P. Hunger (University of Colorado School of Medicine, Colorado, USA) Prof. Dr. M.W.M. van den Brekel (Academic Medical Center Amsterdam, Amsterdam, Netherlands) Prof. Dr. M Sitki Copur (University of Nebraska Medical Center, Nebraska, USA) Prof. Dr. Derek Raghavan (UNC School of Medicine, Levine Cancer Institute, Charlotte, NC, USA) Prof. Dr. Richard J. Ablin (University of Arizona, Arizona, USA) Prof. Dr. Florian Strasser (Cantonal Hospital St. Gallen, Switzerland) Prof. Dr. Michel Rigaud (Scientific advisor - IRST, Meldola, Italy) Associate Prof. Dr. Mishu Popa McKiver (Massachusetts General Hospital, Massachusetts, USA) Assistant Prof. Dr. Alina Mihai (Univ Pittsburgh School Medicine, Pittsburgh, USA) Assistant Prof. Dr. Doru Paul (Hofstra North Shore-LIJ School of Medicine, New York, USA) Assistant Prof. Dr. Bruno Vincenzi (University Campus Bio-Medico, Rome, Italy Assistant Prof. Dr. Elizabeta C. Popa (Weill Cornell Medical College, NY, USA) Assistant Prof. Dr. Gabriela Oprea (Emory University, Atlanta, USA) Dr. Wainer Zoli (Director of the Bioscience Laboratory, IRST, Meldola, Italy) Dr. Ciprian Enachescu (Centre Hospitalier Lyon Sud, Lyon, France) Dr. Javier Martín Broto (Son Espases Hospital, Palma de Mallorca Spain) Dr. David Gómez Almaguer (Universidad Autónoma de Nuevo León, Monterrey, México)

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Tipar executat la:

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Editorial

2014: A look behind but also a look ahead [ro] Radoi V.

Current First Remission Consolidation Options For Follicular Lymphoma: Are We There Yet? [en] Popa M.A., Amy M., McCord A.M., Moran J., Quintero J., Carlos F., Santos C.F.

The Devilish Cycle of the Cancer: Circulating Tumor Cells and Epithelial Mesenchymal Transition as Actors [en] Barriere G., Zoli W., Rigaud M.

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News

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Calendar Scientific Events [en]

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Case Presentations Dasatinib-Associated Transient Peripheral Blood Appearance of a Clonal Large Granular Lymphocytic Population in a Philadelphia-Positive Acute Lymphoblastic Leukemia Patient: A Case Report [en] Ghiuzeli C.M.

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Editor's Choice Selection [en]

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Instructions for Authors

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2014: O privire înapoi, dar şi înainte [ro]

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Opțiuni actuale de consolidare a primei remisiuni în limfomul folicular: Ne apropiem de terapia ideală [en]

Rădoi V.

Popa M.A., Amy M., McCord A.M., Moran J., Quintero J., Carlos F., Santos C.F.

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Ciclul diabolic al cancerului: celule tumorale circulante si tranziţia epitelial mezenchimală [en]

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Noutăți

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Evenimente

Barriere G., Zoli W., Rigaud M.

Manifestări ştiinţifice [en]

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Prezentări de Caz Apariția temporară în sânge , asociată cu Dasatinib, a unei populații clonale de limfocite mari granulare la un pacient cu leucemie acută limfoblastică Filadelfia-pozitivă [en] Ghiuzeli C.M.

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Alegerea Editorului din Literatură Selecţie [en]

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Instrucţiuni pentru autori

Editorial

2014: A look behind but also a look ahead

2014: A look behind but also a look ahead 2014: O privire înapoi, dar şi înainte Valentin Rădoi Editor-in-Chief Romanian Journal of Oncology and Hematology; University of Medicine and Pharmacy “Carol Davila” Coresponding author: Valentin Rădoi Email: valentin.radoi@mediasyscom.ro

Întotdeauna este util ca la sfârşitul unei perioade determinate de timp, fie aceasta un an sau un deceniu, să privim în urmă la ce s-a realizat şi înainte la ce ar mai fi necesar. Putem considera acest proces ca fiind asemănător unui studiu clinic care s-a terminat şi este nevoie să vedem şi să înțelegem rezultatele, dar şi să le putem stabili pe cele pentru perioada viitoare.

Conform revistei Science, cea mai mare realizarea în domeniul oncologiei, dar şi a științei în general, din 2013, este imunoterapia în cancer. Aceasta a fost dezvoltată de-a lungul mai multor decenii, folosind propriul sistem imun al corpului în lupta împotriva cancerului (1,2). În 2014, conform aceleiaşi reviste, genomul întreg al pacienţilor va fi cerut din ce în ce mai mult de către clinicieni cu scopul de a “identifica tratamente pentru cancer” printre altele. Totodată, unul dintre cele mai citate articole din domeniul oncologiei din 2013, conform Web of Science, descrie caracterizarea geonomică integrată a carcinoamelor endometriale, rezultatele putând duce la o reclasificare care va influenţa tratamentul adjuvant post-chirurgie (3). Important este şi programul Marii Britanii de a secvenţia genomurile a 100.000 de pacienţi pe parcursul următorilor 4 ani (4).

Printre tratamentele descrise în cele mai citate studii clinice din baza Thompson Reuters se numără şi procarbazina, lumustina şi vincristina adjuvantă în tumorile

Cite this article: Radoi V., 2014: A look behind but also a look ahead. Rom J Oncol Hematol. 2014; 2(1):6-7

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oligodendrogliale anaplastice (5), cabozantinib în cancerul de prostată avansat (6), crizotinib în cancerul pulmonar ALK-pozitiv (7), ibrutinib (PCI-32765) în limfomul de tip B refractar/recidivat (8) şi trametinib în melanomul metastatic BRAF-mutant (9). În privinţa incidenţei şi prevalenţei cancerului în 2013 datele publicate până la ora actuală estimează 854.790 de noi tumori la bărbaţi în 2013 şi 805.500 la femei în SUA. Pe primul loc la bărbaţi se află cancerul de prostată, urmat de cancerul pulmonar şi de cancerul de colon şi de rect, iar la femei pe primul loc se află cancerul mamar urmat de cancerul pulmonar şi de cancerul de colon şi de rect (Fig. 1) (10).

Mortalitatea determinată de cancer în SUA este estimată la 306.920 de decese la bărbaţi şi 273.430 la femei. Pe primul loc la ambele sexe se află cancerul pulmonar, urmat de cancerul de prostată la bărbaţi şi cel mamar la femei (Fig. 2) (11). O listă detaliată a incidenţei şi mortalităţii din SUA este disponibilă în referinţă (12).

International Agency for Research and Cancer (IARC) a publicat la sfârşitul lui 2013 datele privind incidenţa, prevalenţa şi mortalitatea la nivel global în 2012. Numărul de noi cazuri de cancer a crescut de la 12.7 milioane la 14.1 milioane, iar mortalitatea a crescut de la 7.6 milioane la 8.2 milioane (date pentru 2008; respectiv 2012). Cancerul mamar a prezentat o creştere cu peste 20% a incidenţei, dar şi o scădere

Figure 1. Incidenţa

estimată a cazurilor de cancer în 2013 în SUA. Adaptat după (10)

Radoi V.

Figure 2. Numărul de

decese provocate de cancer în 2013 în SUA. Adaptat după (11)

Figure 3. Mortalitatea

în urma cancerului mamar la femei în România. Adaptat după (14)

cu 14% a mortalităţii. Totuşi, aceasta rămâne cea mai mare cauză a decesului la femei (13). În ceea ce priveşte situaţia din România, voi prezenta doar datele furnizate de IARC pentru cancerul mamar: cea mai mare mortalitate a fost atinsă în 2005 (16.49 decese la 100.000 de femei), în 2010 mortalitatea scăzând la 15.03 decese la 100.000 de femei (Fig. 3) (14). Pentru celelalte tipuri de cancer, dar şi pentru alţi parametri poate fi accesată referinţa (14).

Ţinând cont de toate aceste realizări în domeniul oncologiei şi hematologiei, dar şi de importanţa noilor tratamente, scopul Romanian Journal of Oncology şi Hematology în 2014 va fi, în continuare, prezentarea celor mai importante aspecte ale celor două domenii prin articole originale, articole de sinteză (reviewuri) şi prezentări de caz.

Conflicts of Interest/Conflict de Interese: none/ nici unul

Bibliografie 1. Mcnutt M. Cancer Immunotherapy. Science 2013; 342: 1417.

2. Fedorov VD, Themeli M, Sadelain M. PD-1– and CTLA-4–Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses. Sci. Transl. Med 2013; 5:215ra172.

3. Getz G, Gabriel SB, Cibulskis K, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 7447 (497):67-73.

4. Areas to Watch in 2014. Science 2013; 342:1443.

5. van der Bent MJ, Brandes AA, Taphoorn MJB, et al. Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Newly Diagnosed Anaplastic Oligodendroglioma: LongTerm Follow-Up of EORTC Brain Tumor Group Study 26951. Journal of Clinical Oncology 2013; 3(31):344-350.

6. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial. Journal of Clinical Oncology 2013; 4(31):412-419.

7. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus Chemotherapy in Advanced ALKPositive Lung Cancer. New England Journal of Medicine 2013; 25(368):2385-2394.

8. Advani RH, Buggy JJ, Sharman JP, et al. Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies.

Journal of Clinical Oncology 2013; 1(31):88-94.

9. Kim KB, Kefford R, Pavlick AC, et al. Phase II Study of the MEK1/MEK2 Inhibitor Trametinib in Patients With Metastatic BRAF-Mutant Cutaneous Melanoma Previously Treated With or Without a BRAF Inhibitor. Journal of Clinical Oncology 2013; 4(31):482-489.

10. American Cancer Society. Surveillance Research. [Internet] 2013 [cited on 27 February 2014]. Available online from: http://www.cancer.org/acs/groups/content/@ epidemiologysurveilance/documents/document/acspc-037114.pdf 11. American Cancer Society. Surveillance Research. [Internet] 2013 [cited on 27 February 2014]. Available online from: http://www.cancer.org/acs/groups/content/@ epidemiologysurveilance/documents/document/acspc-037115.pdf 12. Siegel R, Naishadham D, Jemal A. Cancer Statistics 2013. Ca:A Cancer Journal for Clinicians; 2013. 1(63):11-30.

13. International Agency for Research and Cancer. Latest world cancer statistics. Global cancer burden rises to 14.1 million new cases in 2012: Marked increase in breast cancers must be addressed [Internet] 2013 [Cited on 27 February 2014]. Available online from: http://www.iarc.fr/en/media-centre/pr/2013/pdfs/pr223_E.pdf 14. Breast cancer death rates, per 100,000 women [Internet] 2014 [Cited on 27 February 2014]. Available online from: http://humanprogress.org/f1/breast-cancer-death-rateswomen/1950/2010/Romania

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Editorial

Current First Remission Consolidation Options For Follicular Lymphoma: Are We There Yet?

Current First Remission Consolidation Options For Follicular Lymphoma: Are We There Yet? Opțiuni actuale de consolidare a primei remisiuni În limfomul folicular: Ne apropiem de terapia ideală Mihaela A. Popa1, Amy M. McCord1, Josue Moran1,2, Jerome Quintero1, Carlos F. Santos1 1. Biovest International Inc., 8500 Evergreen Blvd. NW, Minneapolis, MN, 44533, USA 2. Emory University, 201 Dowman Dr., Atlanta, GA, 30322, USA Coresponding author: Mihaela A. Popa Email: mmckiver@biovest.com

Follicular lymphoma (FL), an indolent B-cell lymphoma, is the most frequent subtype of nodal lymphoid malignancies in Western Europe (1). Of the 73,700 non-Hodgkin’s lymphomas (NHLs) patients in the European Union (EU) in 2008 (2), about 20% represented FL patients (3). The disease burden posed by FL has increased steadily during the past decades, as reflected by the raise in incidence rate from 2-3/100,000 during the 1950’s to 5-7/100,000 currently (1). Concurrently, the median overall survival of FL patients has increased steadily with the introduction of more potent therapies, most notably the anti-CD20 monoclonal antibody, rituximab (4), (5). Recent figures from the Survival, Epidemiology and End Results (SEER) program indicate a 5-year relative survival rate of 85.4% (%95CI: 84.6- 86.2) in adCite this article: vanced stage FL patients (6). Despite its high Popa M.A., McCord A.M., responsiveness to first line therapies, FL reMoran J., Quintero J., mains characterized by multiple relapses and Santos C.F., Current First Remission Consolidation progressively shorter remissions with evenOptions For Follicular tual development of resistance to subsequent Lymphoma: Are We There therapies and ultimate treatment failure in the Yet?. Rom J Oncol Hematol. later stages of disease.

2014; 2(1):8-11

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Individualized treatment planning for FL is essential and depends on the characteristics of both the patient (e.g., age, symptoms, comorbidity, preservation of future therapy options) and the disease (e.g., stage, FL international prognostic index [FLIPI] risk group, sites of involvement, prior therapy, duration of benefit from prior therapy). Current rituximabchemotherapy first line induction therapies are highly effective in reducing tumour burden in advanced-stage FL patients (7),(8), (9) and responding patients can receive subsequent consolidation therapy aiming to eradicate residual cancer cells with the ultimate goal of curing the patient.

An ideal consolidation therapy agent should be extremely safe, improve the duration of remission, not impede the efficacy of future therapies in cases in which these therapies become warranted, and be complementary to induction therapy to effectively eradicate residual cancer cells that are likely to be resistant to the agents used in induction therapy. Given the median age at diagnosis of FL patients of 60-65 years old (10), the projected ageing of the population in the Western world that will likely

Mihaela A. Popa, Amy M. McCord, Josue Moran, Jerome Quintero, Carlos F. Santos

render FL a morbidity burden of the elderly, the essentially symptom-free status of FL patients in first remission, and the quasi-chronic disease status of FL, developing nontoxic therapeutic approaches to extend remission remains highly desirable. The consolidation options authorized in the EU (i.e., rituximab maintenance, radioimmunotherapy, and interferon alpha-2b) demonstrate clinical benefit but pose substantial safety risks and show no plateau in survival (8), (11), (12), (13), (14) . The current focus, therefore, necessarily shifts to improving the safety in addition to the efficacy of remission consolidation therapies in order to extend the quality besides the duration of remissions.

In current clinical practice, about 50% of the FL patients who respond to first-line induction therapy receive no consolidation therapy, and the remainders receive mostly rituximab maintenance (15). However, rituximab is not an ideal agent for consolidation therapy because it is used during induction therapy. Conceivably, one potential mechanism of action by which maintenance rituximab prolongs the remission duration may be by reinducing remission in patients with subclinical relapses rather than by eradicating residual tumour cells after induction therapy. Moreover, the development of nearly universal rituximab resistance (16), (17), (18), (19) suggests that resistant cells present in the original tumor persist and cause progressive (rituximabresistant) disease (20). Therefore, agents used for consolidation therapy should ideally be different from those used in induction therapy and should have a different mechanism of action because residual tumour cells may be resistant to these agents. The prolonged nature of the rituximab maintenance also imposes unique tolerability challenges, specifically a substantial risk for both low-grade and high-grade infections and/ or viral reactivations (8). Therefore, a high unmet need remains for additional therapeutic options which can provide significant clinical benefit with a greatly improved safety profile, and which could therefore balance the benefit/risk ratio associated with the currently available agents.

A novel autologous, active immunotherapeutic, dasiprotimut-T, addresses this unmet medical need by offering FL patients a nearly toxicityfree, highly effective and durable consolidation therapy option (21), (22).

The variable regions of the B-cell receptor (BCR) immunoglobulin (Ig) heavy and light chains combine to form the unique antigen recognition site of antibodies and contain determinants, called idiotypes, that can themselves be recognized as antigens. The idiotypic determinants of the immunoglobulin synthesized by a clonal B-cell cancer, such as FL,

are unique and can thus serve as tumor specific antigens (28), as initially demonstrated in mice (29).

The BCR, composed of the cell distinct surface Ig and associated Igι/Igβ components, regulates a critical and wide-ranging cell signaling pathway critical for cell survival, tolerance, apoptosis, proliferation, and differentiation of the B-cell into antibody producing cells or memory B-cells.

The BCR forms an integral component of a B-cell life cycle, allowing it to interact with antigens via highly conserved structural domains and unique hypervariable regions arising from somatic hypermutation as part of the B-cell maturation in the early stages of immune cell development.

These hypervariable regions arise from a nearly random selection of Variable (V), Diversity (D) and Joining (J) genes and render B-cells with an antigen-recognition diversity of enormous potential.

B-cell malignancies are composed of clonal proliferations of cells synthesizing a single antibody molecule with unique variable regions in the heavy and light chains. Therefore, the idiotypic determinants of the surface Ig of a B-cell lymphoma can serve as a tumor specific marker for the malignant clone for immunotherapeutic development purposes. The tumor specificity of the idiotype allows triggering of an immune response that spares healthy B-cells and other cells which lack the unique BCR of the lymphoma. Therefore, not only would an active immunotherapeutic specifically target tumor cells, but would also target a receptor critical to the tumor cells survival. Moreover, a considerable amount of clinical and in vitro evidence suggests that FL is particularly sensitive to immunotherapy. The high spontaneous remissions rates observed in FL patients (23), (24) , the graft-versus-lymphoma effect postallogeneic stem cell transplant demonstrated in several lymphomas (25), the correlation between survival and the gene expression signature of tumor infiltrating non-malignant immune cells (26) , the intrinsic potential of FL tumor-infiltrating TH-cells to elicit cellular immune responses when tumor-associated immune suppression is attenuated (27), and the high response rates to anti-CD20 therapies together support this proposition.

DasiprotimutT is an autologous lymphomaderived Ig idiotype-KLH [keyhole limpet haemocyanin] conjugate active immunotherapy product designed to stimulate an immune response based on specific recognition of the tumor specific antigen, the Id, which leads to tumor cell lysis and elimination of residual FL cells. This patient-specific protein active immunotherapy product is produced by heterohybridoma rescue fusion, where the Martie 2014

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Editorial

Current First Remission Consolidation Options For Follicular Lymphoma: Are We There Yet?

patient’s lymphoma cells are fused to a mouse heteromyeloma cell in order to produce the tumorspecific Ig idiotype protein. The outcome of this process is the high fidelity, fully humanized idiotype protein suitable for immunization, which is conjugated to the highly immunogenic carrier protein KLH and administered with granulocyte macrophage colony-stimulating factor (GMCSF) as a vaccine adjuvant in FL patients in first complete remission.

Clinical studies to date demonstrated that dasiprotimut-T comprises all the elements delineating an ideal consolidation therapy (30), (31), (32), (33), (34), (21) . From a clinical outcomes standpoint, dasiprotimut-T improves remission duration and is highly safe and well tolerated.

In a phase 3 randomized, double-blinded, controlled trial dasiprotimut-T demonstrated a similar reduction in the risk of relapse (HR = 0.58; 95%CI: 0.370, 0.960) to that of rituximab maintenance (HR = 0.57; 95% CI: 0.44, 0.74(8)). Safety data collected over 19 years indicate that the most common treatment emergent, vaccine related adverse events were injection site reactions. Serious adverse events were very uncommon and there were no vaccine related deaths. Most importantly, as an active immunotherapy selectively targeting malignant cells, dasiprotimut-T does not induce immunosuppression and spares patients from the consequences of extended immunosuppression or myelotoxic radiation exposure associated with the use of current consolidation regimens (8), (11), (35) .

From an immunogenicity standpoint, dasiprotimutT induces nearly universal durable and persistent memory CD4+ and CD8+ T-cell responses to the vaccine antigen, which lead to tumor lysis and elimination (30), (31), (32), (33), (34).

Moreover, because severe circulating B-cell depletion post-rituximab therapy appears not to impair T-cell priming (36), (37) and memory B-cells may persist in lymphatic tissues and contribute to priming of T-cells (38), (39), dasiprotimutT induces effective tumorspecific T-cell responses even post-rituximab induction therapy (40). Therefore, dasiprotimutT is complementary to current induction regimens, and can effectively eradicate residual cancer cells that are likely to be resistant to the agents used in induction therapy. Lastly, its immunostimulatory rather than immunosuppressive mechanism of action does not hinder the efficacy of future therapies.

To date, there are no new potential consolidation therapy candidates for first line remission in FL, despite of a large array of promising immunotherapy strategies (e.g., PD-1 inhibitors and other immune checkpoint inhibitors) or targeted strategies (e.g., signaling pathways inhibitors, proteasome inhibitors) being investigated as induction therapy options.

Ongoing trials are attempting to establish the ideal rituximab maintenance schedule and duration, or are investigating the combination between rituximab maintenance and radioimmunotherapy consolidation. While these efforts will unquestionably enhance the clinical outcomes of these existing regimens, it is unlikely they will provide solutions to the most persistent shortcomings of prolonged anti-CD20 monoclonal antibody therapy: protracted B-cell depletion and refractoriness development.

Dasiprotimut-T has the potential to change the risk/benefit ratio of first line consolidation therapies for FL from the currently acceptable to desirable, and herald a new therapeutic paradigm in FL.

Bibliography 1. Dreyling M, Ghielmini M, Marcus R, Salles G, Vitolo U. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22 Suppl 6:vi59-vi63.

2. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46(4):765-81.

3. Sant M, Allemani C, De Angelis R, Carbone A, de Sanjose S, Gianni AM, et al. Influence of morphology on survival for non-Hodgkin lymphoma in Europe and the United States. Eur J Cancer. 2008;44(4):579-87.

4. Fisher RI, LeBlanc M, Press OW, Maloney DG, Unger JM, Miller TP. New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol. 2005;23(33):8447-52.

5. Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M, et al.

Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2006;24(10):1582-9.

6. Howlader N NA, Krapcho M, Garshell J, Neyman N, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). . SEER Cancer Statistics Review, 1975-2010 National Cancer Institute. Bethesda, MD2013 [cited 2013].

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7. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106(12):3725-32.

8. Salles GA, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377(9759):42-51.

9. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet.

2013.

10. Rohatiner AZ, Lister TA. The clinical course of follicular lymphoma. Best Pract Res Cl Ha. 2005;18(1):1-10.

11. Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H,

Mihaela A. Popa, Amy M. McCord, Josue Moran, Jerome Quintero, Carlos F. Santos et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26(32):5156-64.

12. Baldo P, Rupolo M, Compagnoni A, Lazzarini R, Bearz A, Cannizzaro R, et al. Interferon-alpha for maintenance of follicular lymphoma. Cochrane Database of Systematic Reviews 2010(1).

13. Witzig TE. Safety of Yttrium-90 Ibritumomab Tiuxetan Radioimmunotherapy for Relapsed Low-Grade, Follicular, or Transformed Non-Hodgkin’s Lymphoma. J Clin Oncol. 2003;21(7):1263-70.

14. van Oers MH, Kersten MJ. Treatment strategies in advanced stage follicular lymphoma. Best practice \& research Clinical haematology.

2011;24(2):187-201.

15. Flowers C, Taylor M, Hirata J, Dillon HH, Zelenetz AD, Hainsworth JD, et al. Use of maintenance rituximab (R) in the United States following R-based induction for follicular lymphoma (FL). J Clin Oncol. 2010;28:15s:Abs. No. 8100.

16. Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, Czuczman MS, Link BK, et al. Rituximab anti-CD20 monoclonal antibody therapy in nonHodgkin’s lymphoma: safety and efficacy of re-treatment. J Clin Oncol.

2000;18(17):3135-43.

17. McLaughlin P, Grillo-Lopez AJ, Link B. Rituximab chimeric anitCD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol.

1998;16(8):2825-33.

18. Rezvani AR, Maloney DG. Rituximab resistance. Best Pract Res Cl Ha. 2011;24(2):203-16.

19. Witzig TE, Vukov AM, Habermann TM, Geyer S, Kurtin PJ, Friedenberg WR, et al. Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin’s lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol.

2005;23(6):1103-8.

20. van Meerten T, Hagenbeek A. Novel antibodies against follicular nonHodgkin’s lymphoma. Best Pract Res Cl Ha. 2011;24(2):231-56.

21. Schuster SJ, Neelapu SS, Gause BL, Janik JE, Muggia FM, Gockerman JP, et al. Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma. J Clin Oncol. 2011;29(20):2787-94.

22. Schuster SJ, Neelapu SS, Santos CF, Popa-McKiver MA, McCord AM, Kwak LW. Idiotype vaccination as consolidation therapy: time for integration into standard of care for follicular lymphoma? J Clin Oncol.

2011;29(36):4845-6.

23. Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003;362(9383):516-22.

24. Horning SJ, Rosenberg SA. The natural history of initially untreated lowgrade non-Hodgkin’s lymphomas. New Engl J Med. 1984;311(23):1471-5.

25. Thomson KJ, Mackinnon S. Role of allogeneic transplantation in lowgrade lymphoma and chronic lymphocytic leukemia. Curr Opin Hematol.

2006;13(4):273-9.

26. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, et al.

Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. New Eng J Med. 2004;351(21):2159-69.

27. Hilchey SP, Rosenberg AF, Hyrien O, Secor-Socha S, Cochran MR, Brady MT, et al. Follicular lymphoma tumor-infiltrating T-helper (TH) cells have the same polyfunctional potential as normal nodal TH cells despite skewed differentiation. Blood. 2011;118(13):3591-602.

28. Stevenson GT, Stevenson FK. Antibody to a molecularly-defined antigen confined to a tumour cell surface. Nature. 1975;254(5502):714-6.

29. Lynch RG, Graff RJ, Sirisinha S, Simms ES, Eisen HN. Myeloma proteins as tumor-specific transplantation antigens. P Natl Acad Sci USA. 1972;69(6):1540-4.

30. Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R. Introduction of Immune Respones in Patients with B-Cell Lymphoma Against the Surface-Immunoglobulin Idiotype Expressed by Their Tumors. New Engl J Med. 1992;327(17):1209-15.

31. Nelson EL, Li X, Hsu FJ, Kwak LW, Levy R, Clayberger C, et al. Tumorspecific, cytotoxic T-lymphocyte response after idiotype vaccination for B-cell, non-Hodgkin’s lymphoma. Blood. 1996;88(2):580-9.

32. Hsu FJ, Caspar CB, Czerwinski D, Kwak LW, Liles TM, Syrengelas A, et al.

Tumor-Specific Idiotype Vaccines in the Treatment of Patients With B-Cell Lymphoma---Long-Term Results of a Clinical Trial. Blood. 1997;89(9):312935.

33. Bendandi M, Gocke CD, Kobrin CB, Benko FA, Sternas LA, Pennington R, et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med. 1999;5(10):1171-7.

34. Neelapu SS, Gause BL, Nikcevich DA, Schuster SJ, Winter J, Gockerman JP, et al. Phase III randomized trial of patient-specific vaccination for previously untreated patients with follicular lymphoma in first complete remission: protocol summary and interim report. Clin Lymphoma. 2005;6(1):61-4.

35. Hagenbeek A, Radford JA, Van Hoof A, Vitolo U, Rohatiner AZ, Salles G, et al., editors. 90Y-Ibritumomab Tiuxetan (Zevalin) Consolidation of First Remission In Advanced-Stage Follicular Non-Hodgkin’s Lymphoma: Updated Results After a Median Follow-up of 66.2 Months From the International, Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients. American Society of Hematology Annual Meeting; 2010; Orlando, FL: Blood.

36. Qin Z, Richter G, Schuler T, Ibe S, Cao X, Blankenstein T. B cells inhibit induction of T cell-dependent tumor immunity. Nat Med. 1998;4(5):627-30.

37. Gajewski TF, Pinnas M, Wong T, Fitch FW. Murine Th1 and Th2 Clones Proliferate Optimally in Response to Distinct Antigen-Presenting Cell Populations. J Immunol. 1991;146(No.6):1750-8.

38. Schröder C, Azimzadeh AM, Wu G, Price JO, Atkinson JB, Pierson RN. Anti-CD20 treatment depletes B-cells in blood and lymphatic tissue of cynomolgus monkeys. Transpl Immunol. 2003;12(1):19-28.

39. Kneitz C. Effective B Cell Depletion with Rituximab in the Treatment of Autoimmune Diseases. Immunobiology. 2002;206(5):519-27.

40. Neelapu SS, Kwak LW, Kobrin CB, Reynolds CW, Janik JE, Dunleavy K, et al. Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma. Nat Med. 2005;11(9):986-91.

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Editorial

The Devilish Cycle of the Cancer: Circulating Tumor Cells and Epithelial Mesenchymal Transition as Actors

The Devilish Cycle of the Cancer: Circulating Tumor Cells and Epithelial Mesenchymal Transition as Actors Ciclul Diabolic al Cancerului: Celule Tumorale Circulante Și Tranziţia Epitelial-Mezenchimală Guislaine Barriere, Wainer Zoli, Michel Rigaud IRCCS - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Coresponding author: Michel Rigaud michel.rigaud@yahoo.fr

Keywords: EMT, Circulating Tumor Cells, Mesenchymal cells, Cancer stem cells, Metastasis

Cite this article: Barriere G, Zoli W, Rigaud M, The Devilish Cycle of the Cancer: Circulating Tumor Cells and Epithelial Mesenchymal Transition as Actors. Rom J Oncol Hematol. 2014; 2(1):12-14

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Breast cancer remains one of the major causes of death in women worldwide. This cancer related death arises from tumor metastasis to secondary sites. A critical event for cancer metastasis to occur is that a subpopulation of malignant cells (tumor initiating cells) has to acquire the ability to migrate and to invade a metastatic niche via blood. Such a role can be assigned at least to some circulating tumor cell (CTC) subpopulations. Epithelial mesenchymal transition (EMT) supports the mobilization of primary tumor cells which get involved with tumor progression.

EMT is a normal and reversible process which is implicated in embryological steps like gastrulation, organogenesis of heart, musculoskeletal system and the peripheral nervous system. More recently, its role in diseased states was delineated, particularly during primary tumor metastasis (1). However, the two types are not superimposed. Not all steps described in developmental EMT are necessary for the invasive phenotype to be established and a partial EMT is sufficient to give rise to initiating tumor cells at least in breast carcinoma. One way to fight cancer would be to find therapeutic agents that can reverse EMT or eliminate mesenchymal and stem cancer cells from the blood.

Before addressing CTC, we shall consider events that support cancer EMT. Transforming

growth factor β (TGFβ) is an essential EMT inducer. When TGFβ binds to its receptors, activation of kinase functions leads to phosphorylation of smad-2 and 3 which form a complex with smad-4 translocated from the cytoplasm to the nucleus.

The latter interacts with gene expression activators and repressors. TGFβ regulates EMT genes through smad pathway (2). EMT converts polarized epithelial cells with cobblestone structure to individual, motile spindle cells (3). The transition leads to reduction of cell-cell contacts, (adherens junctions) transcriptional repression of Ecadherin expression, degradation of cell-matrix adhesions, and rearrangement of the actin cytoskeleton. Lack of E-cadherin expression is one of the defining features of invasive mesenchymal cancer cells. Decreased E-cadherin expression is often associated with inappropriate expression of N-cadherin (4).

The reality seems more complex as partial EMT leads to an intermediate phenotype, where some characteristics of epithelium are retained, but features of mesenchymal cells also appear (5).

In fact this concept is corroborated by detection in cancer patient blood of the CTC subpopulations with mixed characteristics (6). Moreover, in a model of an EMT decision network -(miR-34/ SNAIL) coupled with (miR-200/ZEB)-, Lu et al. explained the existence of a partial EMT state or

Guislaine Barriere, Wainer Zoli, Michel Rigaud

Figure 1. Devilish cycle of cancer and EMT hybrid epithelial/mesenchymal phenotype (7).

They showed that the (miR-200/ZEB) loop has three steady states: epithelial (high miR-200, low ZEB), mesenchymal (low miR-200, high ZEB) and partial EMT (medium miR-200, medium ZEB). The situation becomes even more complicated as mesenchymal cells are endowed with stemness characteristics. Finally among CTC subpopulations we can find: epithelial, epithelial-mesenchymal, mesenchymal and mesenchymal stem cells.

These subpopulations are not strictly distinct as there is a continuum between their different stages. At the end of this EMT, the reverse process, mesenchymal-epithelial transition (MET) will transform mesenchymal-stem cancer cells to epithelial -stem cancer. Cells with mesenchymal characteristics have a poor capacity to proliferate but when again acquiring the epithelial status they will be able to develop a relapse in a metastatic niche. So a real devilish cycle of cancer invasion becomes established through CTC subpopulations. The following scheme summarizes this paradigm.

Many publications deal with CTC. They were first described in 1869 by Ashworth (8). Research on this topic started again with the development of the CellSearch system able to numerate foreign entities in the blood of cancer patients (Veridex, Warren, New Jersey, USA). The methodology is based on the capture of the CTC

by EpCam antibody, the antigen being not expressed by blood cells. Until now, the number of detected cells was used to set the prognostic of the cancer disease. Observed discrepancies between published CTC analysis methods demonstrate that a gold standard method is still missing (9). New improvements are ongoing. Generally the detection of CTC is based on a blood volume sample from 7 to 30 ml.

Due to the Poisson statistics many false negative results can be alleged. The development of Seldinger device overcomes this gap (10). When CTC capture will be considered as perfect, many other problems still have to be solved.

It is mandatory to define biochemical markers able to characterize CTC subpopulations. We Martie 2014

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Editorial

The Devilish Cycle of the Cancer: Circulating Tumor Cells and Epithelial Mesenchymal Transition as Actors

cannot be satisfied with solely epithelial markers as the previously described EMT endows cells with different phenotypes. They may or may not include EpCam expression. Thus to validate the use of CTC analyses and their applications in clinical settings, reworking in our mind thinking is absolutely necessary. How to develop a gold standard method? How to establish the correlation between this type of analyses, clinical following and therapy efficacy?

Can pathological EMT studies support discovery of new drugs leading to the breakdown of cancer residual disease? Finally, our major

goal might be to interrupt the devilish cycle of cancer recurrence.

Epithelial cells (cobble stone structure) from primary tumors become motile mesenchymal cells (spindle cells) and by shedding, invade blood. They are endowed with stemness features: mesenchymal cancer stem cells (CSC). After extravasation, mesenchymal CSC overrun a niche leading to metastasis. From the latter a new cycle of EMT can arise.

Conflicts of Interest/Conflict de Interese: none/nici unul.

Bibliography 1. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol, 2003, 15(6): 740-746.

2. Moustakas A, Heldin CH. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007, 98(10):1512-1520.

3. Savagner P. Leaving the neighborhood: molecular mechanisms involved during epithelialmesenchymal transition. Bioessays. 2001, 23(10): 912-923.

4. Hazan RB, Qiao R, Keren R, Badano I, Suyama K. Cadherin switch in tumor progression. Ann N Y Acad Sci. 2004, 1014: 155-163.

5. de Herreros AG, Peiró S, Nassour M, Savagner P. Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. J Mammary Gland Biol Neoplasia. 2010, 15(2):135-147.

6. Barrière G, Riouallon A, Renaudie J, Tartary M, Rigaud M. Mesenchymal and stemness circulating tumor cells in early breast cancer diagnosis. BMC Cancer. 2012, 12: 114.

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7. Lu M, Jolly MK, Levine H, Onuchic JN, Ben-Jacob E. MicroRNA-based regulation of epithelialhybrid-mesenchymal fate determination. Proc Natl Acad Sci U S A. 2013, 110(45):1814418149.

8. Ashworth T. R. A case of cancer in which cells similar to those in the tumors were seen in the blood after death. Australian Medicine Journal,1869,14, 146–149.

9. Sieuwerts AM, Kraan J, Bolt J, van der Spoel P, Elstrodt F, Schutte M, Martens JW, Gratama JW, Sleijfer S, Foekens JA. Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst. 2009, 101(1): 61-66.

10. Saucedo-Zeni N, Mewes S, Niestroj R, Gasiorowski L, Murawa D, Nowaczyk P, Tomasi T, Weber E, Dworacki G, Morgenthaler NG, Jansen H, Propping C, Sterzynska K, Dyszkiewicz W, Zabel M, Kiechle M, Reuning U, Schmitt M, Lücke K. A novel method for the in vivo isolation of circulating tumor cells from peripheral blood of cancer patients using a functionalized and structured medical wire. . Int J Oncol. 201, 41(4):1241-1250.

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Rolul comisiei de tumor board în chirurgia oncologică

Rolul comisiei de “tumor board” în chirurgia oncologică Interviu cu prof. dr. Irinel Popescu, medic chirurg Spitalul OncoFort

De curând , cel mai nou spital privat inaugurat în Capitală a reunit o echipă de elită în chirurgia oncologică coordonată de ilustrul prof. dr. Irinel Popescu. Încă de la inaugurare, în spital s-a efectuat o intervenție în premieră de către ilustrul chirurg prof. dr. Irinel Popescu.

„

„

O dată cu succesul acestei dificile intervenții chirurgicale, m-am simțit la începutul unui drum pe care l-am așteptat de ceva vreme și pe care mi-l doresc cu cât mai multe împliniri ...ne-a declarat „la cald” prof. dr. Irinel Popescu. mai mare parte din cazuri în ceea ce privește debutul unei afecțiuni hepatice.

Se spune că celulele ficatului se regenerează.

Este cazul să luăm fără a merge la medic medicamente pe care le vedem în reclame cu indicația că ajută la regenerarea celulelor ficatului?

Noutatea medicală o reprezintă operația foarte dificilă efectuată unui pacient diagnosticat cu me­ tastază hepatică voluminoasă cu punct de pleca r­e colonic. Cu atât mai dificil a fost faptul că pacient­ ul era în programul de dializă de mai mulți ani pentru insuficiență renală cronică, iar anestezia a fost cu totul specială pentru o astfel de operație, riscul de complicații intra și post-operatoriu fiind foarte ridicat. În fiecare lună sunt abordate peste 60 de intervenții chirurgicale oncologice, cu nivel de complexitate ridicat, iar fiecare caz refuzat în spitalele de stat devine o provocare pentru specialiștii din cadrul spitalului.

Care sunt primele semne că ceva nu este în ordine cu ficatul nostru și ar trebui să mergem la medic?

Un semn important este oboseala, tradusă prin capacitate mai redusă de efort, nevoia de a face pauze mai dese și tendința la somnolență. Se pot adăuga balonări, grețuri, dureri în aria de proiecție a ficatului (hipocondrul drept).

Setul curent de analize pe care ar trebui să le facem fiecare anual este suficient pentru depistarea afecțiunilor hepatice?

De regulă, da. Transaminazele, bilirubina, gamaglutamil-transpeptidaza sunt edificatoare în cea

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Nu există nici un medicament care să ajute cu adevărat procesul de regenerare, de aceea recomand multă prudență în utilizarea medicamen­telor cărora li se face reclamă în acest sens.

De curând efectuați intervenții chirurgicale complexe în privat, ce tipuri de operații ați efectuat?

Până în prezent am efectuat rezecții de colon și rect, gastrectomii totale, rezecții hepatice, operații pentru cancer de col uterin, operații pentru cancer de ovar, operații pentru cancer de sân etc.

De multe ori, cazurile dificile (ex: cancerul) sunt abordate multidisciplinar, aveți cazuri pe care le-ați tratat într-o comisie de tipul „tumor board”? Care sunt avantajele unei astfel de comisii?

Toate cazurile pe care le operez trebuie discutate în “tumor board” pentru că numai astfel pacientul poate să beneficieze de cel mai bun prognostic de care poate beneficia în momentul de față. A opera fără o discuție a pacientului în “tumor board” înseamnă, în opinia mea, a-i reduce bolnavului șansele terapeutice.

Câți pacienți din totalul celor care au nevoie pot beneficia de transplant în timp util? În prezent, în România, cred că aproximativ 80%.

Nume autori

Martie 2014

17

News

Sărbătorind succesul tomosintezei

SĂRBĂTORIND SUCCESUL TOMOSINTEZEI Timpul, efortul şi cheltuielile investite pentru dezvoltarea unei noi tehnologii nu oferă garanţia că investiţia va fi eficientă. Recompensa este cu atât mai mare când aceste investiţii se amortizează şi apar poveşti de succes aşa cum se întâmplă cu SELENIA DIMENSION – sistemul de mamografie digitală cu tomosinteză de la Hologic (SUA).

Din 2008, de când a obţinut marca CE, tomosinteza Hologic (SUA) a fost instalată în peste 50 de ţări şi 48 de state din Statele Unite ale Americii.

Peste 1 milion de femei au fost vizualizate cu acest sistem. SELENIA DIMENSION a fost citat în peste 60 de publicaţii clinice, prezentări şi abstracte.

Mult mai important, numărul în creştere de publicaţii care arată că folosirea tomosintezei Hologic (SUA) împreună cu imaginile 3D convenţionale conduc la o creştere semnificativă, cu până la 27%, a ratei de detecţie a cancerului, în particular a cancerului minim invaziv, scăzând în acelaşi timp rata rechemărilor fals pozitive cu până la 40%. În plus, DOAR Hologic (SUA), prin SELENIA DIMENSION şi sistemul de stereotaxie Affirm, oferă posibilitatea efectuării biopsiei de sân 3D. Toate acestea duc la salvarea de vieți printr-o diagnosticare precoce și începerea din timp a tratamentului.

2013 este al doilea an consecutiv când sistemele de mamografie digitală Hologic (SUA) ocupă primele 3 locuri în topul satisfacţiei utilizatorilor, iar sistemul cu tomosinteză SELENIA

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DIMENSION, premiul “Best in KLAS”. Acest premiu se acordă celui mai performant echipament medical și se bazează pe valori primite de la mii de centre de diagnostic din Statele Unite și Canada.

Tomosinteza HOLOGIC și-a dovedit clinic superioritatea atât prin numeroasele studii clinice publi­cate atât în Statele Unite, cât și în numeroase țări din Europa sau alte părți ale lumii, dar și prin particularitățile tehnologice care o fac să fie cea mai performantă în acest moment.

• Imagini de o calitate excepțională pentru vizualizarea celor mai mici detalii.

• Posibilitatea de a avea o achiziție rapidă atât a imaginilor 2D de screening, cât și a celor 3D tomosinteză în doar 10 secunde și o singură compresie.

• Caracteristici tehnice ergonomice, sofisticate, dezvoltate special pentru confortul pacientului.

Din ce în ce mai multe femei sunt informate despre beneficiile tomosintezei și caută centre medicale care le pot oferi avantajele folosirii unei astfel de tehnologii. Şi în România, Hologic se menţine în top, având în momentul de faţă trei sisteme cu tomosinteză instalate la Institutul Clinic Fundeni, Institutul Oncologic Cluj şi în Bucureşti, la o clinică privată.

HOLOGIC este o companie americană, lider mondial în mamografia digitală, cu o cotă de piaţă de 52% la nivel mondial şi peste 70% în SUA în ceea ce priveşte vânzarea de mamografe digitale.

în peste 60 Peste 50 de publicaţii 40% de ţări cu prezentări Peste 1 șimilion

creștere în detecţia cancerului mamar invaziv

sisteme în utilizare

de femei examinate cu sistemul cu tomosinteză Hologic Selenia Dimensions

27% Până la

5

creștere 40% scădere în detecţia în rechemările totală a fals pozitive cancerului de sân

ani de la obţinerea certificatul u i CE Prezenţa

în peste 60 Peste 50 de publicaţii de ţări cu și prezentări

Singurul sisteme în utilizare

di s pozi t i v 5 aprobat de FDA Singurul ani de la obţinerea certificatului CE

dispozitiv România prin: aprobatDistribuit dein FDA

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Events

Scientific Events

Scientific Events ONCOLOGY ESTRO 33 04 - 08 April 2014 Vienna, Austria

It is my privilege and great pleasure as President of ESTRO and Chair of the congress, to invite you to ESTRO 33 that will take place in Vienna from 4 to 8 April 2014.

ESTRO 33 is the premier European event in Radiation Oncology and will focus on new and emerging developments in the field.

Since the foundation of ESTRO, more than 30 years ago, Radiation Oncology has fortunately seen continuous change with virtually every aspect of the basic science of our discipline and of the clinical treatment drastically improving for the benefit of patient care. In this context, ESTRO 33 will assist ESTRO’s recent Vision for 2020 statement that: “Every cancer patient in Europe will have access to state of the art radiation therapy, as part of a multidisciplinary approach where treatment is individualised for the specific patient’s cancer, taking account of the patient’s personal circumstances”.

In line with the ESTRO Vision document, the ESTRO 33 Scientific Programme will aim to cover mainly the following scientific topics.

• The integration of new clinical and preclinical evidence from biology, molecular/functional and anatomic imaging in Radiation Oncology • The physical and biological optimisation of radiation therapy

• The use of new systemic agents together with the delivery of high precision radiation therapy in a safety aware environment • Combined-modality treatment using radiation and either cytotoxic and/or targeted therapeutics • The use of high-precision radiotherapy used with curative intent in patients with metastatic and locally recurrent disease • New developments in radiation oncology that further improve the safety of high-precision radiotherapy • New approaches to adaptive radiotherapy integrating novel developments in biology, imaging, technology, and the assessment of tumour response and patient outcome • The potential future use of novel biological modifiers of tumour and normal tissue response • The development of validated predictive models of treatment outcome based on complex databases comprising clinical, biologic, genetic, imaging, dosimetric and population data • Quality programmes, including clinical audit and comprehensive safety systems in Radiation and Clinical Oncology that maintain the principles of providing the highest quality of patient care and treatment in a safety-aware environment • Health services research in radiotherapy and oncology, including the long term analysis of changes in specialist staffing in the discipline, the level of equipment, the appropriate implementation of new technology, patient access to new treatment approaches; together with the critical analysis of these strategic developments using cost-benefit, cost- utility and other means of health economic review and health technology assessment • Clinical trials (phase 0, I, II, and III) in radiotherapy and combined modality Together, in sharing this patient-centered objective, we will move the ESTRO Vision forward

Congresul Bienal de Cancer Mamar 14-17 mai 2014, Băile Felix Congresul Bienal de Cancer mamar Băile Felix este deja tradiție, ajungând la a X-a ediție. Receptat cu mult interes de către participanți, “Bienala de sân” a adus întotdeauna în dezbatere probleme de actualitate privind diagnosticul și tratamentul cancerului mamar, contribuind personalități medicale și științifice de valoare națională și internațională. Multidisciplinaritatea, precum și posibilitatea de exprimare a experienței clinice au condus, ediție după ediție, la creșterea numărului de participanți.

Sunteți invitați la a X-a ediție a Congresului Bienal de Cancer Mamar din 14-17 mai 2014, Băile Felix.

Informații suplimentare puteți găsi pe site-ul: www.oncobihor.ro.

Dr. Simona Mihuțiu

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and build what promises to be an event looking at the challenges of the future.

The 7th International Conference on “HPV, Polyomavirus and UV in Skin Cancer” 09 - 12 April 2014 Novara, Italy The 7th International Conference on “HPV, Polyomavirus and UV in Skin Cancer” will be held in Novara, Italy, April 9-12 2014. It will bring together leading scientists that will discuss the latest research developments in UV & Virus – related skin cancer. Our goal is to serve as a forum for the exchange of state-of-the-art information on human papillomavirus (HPV) and polyomavirus (HPyV) research and its future perspectives following up on the proceedings of the 6th International Conference of Berlin in 2012.

The European Congress on Head and Neck Oncology (ECHNO 2014) 24 - 26 April 2014 Liverpool, United Kingdom Welcome to the European Congress on Head and Neck Oncology (ECHNO 2014), being held at The ACC, Liverpool, UK from 24-26 April 2014.

An emphasis has been placed on addressing the need for a multidisciplinary approach to facilitate cooperation between the various clinical and research specialties involved in the management of head and neck cancer.

ECHNO 2014 will provide you with the latest research and techniques in the ongoing effort to improve the lives of patients everywhere. The Congress’s stellar scientific programmme will feature experts from around the world, who will facilitate stimulating debates about the most controversial topics in Proton Therapy, Robotics and Transoral Laser.

The compelling, challenging ECHNO 2014 programme will keep you busy by day. In the evening, you’ll have the opportunity to explore the historic city of Liverpool, famous around the world as a musical and entertainment hub.

The congress venue is centrally located which will allow you easy access to all the best attractions that Liverpool has to offer. Join colleagues and friends for three days of debates, discussions and collaboration at ECHNO 2014.

The 15th World Congress for Cervical Pathology and Colposcopy (IFCPC 2014) 26-30 May 2014 London, United Kingdom The 15th World Congress for Cervical Pathology and Colposcopy (IFCPC 2014) will promote the

best possible standards of Colposcopy around the world with the goal of guaranteeing that women everywhere receive excellent care. IFCPC will feature structured training sessions that will improve clinician competence, performance and patient outcomes through educational activities focused around the study, prevention, diagnosis, and management of HPV and genital tract diseases.

By placing the latest research and techniques at the service of health care professionals on every continent, the congress seeks to bridge the gap between theory and practice.

The BSCCP and 32 National Societies represented by the IFCPC, this congress will provide the perfect forum for sharing international knowledge and experience, dealing with core issues in cervical pathology and colposcopy. Meet the best and brightest minds working in the field at IFCPC 2014.

ASCO 50th Annual Meeting 30 May - 3 June 2014 Chicago, Illinois Attendees of the 2014 Annual Meeting will find cutting-edge scientific presentations and comprehensive educational content.

The ASCO Annual Meeting brings together more than 25,000 oncology professionals from a broad range of specialties, making it an excellent venue for exploring the theme of the Meeting — “Science and Society.”

Description of Session Types The 2014 Annual Meeting, developed by the ASCO 2013-2014 Cancer Education Committee and Scientific Program Committee, is made up of the following session types: Education Sessions Education Sessions offer interdisciplinary or multidisciplinary explorations of focused areas of clinical oncology. ASCO’s Cancer Education Committee determines topics and format for these sessions that will best serve the educational needs of Annual Meeting attendees. Particular care is taken to ensure that these sessions address issues including surgical, radiation, and geriatric oncology; symptom management; health services research; international perspectives; and pathology, as appropriate.

Clinical Problems in Oncology Sessions Clinical Problems in Oncology Sessions combine the use of case-based panel discussion with interactive keypad technology for audience participation. These sessions are ticketed and require an additional registration fee.

Meet the Professor Sessions Meet the Professor Sessions enable interactive discussion between attendees and recognized experts in a variety of subspecialty fields. The format is informal with an emphasis on a face-toface exchange with the expert. These sessions are ticketed and require an additional registration fee.

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Events

Scientific Events

Core Sessions Track The Core Sessions track highlights the latest updates in science and clinical practice. Designed to help busy oncologists streamline their Annual Meeting experience, Core Sessions may include such topics as controversies in a particular disease site, personalized care, or new developments in the field. The Cancer Education Committee has designated one or more education sessions in each track as Core Sessions.

Special Sessions Special Sessions include the presentation of Awards and Award Lectures as well as symposia recommended by other oncology-related organizations, the Cancer Education Committee, the Scientific Program Committee, and the ASCO Board of Directors as being of particular interest, importance, and relevance to Meeting attendees.

Plenary Session The Plenary Session includes 15-minute didactic presentations highlighting abstracts of scientific research deemed to have the highest merit and greatest impact on oncology research and practice.

Experts in the field will serve as Discussants to place research findings into perspective. The Plenary Session will take place on Sunday, June 1, 2014, 1:00 PM-4:00 PM. Oral Abstract Sessions Oral Abstract Sessions include didactic presentations of abstracts representing important clinical and translational research findings by topic category. Presenting authors may use PowerPoint slides to accompany their oral presentation.

Experts in the field (Discussants) are chosen to provide comprehensive themed discussions of the findings from predetermined abstracts.

Clinical Science Symposia Clinical Science Symposia provide a forum for science in oncology, combining didactic lectures on a specific topic with the presentation of abstracts.

Experts in the field (Discussants) place studies in the appropriate context based on the strength of the evidence and critically discuss the conclusions in terms of their applicability to clinical practice.

Highlights of the Day Sessions Highlights of the Day Sessions invite expert discussants to present key findings, put abstracts into clinical context, and provide an overview of the previous day’s oral abstract sessions.

Poster Discussion Sessions Posters Discussion Sessions highlight selected abstracts of clinical research in poster format. The posters are grouped by topic and are on display for a specified time, followed by a discussion session in which expert Discussants comment on the research findings.

General Poster Sessions General Poster Sessions include selected abstracts of clinical research in poster format. The posters are grouped by topic and are on display for a specified time. The Annual Meeting will again include Trials in Progress poster presentations within each track, designed to facilitate awareness of open, ongoing clinical trials of any phase.

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Oncologic Imaging Course 2013 CT, MRI, PET/CT, and Interventions in Cancer Patients: A Practical Approach 27 - 29 June 2013 Dubrovnik/Croatia On behalf of the three course organisers Prof.Dr. Christian Herold, Prof. Dr. Dr.h.c. Hedvig Hricak and Prof. Dr. Dr.h.c. Maximilian F. Reiser as well as the whole OIC team, we would like to cordially thank you for your participation at this year’s Oncologic Imaging Meeting, held from June 27-29, 2013, in Dubrovnik/Croatia.

The scientific programme of the course was focused on CT, MRI, PET/CT, and Interventions in Cancer Patients: A Practical Approach and attracted more than 120 participants from Europe, the United States of America, Asia and Australia.

After the regular course, workshops in breast imaging and advanced post-processing took place.

We hope you have enjoyed the course and are looking very much forward to welcoming you again in 2014, when the meeting will again be held in the beautiful city of Dubrovnik.

The International Symposium on Pediatric Neuro-Oncology (ISPNO) 28 June - 02 July 2014 Singapore, Singapore

Dear Colleagues and Friends of the Pediatric Neuro-Oncology Community, It is with great honor that I invite you to the 16th ISPNO meeting from 28 June – 02 July 2014, which will be held in conjunction with the 8th St. JudeVIVA Forum in Pediatric Oncology in Singapore for the first time. Since the first ISPNO meeting in 1986, this biennial scientific conference has witnessed progress that was unimaginable in the 1980s. The pace of discovery and our knowledge of biology, treatment and late effects of pediatric CNS tumors has increased dramatically but many challenges remain, particularly in translating these advances to clinical care in developing nations.

This year is the first time ISPN (International Society of Pediatric Neurosurgery), the ESPN (European Society of Pediatric Neurosurgery), and WFNS (World Federation of Neurosurgical Societies) have collaborated in developing themes and content for multidisciplinary sessions aimed at

boosting participation from both regional pediatric neurosurgeons and leaders in the international pediatric neurosurgery community.

It is also the first time the Pediatric Radiation Oncology Society (PROS), has formally joined our International Advisory Board to lead opinions and assist in the design of multidisciplinary sessions during the main ISPNO meeting. We expect this new emphasis to attract even more regional and international pediatric radiation oncology delegates. This meeting is expected to provide a unique opportunity to showcase the latest innovations in radiation oncology and diagnostic imaging as these disciplines are essential elements of therapeutic planning in patients with CNS tumors.

ISPNO is the forum of choice for researchers from North America and Europe to announce pediatric neuro-oncology research results. The meeting encompasses advances in molecular diagnostics and classification, the chemotherapy of tumors of the CNS in Phase III trials, results of trials of investigational new agents from Phase I and II trials and the latest in supportive care.

Professionals involved in the care of children and adolescents are encouraged to benefit from this valuable opportunity to engage with experts, gain insights and establish new collaborations from the enriching plenaries, poster program and more.

Join us in Singapore for an unforgettable meeting!

About ISPNO The International Symposium on Pediatric NeuroOncology (ISPNO) is the major biennial global

meeting of the multi-disciplinary international community of professionals involved in the research, diagnosis, treatment and rehabilitation of infants and children with brain tumors. ISPNO has enjoyed consistent growth since its first meeting in 1986 with over 800 delegates drawn mostly from oncology, neurosurgery and radiation oncology.

16th ISPNO in 2014 will mark the third meeting of ISPNO in the Asian region, as well as the first time it returns to Asia since the 2004 meeting in Japan.

Throughout the entire symposium, attendees will engage in dialog regarding new surgical treatments, innovative research and advances in pediatric neuro-oncology in a dynamic and interactive forum designed to significantly expand the knowledge base of attendees and further enhance overall patient care worldwide.

16th ISPNO in Singapore Widely regarded as the leading conference destination in Asia, Singapore offers a safe and enriching experience in a bustling cosmopolitan setting with countless culinary and cultural experiences! Singapore is Asia’s leading medical hub with a global reputation as a medical convention and training center, a fast-growing basic and clinical research hub and a center for regional referrals.

Held in Suntec Singapore Convention and Exhibition Centre (Suntec Singapore), the 16th ISPNO will showcase the leading international advances in basic, translational and clinical research and also recent advances in addressing the global burden of pediatric central nervous system (CNS) tumors.

HEMATOLOGY The 9th Baltic Conference of Hematology 2014 (BCH 2014) 24 - 26 April 2014 Vilnius, Lithuania

Dear Colleagues and Guests, It is my honour and great pleasure to welcome you to the 9th Baltic Conference of Hematology on behalf of the Lithuanian Society of Hematology.

Baltic Conferences of Hematology are held every other year and have turned out to be not just regional but also international forums for professionals interested in the improvement and development of hematological care.

The substantial progress has been made in hematology during the last years, we experience ever faster changes – new technologies, new medications, and therefore contacts between

colleagues are becoming more and more important. Without any doubt, Baltic Conferences of Hematology are a great opportunity to participate in presentations and discussions of the most recent advances in this field of medicine and also a great opportunity to establish long-term international collaboration. One special and traditional feature of the Baltic Conferences of Hematology has been an amusing and joyful feeling of being together. I hope that we can also fulfil the demands of social life here in Vilnius and offer you a pleasant time to communicate and have fun after the scientific sessions. I hope you will enjoy the beautiful Lithuania with its ancient history, modern social life and progressive economic development.

I would like to wish all of us a very stimulating, interesting meeting, lots of useful bring-back ideas and especially – to get the message of friendship and collaborating in promoting the advance in our specialty and beyond.

With warm regards, Arturas Slobinas President of Lithuanian Society of Hematology Martie 2014

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Events

Scientific Events

The British Society For Hematology 54th Annual Scientific Meeting 2014 (BSH 2014) Birmingham, United Kingdom 28 - 30 April 2014 Dear Friends and Colleagues, It is a huge honour to be President of the BSH and to introduce the 54th Annual Scientific Meeting. The meeting will be held at the ICC which is located in the heart of Birmingham. As many of you will know, Birmingham is a vibrant, bustling, cosmopolitan city and apparently boasts more miles of canal than Venice!

I have always been passionate about Hematology and have always felt it is a privilege to have a career in such a fascinating speciality. Hematology embraces so many different aspects of medicine and I hope our meeting will reflect the breadth and very essence of our practice as haematologists.

Throughout my career I have loved debate and the controversies that surround progress. Often it is not the data but how we interpret the data that matters as we treat our patients. I hope this meeting will be stimulating, challenging and full of friendly debate and discussion.

Finally we all make great friends as we have pursue our careers and our ASM is always the friendliest of meetings so come to Birmingham to learn, to discuss, to relax and to enjoy.

with a cosmopolitan sense of life. The historic area shows in its buildings and monuments the incredible heritage of this city, while its cultural and modern attractions indicate an active and dynamic city. The attendees to MLTD-2014 will be able to enjoy an excellent scientific meeting in a warm, hospitable and enchanting city.

The venue, the Palacio de Congresos de Valencia, is conveniently located beside nice hotels and amenities with easy public transportation to the entire city.

We have prepared an exciting and integrated meeting offering a unique programme which covers the whole basic, translational and clinical spectrum of thrombosis, platelets, coagulation, fibrinolysis, haemostasis and vascular biology with care and appreciation for your scientific and personal enjoyment.

The 19th Congress of the European Hematology Association 12 - 15 June 2014 Milan, Italy

The 23rd International Congress on Thrombosis 2014 (ICT 2014) 14 - 17 May 2014 Valencia, Spain

The Congress Executive Committee, the Local Organizing Committee and the Council of the Mediterranean League Against Thromboembolic Diseases take pleasure in welcoming you to the 23rd Biannual International MLTD Congress 2014 in Spain.

We have organized a meeting that brings the best and most novel advances in thrombosis and related sciences to attending delegates. We have especially focused on fostering the needs of younger attendants by stimulating scientific exchange, oral presentations, awards and special social functions.

I like to welcome you to Valencia, the beautiful Mediterranean City that is home to our 2014 meeting. Valencia has a long-lived history since its foundation as a Roman colony in 138 BC. It has the flavour of ancient cultures and traditions together

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After 12 years EHA’s congress is returning to Italy.

Milan is one of Italy’s most fashionable cities and holds several historic and artistic attractions, and a congress center with excellent facilities and a great location.

The Scientific Program Committee will invite authors to submit abstracts to be considered for inclusion in the scientific program as of January 1, 2014. Abstracts can be submitted via this website and here you will find detailed instructions regarding the submission procedures and the full abstract submission guidelines.

The submission of an abstract constitutes a formal commitment by the presenting author to present the abstract (if accepted) orally or as a poster in the session and the time assigned by the Scientific Program Committee. We therefore recommend that submitters of abstracts register for the congress simultaneously with abstract submission.

The official congress registration website will also open as of January 1, 2014. The strict deadline for the submission of abstracts will be March 1, 2014.

Nume autori

Martie 2014

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Events

Scientific Events

Conferinţa “Abordarea Multidisciplinară în Cancer în 2014” Cancerul este una dintre cele mai comune boli ale zilelor noastre. Datoria unui medic oncolog nu este doar aceea de a-l trata pe pacient, ci de a-l ghida spre o stare de spirit, de a-i oferi speranța și încrederea care să îl vindece. În fiecare zi un om bolnav de cancer poate învăța de la capăt care este sensul vieții și al fericirii. În fiecare zi un om care suferă de această boală poate trăi schimbarea unei vieți noi și regăsirea iubirii față de sine, față de cei din jur și față de lume așa cum este ea.

Un pacient de cancer care s-a vindecat este una dintre minunile acelea cu care oamenii de rând se întâlnesc rar, dar prin care medicii oncologi, prin priceperea profesională și înțelegerea umană, ajung la împlinire și aprofundarea caracterului și comportamentului.

Procesul durează mult sau suficient cât între medic și pacient să se creeze o legătură. Din acest motiv, la final, când constați că ai reușit, satisfacția nu vine doar din vindecare în sine, ci din legătura profundă creată cu o altă ființă umană, căreia i-ai determinat cursul vieții.

Fiecare clipă după vindecare este un început diferit și unic, iar medicul oncolog este cel care eliberează lumina în toate zilele care vor urma.

Pacienţii de care comunitatea medicilor oncologi din cadrul conferinţei “Abordarea multidisciplinară în cancer în 2014” are grijă sunt toți oamenii obișnuiți peste care dăm din întâmplare zi de zi. În spatele unui „Mulțumesc!” scurt se ascund oameni care suferă de această boală, fie că îi întâlnim la colțul străzii sau pe scara blocului.

Sunt oameni normali, dar care au o calitate în plus, dezvoltată nu la cerere, ci din forța unui moment care te poate schimba.

Această calitate se numește „voință”, iar specialiștii oncologi sunt cei care ajută la modelarea și creșterea sa o dată cu tratamentul.

Esenţa multidisciplinarităţii cancerului a fost concentrată de către Asociaţia Medisprof, cu sprijinul Asociaţiei Oncologilor Privaţi din România şi Diasan în conferinţa „Abordarea multidisciplinară în cancer în 2014”.

Această conferinţă adună laolaltă specialişti oncologi, nutriţionişti, psihologi clinicieni, farmacişti

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şi asistenţi oncologici. De la sesiuni ştiinţifice precum “Interdisciplinaritate şi medicină personalizată în România, să privim spre viitor” şi până la sesiuni despre “Personalizarea în tumorile mamare incipiente operabile”, participanţii vor avea ocazia să afle şi să înveţe informaţii valoroase din domeniul oncologic.

Pacientul nostru, prietenul nostru Meseria de medic te pune în fața unor situații greu de povestit la masa de duminică. Un întreg tranzit de trăiri și sentimente năvălește atunci când afli că cel mai bun prieten din copilărie suferă de această boală.

Povara unei astfel de afecțiuni poate fi atenuată dacă medicul care se ocupă de caz știe să arate că prietenia se poate naște din cele mai ciudate situații.

Iubeşte-ţi pacientul ca pe tine însuţi Pe lângă sesiunile ştiinţifice care vor fructifica modernitatea tehnicilor medicale oncologice, punem accent pe iubirea față de pacient. Știm că nu puteți pleca acasă cu acest atribut, dar mai știm și că poți învăța să iubești și că tot acest sentiment se naște din grijă.

Avem grijă: - să aplicăm cele mai noi tendinţe din medicina oncologică; - să corelăm toate disciplinele ce pot ajuta pacientul; - să vă oferim accesul la experienţele medicale ale unor somităţi în domeniu; - să vă livrăm cele mai puternice şi pregnante viziuni asupra sistemului medical; - să ajutăm la construirea unei comunităţi interdisciplinare 4 în 1: specialişti oncologi, asistenţi medicali, nutriţionişti şi psihologi clinicieni; - de pacienţii noştri.

Suntem profesionişti, deci avem grijă. Pe lângă grija transmisă sentimental-afectiv, avem grija profesională. Împreună avem grijă, aplicăm cele mai moderne metode, cele mai noi idei de tratamente în cadrul tuturor disciplinelor.

Bojan Zaric

Cristian Moldovan

4 zile numai bune pentru știință!

Cu siguranță vă întrebați care sunt tematicile abordate anul acesta și care este lista completă a speakerilor care vor susține prezentări în cadrul conferinței.

Pentru început, vă prezentăm programul preliminar al sesiunilor, care vor fi prezentate în două limbi: limba engleză și limba română. În paralel cu aceste sesiuni, în holul Hohe Rinne Hotel & Spa Păltiniș, cele mai importante companii din domeniul farmaceutic vor fi prezente în cadrul spațiului expozițional. Acolo veți avea acces la cele mai noi informații referitor la tratamentele existente pe piață dedicate pacienților oncologici.

Program conferinţă Joi 14.00 – 18.00: Primire participanți 19.00 – 22.00: Cină Vineri 9.00 – 9.15: Deschiderea conferinței Dr. Adrian Udrea, președinte Asociația Oncologilor Privați din România Rolul și scopul manifestării conferinței „Abor­ darea multidisciplinară în cancer în 2014” 9.15 – 9.45: Dr. Răzvan Curcă, șef Secție oncologie Spitalul Județean de Urgență Alba Interdisciplinaritate și medicină personalizată în România: să privim spre viitor!

Tumorile pulmonare - interdisciplinaritate și medicină personalizată 9.45 – 10.15: Asist. prof. dr. Bojan Zaric, MD, PhD, Specialist in internal medicine - interventional pulmonology, Medical oncologist, Institute for Pulmonary Diseases of Vojvodina, Clinic for Thoracic Oncology, Head, Clinical Trials Unit, Head, Department for Invasive diagnostics, University of Novi Sad, Faculty of Medicine, Serbia Advanced bronchoscopic techniques in diagnosis and staging of lung cancer.

10.15 - 10.45: Prof. dr. Alina Mihai, Consultant Radiation Oncologist, Clinical Assistant Professor,

Alina Mihai

Xavier Pivot

Univ Pittsburgh School of Medicine, Master of Science, Radation Physics, UPMC Beacon Hospital, Dublin Rolul radioterapiei ablative stereotactice în tratamentul cancerului pulmonar - avantaje și provocări 10.45 – 11.15: Gavin Lawler 11.15 – 11.45: Pauză de cafea Tumorile mamare – noi modalități de abordare, noi tehnici și rezultate recente 12.00 – 12.30: Prof. dr. Xavier Pivot, Centre Hospitalier Régional Universitaire Hôpital Jean Minjoz Besançon (subject to be defined by the speaker) 12.30 – 13.00: Dr. Cristian Moldovan, Praticien Hospitalier, Centre Henri Becquerel, Rouen, France Personalizarea în tumorile mamare incipiente operabile 13.00 – 13.20: Simpozion Zoladex: speaker : dr. Cristina Cebotaru, Oncologie, Cluj-Napoca “Putem personaliza secvența terapeutică în cancerul de prostată rezistent la castrare?”

13.20 – 13.40: Simpozion Faslodex: speaker: dr. Cristina Oprean, Oncologie, Timișoara “Dezvoltarea hormonoterapiei și impactul major asupra calității vieții pacientelor cu cancer de sân” 14.00 – 16.00: Prânz 18.00 – 19.00: Cină Sâmbătă Tumorile gastrointestinale – tehnici moderne intervenționale și de diagnostic 9.00 – 9.30: Dr. Adrian Cătinean, medic primar interne-gastroenterologie, asist. univ. UMF ClujNapoca, Centrul Medical Diasan Tehnici moderne de diagnostic în tumorile gastrointestinale 9.30 – 10.00: Dr. Florin Graur, medic primar chirurg, asist. univ. UMF Cluj, Clinica Chirurgie 3 Cluj- Napoca (subject to be determined by the speaker) 10.00 – 10.30: Dr. Adina Croitoru, medic primar oncolog, Clinica Medisprof Cluj-Napoca Martie 2014

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Events

Scientific Events

Controverse și actualizări în cancerul gastric 10.30 – 11.00: Conf. dr. Gabriel Prada, Medical director - Institutul Ana Aslan București Patologia vârstnicului, sindroame geriatrice 11.00 – 11.30: Pauză de cafea 11.30 – 12.00: Farm. Speranța Prada, farmacist-șef – Institutul Ana Aslan București Constituirea Asociației Farmaciștilor Oncologi din România – perspective, punct de vedere din partea ANM/CNE 12.00 – 12.30: Farm. Liana Nemeth, Clinica Medisprof Cluj-Napoca Farmacia Oncologică 13.00 – 14.00: Prânz Secțiunea dedicată asistenților medicali și per­ sonalului paramedical 14.00 – 16.00: Conf. dr. Șerban Negru, medic oncolog Oncohelp Timișoara Curs asistenți medicali 16.00 – 16.30: Pauză de cafea 16.30 – 17.00: As. Mariana Avram, Clinica Medisprof Cluj-Napoca Camerele implantabile – avantaje, experiența Clinicii Medisprof 17.00 – 17.30: As. Adriana Susu, Clinica Medisprof Cluj-Napoca Sistemul antialopecie Dignicap – experiența Clinicii Medisprof 17.30 – 18.00: Psih. Anca David, Clinica Medisprof Cluj-Napoca Suportul psihologic integrat în tratamentul pa­ cientului oncologic 18.00 – 18.30: Camelia Moldovan, dieteticiannutriționist, Clinica Medisprof Cluj-Napoca Intervenția nutrițională la pacientul oncologic 18.30 – 19.00: Iulia Tutui, dietetician-nutriționist, Clinica Medisprof Cluj-Napoca Nutriția în cancer 19.00 – 20.00: Moment surpriză 20.00 – 21.00: Cină Duminică 12.00 – Check-out

Cât vă costă?

Medici primari și specialiști

250 euro

Medici rezidenți și personal paramedical

200 euro

Grup de minimum 5 persoane de la aceeași instituție/clinică

-10% *

În prețul biletului aveți inclus: - accesul la sesiunile științifice; - accesul la spațiul expozițional; - diplomă EMC; - mapă de participant (ecuson, materiale informative, agendă, pix); - participarea la activitățile sociale; - mese (prânz și cină) și pauze de cafea.

De ce să participaţi?

1. Veţi afla care este viitorul medicinei oncologice în România de la specialişti de renume internaţional, precum: - Bojan Zaric - Cristian Moldovan - Alina Mihai - Xavier Pivot

2. NOUTĂŢI: Veţi afla detalii despre tumorile pulmonare şi rolul radioterapiei ablative

3. Vă veţi bucura de o evadare la munte: plimbări, SPA şi vizită la Arka Park

Informaţii suplimentare Patricia Tulcan - patricia@getaungurean.ro 0751 510 020 Geta Ungurean - gu@getaungurean.ro 0741 095 203 Organizator:

Cu sprijinul: AOPR; Diasan

Posibilități de cazare Special pentru participanții la conferință, în calitate de organizatori, dorim să ne asigurăm că veți beneficia de prețuri preferențiale în hotelurile și pensiunile din Păltiniș. Lista cu prețurile negociate de agenție se regăsește mai jos: Distanța față de Hohe Rinne

Tarif cameră/noapte

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Hotel

Stele

STANDARD DOUBLE ROOM double use

SUPERIOR DOUBLE ROOM double use

STANDARD DOUBLE ROOM single use

SUPERIOR DOUBLE ROOM single use

STANDARD FAMILY SUITE

SUPERIOR FAMILY SUITE

Hohe Rinne Păltiniș Hotel & Spa.

4*

193 RON

219 RON

170 RON

193 RON

253 RON

280 RON

0

Cindrel

4*

220

280

170

215

440

500 m

Vila Romană Păltiniș

3*

119

220

4 km

Nume autori

Martie 2014

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Case Presentations

Dasatinib-Associated Transient Peripheral Blood Appearance of a Clonal Large Granular Lymphocytic Population in a Philadelphia-Positive Acute Lymphoblastic Leukemia Patient: A Case Report

Dasatinib-Associated Transient Peripheral Blood Appearance of a Clonal Large Granular Lymphocytic Population in a Philadelphia-Positive Acute Lymphoblastic Leukemia Patient: A Case Report Apariția Temporară în Sânge, Asociată cu Dasatinib, a Unei Populații Clonale de Limfocite Mari Granulare la un Pacient cu Leucemie Acută Limfoblastică Filadelfia-Pozitivă Cristina M. Ghiuzeli North-Shore University Hospital and Long Island Jewish Medical Center, Hofstra North Shore-LIJ School of Medicine, Manhassett, NY, USA Coresponding author: Cristina M. Ghiuzeli cghiuzeli@nshs.edu

Abstract: Keywords:

Cite this article: Ghiuzeli C M, DasatinibAssociated Transient Peripheral Blood Appearance of a Clonal Large Granular Lymphocytic Population in a Philadelphia-Positive Acute Lymphoblastic Leukemia Patient: A Case Report. Rom J Oncol Hematol. 2014; 2(1):30-34

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Dasatinib, Sprycel, Large Granular Lymphocytes, Lymphocytosis, Acute Lymphoblastic Leukemia, Philadelphia Chromosome

Dasatinib (Sprycel) is a potent Breakpoint Cluster Region-Abelson (BCR-ABL) oral tyrosine kinase inhibitor which has been used in the treatment of Philadelphia-positive hematological malignancies such as Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL). Herein, we describe a case in which the continuous administration of Dasatinib led, after two months, to the transient appearance of a clonal, Natural-Killer (NK)-like T-cell population.

This was first detected by the presence of an increased white blood cell count consisting of lymphocytes, and review of the peripheral smear showed large granular lymphocytes. The lymphocytosis and the associated leukocytosis resolved within three weeks without any interventions while the patient continued Dasatinib. This paper will review the current literature on this subject, which suggests that Dasatinib-associated large granular lymphocytosis (LGL) is associated with a superior disease response.

Ghiuzeli M. Cristina

Rezumat: Cuvinte-cheie: Dasatinib, Sprycel, limfocite mari granulare, leucemie acuta limfoblastică, cromozomul Filadelfia

Dasatinib (Sprycel) este un inhibitor oral extrem de eficient al tirozinkinazei Breakpoint Cluster Region-Abelson (BCR-ABL) folosit în tratamentul tumorilor maligne hematologice, cum ar fi leucemia cronică mieloidă și leucemia acută limfoblastică. În acest articol descriem un caz în care administrarea continuă a Dasatinibului a provocat după două luni apariția temporară a unei clone de celule de tipul Natural-Killer (NK)-like T-cells. Această clonă a fost inițial detectată prin prezența unei limfocitoze periferice; revizuirea frotiului de sânge a arătat o populație de limfocite mari granulare. Limfocitoza și leucocitoza asociată au revenit la normal în decursul a trei săptămâni fără nici o intervenție. În acest articol rezumăm literatura curentă pe acest subiect, care sugerează că limfocitoza granulară cu celule mari indusă de Dasatinib este asociată cu răspunsuri superioare în tratamentul tumorilor maligne hematologice.

Abbreviations: BCR-ABL=Breakpoint Cluster Region-Abelson, ALL=Acute Lymphoblastic Leukemia, CML=Chronic Myeloid Leukemia, TKI=Tyrosine Kinase Inhibitor, LGL=Large Granular Lymphocyte, TCR=T-cell receptor, WBC=White Blood Cells, PCR=Polymerase Chain Reaction, NK=Natural Killer cells, PCR=Polymerase Chain Reaction, CMV=Cytomegalovirus, BAL= Bronchoalveolar Lavage

Introduction: Tyrosine kinase inhibitors are a family of oral, smallmolecule drugs that are targeted against the oncogenic fusion protein BCR-ABL, which is formed when the ABL gene on chromosome 9 joins to the BCR gene on chromosome 22, leading to the characteristic t (9;22) known as the Philadelphia chromosome (1-3). This is the pathognomonic translocation in CML, but can also be found in 20% of adult ALL and 50% of elderly ALL patients (4).

The first generation BCR-ABL TKI is Imatinib (Gleevec), with second-generation BCR-ABL Dasatinib (Sprycel), Nilotinib (Tasigna) and Bosutinib (Bosulif) which are several orders of magnitude more potent than Imatinib. Nilotinib, for example, is a close analog of Imatinib, but it has a 20-fold higher potency for BCR-ABL kinase inhibition than Imatinib, whereas Dasanitib has yet another 10-fold increased potency compared to Nilotinib (5,6). In addition, novel kinase and non-kinase targets have been described in these TKI’s, and Dasatinib in particular was developed as an immunosuppressor with dual specificity against BCR-ABL and SRC-kinases (7,8).

Dasatinib’s unique SRC-kinase and TEC family kinase activities are thought to contribute to its immunomodulatory properties, as these proteins play a role in the signaling pathways of the T- and B-cell receptors (7). One such immunomodulatory phenomenon that has been observed is the appearance of Large Granular Lymphocytosis (LGL) in the peripheral blood of approximately 30% of patients treated

with this drug (9-14). Furthermore, the patients with LGL were also noted to present an increased incidence of autoimmune-mediated side effects such as pleural effusions, colitis, and fever (8,11,15).

In this paper, we describe the case of a Philadelphiapositive Acute Lymphoblastic Leukemia patient who was treated with Dasatinib, developed LGL and ple­ ural effusions, and had a favorable clinical response.

Case Presentation: Mr. V.S. is a 73 year old male who initially presented to his primary care physician with dyspnea on exertion and lower extremity edema. A complete blood count done by his primary care physician revealed a white blood cell count (WBC) of 50,000/ul (10% neutrophils, 1% myelocytes, and 89% blasts), a hemoglobin concentration of 5.9 g/dl, and a platelet count of 181,000/ul, and based on it he was referred for hospital admission.

The blood chemistry data obtained on admission were as follows: sodium of 139 mmol/L, potassium of 4.3 mmol/L, chloride of 103 mmol/L, carbon dioxide of 24 mmol/L, blood urea nitrogen of 24 mg/dl and a creatinine of 1.27 mg/dl. The liver function testing showed a total protein of 7.1 g/dl, serum albumin of 3.7 g/dl, aspartate aminotransferase (AST/SGOT) of 40 U/L, alanine aminotransferase (ALT/SGPT) of 21 U/L, total bilirubin of 0.3mg/dl, and an alkaline phosphatase of 86 U/L. The lactate dehydrogenase level was significantly elevated at 1056 U/L (normal range is between 50 and 242 U/L), with a uric acid of 8.4 mg/dl. The coagulation profile showed an activated partial thromboplastin time of 24.7 seconds, a prothombin time of 13.9 seconds with a corresponding INR ratio of 1.23, a fibrinogen of 478 mg/dl and an elevated D-dimer assay of 1067 ng/ml (normal range is between 0 and 499 ng/ml).

The patient received packed red blood cell transfusions for the anemia which led to symptomatic improvement. The physical exam was significant for lower extremity edema bilaterally, with no lymphaMartie 2014

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Case Presentations

Dasatinib-Associated Transient Peripheral Blood Appearance of a Clonal Large Granular Lymphocytic Population in a Philadelphia-Positive Acute Lymphoblastic Leukemia Patient

Figure 1

denopathy or hepatosplenomegaly. Computer tomography (CT) scanning of the chest/abdomen/pelvis showed a left lower lobe pneumonia which was treated with intravenous antibiotics, but there was no evidence of lymph node enlargement, mediastinal masses, or hepatic/splenic enlargement.

A bone marrow biopsy was performed, which showed a hypercellular marrow (up to 100% cellularity) with an extensive infiltrate of immature cells, scattered erythroid precursors and megakaryocytes with normal morphology. The flow cytometry studies showed a lymphoblast population (78% of cells), positive for HLA-DR, CD38, (partial) CD34, CD19, CD10, CD22, (partial) CD20, (partial) CD15 and negative for CD13, CD 33, CD117 and surface kappa and lambda light chain determinants. The blasts were positive for TdT by immunofluorescence staining. The findings were consistent with B-lymphoblastic leukemia. Chromosomal analysis showed an abnormal karyotype: eleven out of twenty examined metaphases had the t(9;22) Philadelphia (Ph+) chromosome, nine metaphases had a normal 46XY male karyotype, and one of the eleven Ph+ metaphases had additional copies of chromosomes 6, 8, 12, 14, 21 making up for a total of 54 XY. Florescence in situ hybridization (FISH) was also positive for BCR/ABL1 (9q34/22q11.2) rearrangement in 83.5% of cells.

The patient consented to be enrolled in a phase II multi-institutional clinical trial of Dasatinib as a primary treatment in Ph+ ALL adults over the age of 50 (Cancer and Leukemia Group B, CALGB 10701, NCT01256398). A pre-treatment Multiple-Gated Acquisition (MUGA) scan showed a normal ejection fraction of 60%. His induction course consisted of continuous Dasatinib 140 mg orally daily in combination with Dexamethasone 10 mg/m2/day orally for days 1-7, and given the good response on the day 15

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bone marrow biopsy (less than 20% marrow blasts), the patient continued treatment on single agent Dasatinib treatment.

After 20 days, the patient developed shortness of breath, and a chest X-ray showed new bilateral pleural effusions. There was no change to his ejection fraction on a trans-thoracic echocardiogram, and the effusions were attributed to Dasatinib. He was treated with the diuretic Furosemide, and due to persistence of symptoms, Dasatinib was briefly interrupted and the patient underwent a thoracoscopy which effusion drainage. The dose of his Dasatinib was resumed at 100 mg orally daily, which he then tolerated well. A day 30 bone marrow biopsy showed complete morphological remission as well as a normal karyotype, 46XY and FISH negative for BCR-ABL1.

As an outpatient, he continued on oral Dasatinib 100mg daily with Furosemide for residual lower extremity edema and small pleural effusions, and his complete blood counts were drawn at weekly intervals. He was noted (after about two months from the initiation of Dasatinib) to have an elevated WBC count of 10.4 K/ul, with an absolute neutrophil number of 3400/ul, absolute lymphocyte number of 6200/ul (normal range is between 1000/ul and 3300/ul), absolute monocyte count of 800/ul, 100/ul eosinophils and 0 basophils. Peripheral smear showed an increased number of large granular lymphocytes, with no blasts present. The hemoglobin was 10.8 g/dl, with a platelet count of 306 k/ul. Peripheral blood was sent for flow cytometry and it identified, by morphology, 42% lymphocytes and 36% large granular lymphocytes. The immunophenotype showed Natural-Killer (NK)-like T cells (19% of cells) positive for CD2, CD3, CD5, CD7, CD8, CD56, CD57 and TCR alpha/beta.

Natural killer cells were also present (10% of cells) and T-cells, with decreased CD4 to CD8 ratio (CD4% was

Ghiuzeli M. Cristina

Figure 2

16, CD8% was 72, with CD4/8 ratio of 0.23 –normal range is between 0.90 and 3.60). Molecular studies for T-cell receptor (TCR) gene rearrangement identified discrete bands in both TCR-beta and TCR-gamma analysis, suggestive of a clonal T-cell population. The patient had no lymphadenopathy, hepatosplenomegaly or dyspnea. As a result of a low-grade fever (100.8 degrees Fahrenheit), blood cultures, urine cultures, chest x-rays and Cytomegalovirus (CMV) titer via Polymerase Chain Reaction (PCR) were checked.

The CMV PCR titer was low-positive at 500; this was monitored with no antiviral therapy, and it became negative approximately two weeks later.

The patient was monitored clinically, and his lymphocytosis was noted to gradually decrease over the course of three weeks to normal, and not to recur despite the continued administration of Dasatinib at the same dose. He achieved a deep disease response at six months of treatment, namely bone marrow molecular complete response as evidenced by a negative BCR-ABL by Polymerase Chain Reaction (PCR). He is currently on continuous maintenance phase, which includes Dasatinib in addition to oral Methotrexate, oral 6-Mercaptopurine and monthly intravenous Vincristine and oral Dexamethasone, and has maintained a bone marrow morphological remission at a year and a half since diagnosis.

Discussions Large Granular Lymphocytes (LGL) generally represent 10-15% of the circulating mononuclear cells in adults, with most having an NK-cell phenotype (CD3-, CD16+, CD56+) (9). A clonal increase in the number of peripheral blood LGL’s generally leads to the diagnosis of LGL Leukemia, an indolent lymphoproliferative disorder that is clinically characterized by lymphocytosis, cytopenias (most commonly neutropenia and ane-

mia), hepatosplenomegaly, fever, and autoimmune conditions (most commonly rheumatoid arthritis) (16).

LGL Leukemia, in the appropriate clinical setting (such as severe neutropenia or anemia), requires treatment with immunosuppressive agents, typically oral Methotrexate or oral Cyclophosphamide (17).

However, it has been recognized that both monoclonal and oligoclonal LGL expansions can occur after allogeneic stem cell transplantation, and in the setting of chronic viral infections (18). When present, they are associated with long-term remission in leukemic patients (19). Similarly, LGL has been described in around 30%-40% of leukemia patients on Dasatinib, and its presence has been associated with increased therapeutic response (12-14). In contrast to LGL leukemia, the lymphocytosis does not require any intervention, and it ceases once Dasatinib is discontinued, though lymphocyte values can vary during treatment (14) . Similarly, in our patient, lymphocytosis developed two months after Dasatinib treatment, but it decreased to normal values and remained in the normal range after three weeks.

Mustjoki et. al. (12), in a comparative study of 55 leukemia patients treated with a TKI, showed that the large granular lymphocytosis (LGL) is a phenomenon that is unique to Dasatinib (present in 38% of patients), and is not observed in patients who were treated with Imatinib, Nilotinib or Bosutinib, though all TKI’s can lead to clonal expansions of memory cytotoxic T-cells (11). In patients who developed LGL, both with an underlying diagnosis of CML and Ph+ ALL, molecular responses obtained were superior to the patients who did not have lymphocytosis (13,14). This was seen in our patient, who obtained a complete molecular response by bone marrow PCR about six months after diagnosis, thus after the development of the transient lymphocytosis and LGL. Martie 2014

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Case Presentations

Dasatinib-Associated Transient Peripheral Blood Appearance of a Clonal Large Granular Lymphocytic Population in a Philadelphia-Positive Acute Lymphoblastic Leukemia Patient

However, the Dasatinib-induced lymphocytosis has been implicated in the autoimmune-like adverse events reported with this drug, namely lung manifestations (both pleural effusions and lung parenchymal involvement), colitis, and fevers (13). In a study of 40 patients with CML treated on Dasatinib, 22.5% developed lung abnormalities attributable to Dasatinib; pleural effusion fluid revealed lymphocyte-predominant exudates, and these findings were consistent with pleural biopsy and Bronchoalveolar Lavage fluid (BAL) analyses (8,15). Pleural fluid immunophenotyping done in another trial by Mustjoki et. al. in patients treated with Dasatinib who experienced pleural effusions confirmed the presence of a clonal T-LGL cell population (13). Our patient developed pleural effusions prior to the appearance of lymphocytosis, and temporary discontinuation of the Dasatinib as well as thoracocentesis led to symptomatic improvement of dyspnea.

Another association with the clonal expansion of NK/T-cells in Dasatinib treated patients has been CMV reactivation. In the Mustjoki et. al. trial which included 22 Ph+ ALL patients on Dasatinib with lymphocytosis, 9 patients had modest CMV reactivation, with CMV genome load paralleling the degree of lymphocytosis (13). This resolved without any antiviral treatment, as it did in our patient. Also, CD4+ T-cell counts were noted to be decreased, with an increase in CD8+ T-cells, as seen in our patient (13,18).

Finally, it is important to highlight two more findings related to the Dasatinib-induced LGL process.

The first is that it appears that a significant number of patients have clonal lymphocytes present at CML diagnosis, and the clone size expands with the administration of Dasatinib, but not Imatinib, leading to the observed peripheral blood lymphocytosis (20).

In the study population of 34 CML patients, (20 of whom subsequently received Dasatinib and 14 were given Imatinib), 83% had a clonal, BCR-ABL1 negative lymphocyte population, whereas clonal lymphocytes were seen in only 8% of healthy control patients (20) . In 69% of the cases, the clone found in follow-up samples was identical to the one at diagnosis, supporting the observation that Dasatinib favors the expansion of this preexisting clone.

The second interesting finding comes from a recent study published by Mustjoki et. al. in which 55 Ph+ ALL patients on TKI’s had blood samples drawn at specified time points from drug intake (12). It appears that the fluctuation in lymphocyte counts is associated with the timing of blood draws, and the degree of lymphocytosis is dose-dependent, with peak drug and lymphocyte levels at one to two hours after drug intake, and with a rapid decline thereafter.

The authors conclude that the previously observed lymphocytosis is merely a reflection of drug administration-related timing.

In our patient, the LGL lymphocytosis was shortlived, and it did not recur despite frequent blood count monitoring, but Mustjoki’s study does raise the issue of consistent monitoring of lymphocyte counts at a constant time-interval from oral Dasatinib administration. In the future, complete blood counts with differentials drawn precisely one to two hours after Dasatinib should be followed in all patients. Based on the degree of lymphocytosis at that time point, drug dose intensification should be investigated in clinical trials given the favorable clinical outcomes seen in patients with lymphocytosis.

Conflicts of Interest/Conflict de Interese: none/ nici unul.

Bibliography 1. Denny CT, Shah NP, Ogden S, et al: Localization of preferential sites of rearrangement within the BCR gene in Philadelphia chromosome-positive acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 86:4254-8, 1989 2. Barrett J, Guimaraes A, Cullis J, et al: Immunological characterization of the tumor-specific bcr/abl junction of Philadelphia chromosome positive chronic myeloid leukemia. Stem Cells 11 Suppl 3:104-8, 1993 3. Dhut S, Chaplin T, Young BD: BCR-ABL and BCR proteins: biochemical characterization and localization. Leukemia 4:745-50, 1990 4. Ribera JM: Optimal approach to treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: how to best use all the available tools. Leuk Lymphoma 54:21-7, 2013 5. Lombardo LJ, Lee FY, Chen P, et al: Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658-61, 2004 6. Weisberg E, Manley PW, Breitenstein W, et al: Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7:129-41, 2005 7. Rix U, Hantschel O, Dürnberger G, et al: Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 110:40554063, 2007 8. Sillaber C, Herrmann H, Bennett K, et al: Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest 39:1098-109, 2009 9. Valent JN, Schiffer CA: Prevalence of large granular lymphocytosis in patients with chronic myelogenous leukemia (CML) treated with dasatinib. Leuk Res 35:e1-3, 2011 10. Kreutzman A, Juvonen V, Kairisto V, et al: Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood

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116:772-782, 2010 11. Powers JJ, Dubovsky JA, Epling-Burnette PK, et al: A molecular and functional analysis of large granular lymphocyte expansions in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors. Leuk Lymphoma 52:668-79, 2011 12. Mustjoki S, Auvinen K, Kreutzman A, et al: Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy. Leukemia 27:914-24, 2013 13. Mustjoki S, Ekblom M, Arstila TP, et al: Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia 23:1398-405, 2009 14. Kim DH, Kamel-Reid S, Chang H, et al: Natural killer or natural killer/T cell lineage large granular lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive leukemia. Haematologica 94:135-9, 2009 15. Bergeron A, Rea D, Levy V, et al: Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. Am J Respir Crit Care Med 176:814-8, 2007 16. Zhang D, Loughran TP: Large granular lymphocytic leukemia: molecular pathogenesis, clinical manifestations, and treatment. ASH Education Program Book 2012:652-659, 2012 17. Lamy T, Loughran TP, Jr.: How I treat LGL leukemia. Blood 117:2764-74, 2011 18. Kreutzman A, Ladell K, Koechel C, et al: Expansion of highly differentiated CD8+ T-cells or NKcells in patients treated with dasatinib is associated with cytomegalovirus reactivation. Leukemia 25:1587-97, 2011 19. Mohty M, Faucher C, Vey N, et al: Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis. Leukemia 16:2129-33, 2002 20. Kreutzman A, Juvonen V, Kairisto V, et al: Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood 116:772-82, 2010

Nume autori

“Îndrumar pentru examenul practic în specialitatea ORL și chirurgie cervico-facială” Apariție: 2013 Autori: Prof. Dr. Romeo Călărașu, Dr. Tiberiu Dimitriu, Dr. Daniela Safta Coautori: Dr. Ileana Linaru și Dr. Loredana Mitran Adresare: medici primari și specialiști ORL, chirurgi, studenți, rezidenți “Numeroasele examene şi concursuri pe care trebuie să le susţină fiecare medic după terminarea facultăţii solicită din partea fiecărui cadru medical o susţinută şi continuă documentare. În sprijinul acestora, periodic s-au publicat diferite materiale, ce au folosit la buna desfăşurare a acestor examene.

În acest context, ne-am gândit să venim în ajutorul colegilor mai tineri, cu experienţa noastră, acumulată în decursul anilor, în activitatea clinică, dar şi în pregătirea pe care noi înşine a trebuit să o facem, când am fost nevoiţi să susţinem diferite examene şi concursuri.

Tematica, stabilită de minister,

pe specialităţile cu profil chirurgical, implică, obligatoriu, o probă practică, cu diferite operaţii, ce trebuie susţinută şi practicată de către candidat.”

Prof. Dr. Romeo Călăraşu, Dr. Daniela Safta, Dr. Tiberiu Dimitriu

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ONCOLOGy

Most of these articles are freely available by searching the Medline database (pubmed.com) for the article’s name, the first author’s name and/or the journal’s name. A Google search is useful for article collections that are recommended here.

Effect of Acute Exercise on Prostate Cancer Cell Growth Helene Rundqvist et al.

Abstract Physical activity is associated with reduced risk of several cancers, including aggressive prostate cancer. The mechanisms mediating the effects are not yet understood; among the candidates are modifications of endogenous hormone levels. Long-term exercise is known to reduce serum levels of growth stimulating hormones. In contrast, the endocrine effects of acute endurance exercise include increased levels of mitogenic factors such as GH and IGF-1. It can be speculated that the elevation of serum growth factors may be detrimental to prostate cancer progression into malignancy. The incentive of the current study is to evaluate the effect of acute exercise serum on prostate cancer cell growth. We designed an exercise intervention where 10 male individuals performed 60 minutes of bicycle exercise at increasing intensity. Serum samples were obtained before (rest serum) and after completed exercise (exercise serum). The established prostate cancer cell line LNCaP was exposed to exercise or rest serum. Exercise serum from 9 out of 10 individuals had a growth inhibitory effect on LNCaP cells. Incubation with pooled exercise serum resulted in a 31% inhibition of LNCaP growth and pre-incubation before subcutaneous injection into SCID mice caused a delay in tumor formation. Serum analyses indicated two possible candidates for the effect; increased levels of IGFBP-1 and reduced levels of EGF. In conclusion, despite the fear of possible detrimental effects of acute exercise serum on tumor cell growth, we show that even the short-term effects seem to add to the overall beneficial influence of exercise on neoplasia.

Citation: Rundqvist H, Augsten M, Strömberg A, Rullman E, Mijwel S, et al. (2013) Effect of Acute Exercise on Prostate Cancer Cell Growth. PLoS ONE 8(7): e67579. doi:10.1371/journal.pone.0067579

Genetic Variants in Hormone-Related Genes and Risk of Breast Cancer Tess Clendenen et al.

Abstract Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.

Citation: Clendenen T, Zeleniuch-Jacquotte A, Wirgin I, Koenig KL, Afanasyeva Y, et al. (2013) Genetic Variants in Hormone-Related Genes and Risk of Breast Cancer. PLoS ONE 8(7): e69367. doi:10.1371/ journal.pone.0069367

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A Gene Signature to Determine Metastatic Behavior in Thymomas Yesim Gรถkmen-Polar et al.

Abstract Purpose Thymoma represents one of the rarest of all malignancies. Stage and completeness of resection have been used to ascertain postoperative therapeutic strategies albeit with limited prognostic accuracy. A molecular classifier would be useful to improve the assessment of metastatic behaviour and optimize patient management.

Methods qRT-PCR assay for 23 genes (19 test and four reference genes) was performed on multiinstitutional archival primary thymomas (n = 36). Gene expression levels were used to compute a signature, classifying tumors into classes 1 and 2, corresponding to low or high likelihood for metastases. The signature was validated in an independent multi-institutional cohort of patients (n = 75).

Results A nine-gene signature that can predict metastatic behavior of thymomas was developed and validated. Using radial basis machine modeling in the training set, 5-year and 10-year metastasisfree survival rates were 77% and 26% for predicted low (class 1) and high (class 2) risk of metastasis (P = 0.0047, log-rank), respectively. For the validation set, 5-year metastasis-free survival rates were 97% and 30% for predicted low- and high-risk patients (P = 0.0004, log-rank), respectively.

The 5-year metastasis-free survival rates for the validation set were 49% and 41% for Masaoka stages I/II and III/IV (P = 0.0537, log-rank), respectively. In univariate and multivariate Cox models evaluating common prognostic factors for thymoma metastasis, the nine-gene signature was the only independent indicator of metastases (P = 0.036).

Conclusions A nine-gene signature was established and validated which predicts the likelihood of metastasis more accurately than traditional staging. This further underscores the biologic determinants of the clinical course of thymoma and may improve patient management.

Citation: Gรถkmen-Polar Y, Cook RW, Goswami CP, Wilkinson J, Maetzold D, et al. (2013) A Gene Signature to Determine Metastatic Behavior in Thymomas. PLoS ONE 8(7): e66047. doi:10.1371/ journal.pone.0066047

Interferon-Based Therapy Decreases Risks of Hepatocellular Carcinoma and Complications of Cirrhosis in Chronic Hepatitis C Patients Ching-Sheng Hsu et al.

Abstract Background Interferon-based therapy (IBT) has been the standard of care for hepatitis C virus (HCV) infection.

However, conflicting results exist regarding the effects of IBT on risk of developing hepatocellular carcinoma (HCC) and cirrhosis-associated complications, and most included highly selected patients.

Methods This 8-year cohort study was based on the Longitudinal Health Insurance Database 2000 (LHID 2000) consisting of 1,000,000 beneficiaries randomly selected from all Taiwan National Health Insurance enrollees in 2000 (>23.7 million). Patients with newly detected HCV infections (n = 11,264) were classified based on treatment and clinical outcomes. IBTs were defined as regimens that included interferon- alfa, pegylated interferon- alfa -2a, or pegylated interferon- alfa -2b for at least 3 months.

The Cox proportional hazards models were used to estimate the hazard ratio (HR) and associated confidence interval (CI) of HCC and cirrhosis-associated complications for IBT. Martie 2014

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Alegerea Editorului din Literatură Results The 8-year incidence rate for HCC was 3.9% among patients who received IBT and 5.6% among those who did not. The HCC-free survival rate was significantly higher among patients receiving IBT during the 8-year period than their counterpart (adjusted HR, 0.50; 95% CI, 0.31–0.81; P = .004).

Similarly, the event-free survival rates for esophageal variceal bleeding (adjusted HR, 0.45; 95% CI, 0.22–0.91; P = .026), hepatic encephalopathy (adjusted HR, 0.38; 95% CI, 0.21–0.69; P = .001), ascites (adjusted HR, 0.28; 95% CI, 0.14–0.57; P<.001), and cirrhosis (adjusted HR, 0.63; 95% CI, 0.44–0.91; P = .013) were significantly higher among patients who received IBT than those who did not, after adjustment for associated factors.

ONCOLOGy

Conclusion Treatment with interferon may reduce the 8-year risk of HCC and cirrhosis-associated complications in patients with chronic HCV infection.

Citation: Hsu C-S, Huang C-J, Kao J-H, Lin HH, Chao Y-C, et al. (2013) Interferon-Based Therapy Decreases Risks of Hepatocellular Carcinoma and Complications of Cirrhosis in Chronic Hepatitis C Patients. PLoS ONE 8(7): e70458. doi:10.1371/journal.pone.0070458

Senescence and aging: the critical roles of p 53 A Rufini et al.

Abstract p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is an irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context. In this review, we focus on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and we will discuss p53’s impact on animal lifespan. Moreover, we describe p53-mediated regulation of several physiological pathways that could mediate its role in both senescence and aging.

Citation: Oncogene (2013) 32, 5129–5143; doi:10.1038/onc.2012.640

Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET T Mitamura et al.

Abstract Ovarian cancer is one of the most aggressive female reproductive tract tumors. Paclitaxel (PTX) is widely used for the treatment of ovarian cancer. However, ovarian cancers often acquire chemotherapeutic resistance to this agent. We investigated the mechanism of chemoresistance by analysis of microRNAs using the ovarian cancer cell line KFr13 and its PTX-resistant derivative (KFr13Tx). We found that miR-31 was downregulated in KFr13Tx cells, and that re-introduction of miR31 re-sensitized them to PTX both in vitro and in vivo. miR-31 was found to bind to the 3′-UTR of mRNA of MET, and the decrease in MET correlated to higher sensitivity to PTX. Furthermore, co-treatment of KFr13Tx cells with MET inhibitors sensitized the tumor cells to PTX both in vitro and in vivo. In addition, lower levels of miR31 and higher expression of MET in human ovarian cancer specimens were significantly correlated with PTX chemoresistance and poor prognosis. This study demonstrated miR31-dependent regulation of MET for chemoresistance of ovarian cancer, raising the possibility that combination therapy with a MET inhibitor and PTX will increase PTX efficacy.

Citation: Oncogenesis (2013) 2, e40; doi:10.1038/oncsis.2013.3

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The ‘N-factors’ in pancreatic cancer: functional relevance of NF-κB, NFAT and Nrf2 in pancreatic cancer A Arlt et al.

Abstract Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies, with an overall life expectancy of 6 months. Despite considerable advances in the understanding of the molecular mechanisms involved in the carcinogenesis of PDAC, the outcome of the disease was not significantly improved over the last 20 years. Although some achievements in molecular-targeted therapies have been made (that is, targeting the epidermal growth factor receptor by erlotinib), which already entered clinical settings, and despite the promising outcome of the FOLFIRINOX trial, there is an urgent need for improvement of the chemotherapy in this disease. A plethora of molecular alterations are thought to be responsible for the profound chemoresistance, including mutations in oncogenes and tumor suppressors. Besides these classical hallmarks of cancer, the constitutive or inducible activity of transcription factor pathways are characteristic changes in PDAC. Recently, three transcription factors—nuclear factor-κB (NF-κB), nuclear factor of activated T cells (NFAT) and nuclear factor-E2-related factor-2 (Nrf2)—have been shown to be crucial for tumor development and chemoresistance in pancreatic cancer. These transcription factors are key regulators of a variety of genes involved in nearly all aspects of tumorigenesis and resistance against chemotherapeutics and death receptor ligands. Furthermore, the pathways of NF-κB, NFAT and Nrf2 are functional, interacting on several regulatory steps, and, especially, natural compounds such as curcumin interfere with more than one pathway. Thus, targeting these pathways by established inhibitors or new drugs might have great potential to improve the outcome of PDAC patients, most likely in combination with established anticancer drugs. In this article, we summarize recent progress in the characterization of these transcription-factor pathways and their role in PDAC and therapy resistance. We also discuss future concepts for the treatment of PDAC relying on these pathways.

Citation: Oncogenesis (2012) 1, e35; doi:10.1038/oncsis.2012.35

A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop K E Ware et al.

Abstract Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M ‘gate-keeper’ mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones.

Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC. Citation: Oncogenesis (2013) 2, e39; doi:10.1038/oncsis.2013.4 Martie 2014

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Alegerea Editorului din Literatură MicroRNAs in colorectal cancer stem cells: new regulators of cancer stemness?

S Caruso et al.

ONCOLOGy

Abstract Recently, the hypothesis that colorectal tumors originate from a subpopulation of cells called ‘cancer stem cells’ (CSCs) or tumor-initiating cells, which exhibit stem-like features, has been confirmed experimentally in various human cancers. Several studies have confirmed the existence of colorectal CSCs (CRCSCs) and have demonstrated that this rare cell population can be isolated by the expression of specific cell surface biomarkers. MicroRNAs (miRNAs) are a class of small non-coding RNAs, which are crucial for post-transcriptional regulation of gene expression and participate in a wide variety of biological functions, including development, cell proliferation, differentiation, metabolism and signal transduction. Moreover, new evidences suggest that miRNAs could contribute to preserve stemness of embryonic stem cells and could be involved in maintaining stemness of CSCs. Recent studies have begun to outline the role of miRNAs in regulation of CRCSCs. This review aims to summarize the recent advancement about the roles of miRNAs in CRCSCs that may represent a step forward in understanding the molecular mechanisms and the possible approaches for colorectal cancer therapy.

Citation: Oncogenesis (2012) 1, e32; doi:10.1038/oncsis.2012.33

A Hormone–DNA Repair Circuit Governs the Response to Genotoxic Insult Jonathan F. Goodwin et al.

Abstract Alterations in DNA repair promote tumor development, but the impact on tumor progression is poorly understood. Here, discovery of a biochemical circuit linking hormone signaling to DNA repair and therapeutic resistance is reported. Findings show that androgen receptor (AR) activity is induced by DNA damage and promotes expression and activation of a gene expression program governing DNA repair.

Subsequent investigation revealed that activated AR promotes resolution of double-strand breaks and resistance to DNA damage both in vitro and in vivo. Mechanistically, DNA-dependent protein kinase catalytic subunit (DNAPKcs) was identified as a key target of AR after damage, controlling AR-mediated DNA repair and cell survival after genotoxic insult. Finally, DNAPKcs was shown to potentiate AR function, consistent with a dual role in both DNA repair and transcriptional regulation. Combined, these studies identify the AR–DNAPKcs circuit as a major effector of DNA repair and therapeutic resistance and establish a new node for therapeutic intervention in advanced disease.

SIGNIFICANCE: The present study identifies for the first time a positive feedback circuit linking hormone action to the DNA damage response and shows the significant impact of this process on tumor progression and therapeutic response. These provocative findings provide the foundation for development of novel nodes of therapeutic intervention for advanced disease.

Citation: Cancer Discov; 3(11); 1–18.

Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers William R. Polkinghorn et al.

Abstract We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent

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direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining.

Significance: We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer.

Citation: Cancer Discov; 3(11); 1–9.

Quantifying the natural history of breast cancer K H X Tan et al.

Abstract Background Natural history models of breast cancer progression provide an opportunity to evaluate and identify optimal screening scenarios. This paper describes a detailed Markov model characterising breast cancer tumour progression.

Methods Breast cancer is modelled by a 13-state continuous-time Markov model. The model differentiates between indolent and aggressive ductal carcinomas in situ tumours, and aggressive tumours of different sizes. We compared such aggressive cancers, that is, which are non-indolent, to those which are non-growing and regressing. Model input parameters and structure were informed by the 1978 1984 Ostergotland county breast screening randomised controlled trial. Overlaid on the natural history model is the effect of screening on diagnosis. Parameters were estimated using Bayesian methods.

Markov chain Monte Carlo integration was used to sample the resulting posterior distribution.

Results The breast cancer incidence rate in the Ostergotland population was 21 (95% CI: 17–25) per 10 000 woman-years. Accounting for length-biased sampling, an estimated 91% (95% CI: 85–97%) of breast cancers were aggressive. Larger tumours, 21–50 mm, had an average sojourn of 6 years (95% CI: 3–16 years), whereas aggressive ductal carcinomas in situ took around half a month (95% CI: 0–1 month) to progress to the invasive 10 mm state.

Conclusions These tumour progression rate estimates may facilitate future work analysing cost-effectiveness and quality-adjusted life years for various screening strategies.

Citation: British Journal of Cancer (2013) 109, 2035–2043. doi:10.1038/bjc.2013.471

The cancer biology of whole-chromosome instability P H G Duijf and R Benezra

Abstract One form of chromosome instability (CIN), the recurrent missegregation of whole chromosomes during cell division (W-CIN), leads to aneuploidy. Although W-CIN is a hallmark of most cancers, mutations in genes involved in chromosome segregation are exceedingly rare. We discuss an oncogene-induced mitotic stress model that provides a mechanistic framework to explain this paradox. We also review the tumor-promoting and tumor-suppressing consequences of W-CIN. Importantly, we do this in the context of cancer as a complex systemic disease, rather than as a simple linearly progressing disorder that arises from a single abnormal cell population. Accordingly, we highlight the often neglected effects of W-CIN on key non-cell-autonomous entities, such as the immune system and the tumor microenvironment. Distinct tissue-specific susceptibilities to W-CIN-induced tumorigenesis and the clinical implications of W-CIN are also discussed.

Citation: Oncogene (2013) 32, 4727–4736; Martie 2014

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Alegerea Editorului din Literatură Complete Genes May Pass from Food to Human Blood Sándor Spisák et al.

HEMATOLOGY

Abstract Our bloodstream is considered to be an environment well separated from the outside world and the digestive tract. According to the standard paradigm large macromolecules consumed with food cannot pass directly to the circulatory system. During digestion proteins and DNA are thought to be degraded into small constituents, amino acids and nucleic acids, respectively, and then absorbed by a complex active process and distributed to various parts of the body through the circulation system. Here, based on the analysis of over 1000 human samples from four independent studies, we report evidence that meal-derived DNA fragments which are large enough to carry complete genes can avoid degradation and through an unknown mechanism enter the human circulation system. In one of the blood samples the relative concentration of plant DNA is higher than the human DNA. The plant DNA concentration shows a surprisingly precise log-normal distribution in the plasma samples while non-plasma (cord blood) control sample was found to be free of plant DNA. Citation: Spisák S, Solymosi N, Ittzés P, Bodor A, Kondor D, et al. (2013) Complete Genes May Pass from Food to Human Blood. PLoS ONE 8(7): e69805. doi:10.1371/journal.pone.0069805

Fibrin Clot Structure and Platelet Aggregation in Patients with Aspirin Treatment Failure Søs Neergaard-Petersen et al.

Abstract Background Aspirin is a cornerstone in prevention of cardiovascular events and modulates both platelet aggregation and fibrin clot formation. Some patients experience cardiovascular events whilst on aspirin, often termed aspirin treatment failure (ATF). This study evaluated both platelet aggregation and fibrin clot structure in patients with ATF. Methods We included 177 stable coronary artery disease patients on aspirin monotherapy. Among these, 116 (66%) had ATF defined as myocardial infarction (MI) whilst on aspirin. Platelet aggregation was assessed by Multiplate® aggregometry and VerifyNow®, whereas turbidimetric assays and scanning electron microscopy were employed to study fibrin clot characteristics.

Results Enhanced platelet aggregation was observed in patients with ATF compared with non-MI patients following stimulation with arachidonic acid 1.0 mM (median 161 (IQR 95; 222) vs. 97 (60; 1776) AU*min, p = 0.005) and collagen 1.0 µg/mL (293 (198; 427) vs. 220 (165; 370) AU*min, p = 0.03). Similarly, clot maximum absorbance, a measure of fibrin network density, was increased in patients with ATF (0.48 (0.41; 0.52) vs. 0.42 (0.38; 0.50), p = 0.02), and this was associated with thinner fibres (mean ± SD: 119.7±27.5 vs. 127.8±31.1 nm, p = 0.003) and prolonged lysis time (552 (498; 756) vs. 519 (468; 633) seconds; p = 0.02). Patients with ATF also had increased levels of C-reactive protein (CRP) (1.34 (0.48; 2.94) and 0.88 (0.32; 1.77) mg/L, p = 0.01) compared with the non-MI group. Clot maximum absorbance correlated with platelet aggregation (r = 0.31–0.35, p-values<0.001) and CRP levels (r = 0.60, p<0.001).

Conclusions Patients with aspirin treatment failure showed increased platelet aggregation and altered clot structure with impaired fibrinolysis compared with stable CAD patients without previous MI. These findings suggest that an increased risk of aspirin treatment failure may be identified by measuring both platelet function and fibrin clot structure.

Citation: Neergaard-Petersen S, Ajjan R, Hvas A-M, Hess K, Larsen SB, et al. (2013) Fibrin Clot Structure and Platelet Aggregation in Patients with Aspirin Treatment Failure. PLoS ONE 8(8): e71150. doi:10.1371/journal.pone.0071150

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Characteristics of chronic GVHD after cord blood transplantation L F Newell et al.

Abstract Most reports of chronic GVHD after cord blood transplantation (CBT) have utilized traditional diagnostic criteria. We used traditional criteria and National Institutes of Health (NIH) criteria prospectively to evaluate chronic GVHD in a cohort of 87 adult and pediatric recipients of single or double unrelated CBT for treatment of hematologic malignancies. Fifty-four patients developed traditionally defined chronic GVHD, for an estimated 2-year probability of 64%. Among 54 patients, 25 (46%) met the NIH criteria for persistent, recurrent or late acute GVHD at onset. Twenty-four (44%) had overlap chronic GVHD, including one who presented initially with late acute GVHD, and only seven (13%) had classic chronic GVHD, including one who also presented initially with late acute GVHD. Among patients who successfully discontinued all systemic immunosuppression (SI), the median time to discontinuation of corticosteroid treatment was 315 days (range 28–977), and the median time to discontinuation of all SI was 353 days (range 67–977). Chronic GVHD diagnosed by traditional criteria after CBT had a predominance of acute GVHD clinical features.

Citation: Bone Marrow Transplantation 48, 1285-1290 (October 2013) | doi:10.1038/bmt.2013.48

Pomalidomide: the new immunomodulatory agent for the treatment of multiple myeloma A A Chanan-Khan et al.

Abstract In this report, we provide a comprehensive review on the preclinical and clinical investigations conducted in development of the next-generation immunomodulatory drug (IMiD) pomalidomide for the treatment of relapsed/refractory multiple myeloma (MM). We consulted PubMed, MEDLINE, ASH, ASCO annual symposium abstracts and http://clinicaltrials.gov/ for the purpose of this literature review. Twenty-six preclinical and 11 clinical studies were examined. These studies delineate the mechanisms of action of pomalidomide and attest to the robust clinical activity in relapsed/refractory MM. MM is the second most common hematological malignancy in the US. Despite availability of several therapeutic agents, MM remains incurable. Thus, the development of new therapies remains a priority. Pomalidomide is the newest member of the IMiDs class of drugs, and in preclinical and clinical investigations, it has demonstrated an improved efficacy and toxicity profile in comparison to its sister compounds, lenalidomide and thalidomide. Importantly, recent clinical studies have demonstrated its activity in relapsed or refractory myeloma, particularly in lenalidomide and bortezomib-refractory patients. Thus, the addition of pomalidomide to the antimyeloma armamentarium is widely anticipated to have a significant impact on the overall clinical outcome of advanced stage relapsed and refractory MM patients.

Citation: Blood Cancer Journal (2013) 3, e143; doi:10.1038/bcj.2013.38

“Role of the B-cell receptor and the microenvironment in chronic lymphocytic leukemia’’ P Oppezzo and G Dighiero

Abstract Despite significant progress in treatment, chronic lymphocytic leukemia (CLL) remains an incurable disease. Advances have been made to understand the molecular pathogenesis underlying CLL progression and treatment resistance. We here review the available evidences concerning the role of the B-cell receptor (BCR) and the tumor microenvironment interactions in CLL pathogenesis. Antigen likely has a key role in the selection of the tumoral clone, the mutational status of immunoglobulin genes is a strong prognostic predictor and BCR signaling Martie 2014

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Alegerea Editorului din Literatură has been postulated to have a role for CLL trafficking and interaction with the stromal microenvironment. There is also important evidence, favoring a role for the microenvironment in CLL pathogenesis. Most, if not all, proliferative events occur in the lymph nodes and bone marrow, where leukemic cells receive through microenvironment interactions survival signals aiming to avoid apoptosis and acquire favorable tumoral growing conditions. In addition, the tumoral microenvironment appears to be the site where the acquisition of additional genetic lesions in the clone occur, which should greatly influence clinical outcome. The advent of new tyrosine kinase inhibitors which seem to be able to modulate microenvironment interactions and circumvent the p53 deletion have generated significant promise by raising the possibility that they could provide significant progress in disease treatment.

HEMATOLOGY

Citation: Blood Cancer Journal (2013) 3, e149; doi:10.1038/bcj.2013.45

Hematopoietic SCT in Europe: data and trends in 2011 J R Passweg et al.

Abstract In all, 651 from 680 centers in 48 countries reported 35 660 hematopoietic SCT (HSCT) in 32 075 patients (13 470 allogeneic (42%), 18 605 autologous (58%)) to the 2011 survey.

Main indications were: leukemias; 10 113 (32%; 94% allogeneic); lymphoid neoplasias; non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, plasma cell disorders; 18 433 (57%; 12% allogeneic); solid tumours; 1573 (5%; 5% allogeneic); and non-malignant disorders; 1830 (6%; 92% allogeneic). There were more unrelated donors than HLA identical sibling donors (54% versus 39%); proportion of peripheral blood as stem cell source was 99% for autologous and 73% for allogeneic HSCT. Cord blood was only used in allogeneic transplants (6% of total). In the past 10 years, the overall number of transplants has increased by 53%.

Allogeneic HSCT have doubled (from 7272 to 14 549) while, autologous have increased by 32% and continue to increase by about 1100 HSCT per year since 2001. In the past 2 years, an increase of >2000 HSCT per year was seen. Transplant activity is shown by team size.

For allogeneic HSCT, we show use of reduced-intensity conditioning versus myeloablative conditioning across Europe and use of post-transplant donor lymphocyte infusions with considerable variation across different countries.

Citation: Bone Marrow Transplantation (2013) 48, 1161–1167; doi:10.1038/bmt.2013.51

Light-chain amyloidosis: SCT, novel agents and beyond M Rosenzweig et al.

Abstract Light-chain amyloidosis is a plasma cell dyscrasia characterized by the production of fibrillar proteins comprised of monoclonal light chains, which deposit in tissues causing multiorgan dysfunction and death. The diagnosis is challenging and requires a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains, which improve organ function and extend survival. Standard treatment approaches have included high-dose melphalan followed by autologous hematopoietic SCT or oral melphalan with dexamethasone. The use of novel agents (thalidomide, lenalidomide and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. A risk-adapted approach to SCT followed by novel agents as consolidation, reduces treatment-related mortality with promising activity. Immunotherapy targeting pathologic plasma cells and amyloid fibrils is being developed and could potentially eliminate visceral amyloid deposits. Improved understanding of the biology that renders light-chains amyloidogenic and a commitment to refer patients to specialized centers conducting well-designed clinical trials is essential to improve patient outcomes.

Citation: Bone Marrow Transplantation 48, 1022-1027 (August 2013) | doi:10.1038/bmt.2012.199

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A novel therapeutic molecule against HTLV-1 infection targeting provirus A Tanaka et al.

Abstract Human T-cell leukemia virus type 1 (HTLV-1), which causes adult T-cell leukemia (ATL) in humans, establishes a life-long latent infection. Current therapies are not very effective against HTLV-1-associated disorders. A novel therapeutic approach may help to combat HTLV-1 infection. A molecular therapy that targets the proviral genome is favorable because the therapeutic effect occurs specifically in HTLV-1-infected cells, regardless of whether they express viral genes. In this proof-of-concept study, we developed a therapeutic molecule based on zinc finger nuclease (ZFN) to achieve this goal. We designed a ZFN that specifically recognized conserved region of HTLV-1 long terminal repeat (LTR) and introduced it into various HTLV-1-positive human T-cell lines, including HTLV-1-transformed and ATL-derived cell lines. The ZFN disrupted the promoter function of HTLV-1 LTR and specifically killed HTLV-1-infected cells. We also showed a potential approach of this therapeutic molecule to remove the proviral genome from HTLV-1-infected cells, something that has not been possible before. The therapeutic effect of ZFN was confirmed in an in vivo model of ATL. This strategy may form the basis of a therapy that can eradicate HTLV-1 infection. Similar approaches can be used to target other malignancy-associated viruses.

Citation: Leukemia (15 February 2013) | doi:10.1038/leu.2013.46

The MLL recombinome of acute leukemias in 2013 C Meyer et al.

Abstract Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (~90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

Citation: Leukemia (2013) 27, 2165–2176; doi:10.1038/leu.2013.135;

Reduction of complement factor H binding to CLL cells improves the induction of rituximab-mediated complement-dependent cytotoxicity S Hörl et al.

Abstract A main effector mechanism of rituximab (RTX) is the induction of complement-dependent cytotoxicity (CDC).However, this effector function is limited, because CLL cells are protected from complement-induced damage by regulators of complement activation (RCAs). A prominent RCA in fluid phase is factor H (fH), which has not been investigated in this context yet. Here, we show that fH binds to CLL cells and that human recombinant fH-derived short-consensus repeat 18–20 (hSCR18–20) interferes with this binding. In complement-based lysis assays, CLL cells from therapynaive patients were differently susceptible to RTX-induced CDC and were defined as CDC responder or CDC nonresponder, respectively. In CDC responders, but notably also in non-responders, hSCR18–20 significantly boosted RTX-induced CDC. Killing of the cells was specific for CD20+ cells, whereas CD20− cells were poorly affected. CDC resistance was independent of expression of the membrane-anchored RCAs CD55 and CD59, although blocking of these RCAs further boosted CDC. Thus, inhibition of fH binding by hSCR18–20 sensitizes CLL cells to CDC and may provide a novel strategy for improving RTX-containing immunochemotherapy of CLL patients.

Citation: Leukemia (2013) 27, 2200–2208; doi:10.1038/leu.2013.169 Martie 2014

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Discussion - the authors will present the way the results backup the original hypothesis, as well as the way in which the results are backed up or contradicted by the published literature. A paragraph must be dedicated to presenting the limitations of the study and another one must represent a conclusion in which the authors can present their personal opinion backed up by the study results and/or the literature.

For all other types of articles we recommend the use of a clear structure based on sections and sub-sections.

6. Bibliography The references will be written using the Vancouver style. The references will be numbered, in the order they appear in the text as such: (1). All sources found in the text must be present in the bibliography and all the papers mentioned in the bibliography must appear in the text. All journals will be abbreviated according to international standards. Information obtained from sources which are not published yet, but are accepted for publishing will include at the end of the reference the mention “in print” between round parentheses. If the cited results have not been published yet the mention will be “personal communication” written in the text of article between round parentheses. Only references read by the authors of the article will be cited.

An original article will have at most 50 references, a review will have at most 100 references, a letter to the editor 5 references, whilst all other types of articles will have the minimum number of references required.

Examples of correct citations: - For journals: author(s), article title, abbreviated name of the journal, year, volume, number, first and last page.

Example: Skalsky K, Yahav D, Bishara J, Pitlik S, Leibovici L, Paul M. Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials. BMJ. 2008; 336(7646):701-4.

- For articles which aren’t published in print yet (example): Evans JD, Gomez DR, Chang JY, Gladish GW, Erasmus JJ, Rebueno N, Banchs J, Komaki R, Welsh JW. Cardiac 18F-fluorodeoxyglucose uptake on positron emission tomography after thoracic stereotactic body radiation therapy. Radiother Oncol. 2013 Sep 6. [Epub ahead of print] http://dx.doi.org/10.1016/j.radonc.2013.07.021.

- For books: author(s), title, city, publishing house, year.

Example: Cheers B, Darracott R, Lonne B. Social care practice in rural communities. Sydney: The Federation Press; 2007.

- For book chapters: chapter author(s), chapter name, editor(s), book name, edition, city, publishing house, year. Example: Rowlands TE, Haine LS. Acute limb ischaemia. In: Donnelly R, London NJM, editors. ABC of arterial and venous disease. 2nd ed. West Sussex: Blackwell Publishing; 2009.

- For websites: Author(s) (if known). Webpage name [internet]. Year [date of last change, date of citation]. Exact web address. Example: Atherton, J. Behavior modification [Internet]. 2010 [updated 2010 Feb 10; cited 2010 Apr 10]. Available from: http://www.learningandteaching.info /learning/behaviour_mod.htm The references will be placed in the text in the following way: “leading to lymphocytosis (1).

7. Figures, Images, Tables Figures and Images will be drawn professionally and sent in separate file(s) as jpeg, tiff or png files at a quality of a minimum of 300 dpi. In the text, each figure must be represented by a number, a title and a description.

The authors will indicate where should the figure be placed in the text. All images or figures must come from the author’s personal collection or the author must have rights to publish the image or figure. We do not accept images or figures taken from the Internet.

Tables will be included in the text and each table will have a number and a short description if required.

8. Ownership Rights By sending the article for publication the author(s): - take full responsibility for the scientific content of the text and for the accuracy of the send data; - become (co)author(s) of the manuscript (all further plagiarism accusation are addressed solely to the author(s) who signed the manuscript); - declare they are the rightful owners of the images, figures and/or information sent for publishing and that they have the permission to publish all the materials for which they do not own the intellectual property rights; - declare that the message/content of the manuscript is not influenced in anyway by commercial interests/ previous engagements/any sort of relations with other people or companies; - transfer all rights for the manuscript to Media Systems Communication.

9. Other Previously mentioned limitations can be ignored in special cases with the agreement of the chief-editor and/ or the publisher.

All published materials cannot be returned. The editorial office reserves the right to republish the materials in any journals/magazines.

The official recommendations for medical journals can be consulted at : www.icmje.org.

Not taking into consideration the recommendations mentioned before can lead to delay in publishing the materials or may lead to not publishing the article.

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International articles

Instrucțiuni pentru autori 1. Trimiterea materialelor Responsabilitatea integrală asupra caracterului original al materialelor trimise spre publicare aparţine în întregime autorilor.

Materialele vor fi trimise la adresa de mail: valentin.radoi@mediasyscom.ro Fiecare articol este evaluat de comitetul de peer-review, format din doi referenţi independenţi, respectându-se anonimatul autorului, conform protocolului de peer-review.

Autorii trebuie să sugereze peer-revieweri (preferabil trei) pentru articol. Peer-reviewerii trebuie să nu fie afiliaţi aceleiaşi instituţii ca şi autorii. Numele, afilierea şi adresele lor de e-mail trebuie să fie incluse în e-mail alături de articol.

Editorii îşi rezervă dreptul de a folosi sau de a nu folosi peerrevieweri sugeraţi de autori.

2. Manuscrise publicate/transmise spre publicare Revista Romanian Journal of Oncology and Hematology publică: - articole originale; - rezumate ale literaturii (review-uri); - prezentări de caz; - articole de perspectivă; - declarații de consens din partea unei asociații sau grup de profesioniști; - scrisori către editor.

Nu exista limite de caractere decât pentru scrisorile către editor care vor include maximum 2500 de caractere fără spaţii. Acestea se pot referi fie la un articol deja publicat în revistă, fie pot aduce contribuții originale științifice sau legate de evenimente etc. de interes pentru cititor.

Nu vor fi luate în consideraţie articolele publicate anterior în alte reviste. Dacă materialul a fost anterior trimis spre publicare altei reviste şi nu a fost acceptat, autorul este invitat să trimită şi comentariile sau răspunsul comitetului de peerreview. În cazul în care, ca urmare a recenziei independente (peer-review) sau a corecturii stilistice/lingvistice, manuscrisul necesită modificări minore, articolul este acceptat pentru publicare în forma revizuită, fără a mai fi solicitat acordul autorului. În cazul în care modificările sunt considerate majore (erori ştiinţifice sau de exprimare care pot afecta calitatea mesajului ştiinţific transmis), autorul va fi contactat de un membru al colectivului redacţional, iar articolul va putea fi publicat numai după ce autorul aprobă efectuarea modificărilor considerate necesare de peer-revieweri. În anumite cazuri, pe baza aprobării scrise atât a autorului, cât şi a referentului (peer-reviewer), redactorul-şef şi/sau publisher-ul pot decide publicarea manuscrisului, însoţită de opinia şi justificările re­ ferentului.

Ordinea în care sunt publicate în revistă manuscrisele este determinată de data intrării în redacţie, de necesităţile editoriale şi de respectarea recomandărilor de mai sus. Pot surveni priorităţi pentru unele articole de actualitate, pentru materialele solicitate explicit de redacţie sau pentru cele care prezintă în opinia redacţiei un interes deosebit.

3. Autorii Fiecare autor trebuie să poată dovedi participarea sa activă în studiu. Includerea acestora se bazează numai pe contribuţia substanţială la conceptul, modelul, strângerea datelor sau analiza, prelucrarea şi interpretarea rezultatelor sau revizuirea critică. Acordul fiecăruia pentru versiunea finală trebuie trimis o dată cu manuscrisul. Alte persoane care au contribuit la lucrare, cum sunt participanţii la studii, vor fi menţionate la secţiunea “Contribuţii”.

4. Permisiuni şi etică Pentru citări, tabele, figuri etc. care nu sunt originale, acestea trebuie însoţite de permisiunea scrisă pentru reproducere a autorului împreună cu referinţele în întregime. Fo-

48

Titlul articolului

tografiile persoanelor identificabile trebuie să fie însoţite de acordul acestora semnat pentru publicare sau, în caz contrar, vor trebuie acoperite toate regiunile care permit identificarea persoanei. Autorul trebuie să fi obţinut anterior, pentru toate studiile care includ subiecţi umani, permisiunea acestora pentru a face parte din studiu, fiindu-le respectată anonimitatea.

Prin trimiterea articolului autorul declară că a obţinut această permisiune de la toţi pacienţii. În cazul studiilor cu subiecţi umani, protocolul trebuie să respecte Declaraţia de la Helsinki (1975). În cazul studiilor cu oameni sau animale, autorii trebuie să fi obţinut acordul comisiei de etică de la universitatea/institutul/etc. în cadrul căruia studiul a fost realizat.

5. Redactarea articolelor Redactarea articolelor se conformează în general recomandărilor stabilite de Comitetul Internaţional al Editorilor de Reviste Medicale (www.icmje.org). Sunt acceptate spre publicare manuscrise redactate în limbile engleză SAU română, redactate în mod obligatoriu folosind diacriticele românești pentru manuscrisele în această limbă. Articolele se trimit în format Microsoft Word 2000 (extensia *.DOC) sau Microsoft Word 2003 (extensia *.DOCX), cu corp de literă de mărimea 12, spaţiate la un rând şi jumătate. Manuscrisul trebuie transmis în forma finală, corectat (inclusiv bibliografia) şi trebuie să fie coerent din punct de vedere ştiinţific şi lingvistic. Paginile vor fi numerotate, manuscrisul fiind redactat cu respectarea următoarei succesiuni: titlul, autorii, afi­ lierea autorilor, adresa completă fizică și de e-mail a autorului corespondent, rezumatul redactat bilingv (limbile română şi engleză), cuvinte-cheie (limbile română şi engleză, între 3 şi 5), textul propriu-zis al manuscrisului, mulţumiri şi/sau contribuţii, fonduri obţinute pentru realizarea studiului, bi­ bliografie, legenda figurilor şi a tabelelor. Autorul(ii) îşi asumă responsabilitatea că documentul electronic este complet şi corect la momentul trimiterii, după revizuire şi acceptare.

A. Titlul manuscrisului va fi concis (maximum 100 de ca­ ractere fără spaţii) şi în concordanţă cu conţinutul lucrării. Titlul trebuie redactat atât în limba română, cât şi în limba engleză.

B. Autori. Autorii vor furniza numele şi prenumele complete, gradul universitar, cel mai înalt titlu academic, afilierea, oraşul şi ţara de reşedinţă la data redactării manuscrisului. Autorul corespondent își va trece adresa fizică şi de e-mail. Fiecare manuscris va fi semnat de maximum 12 autori. Excepție fac scrisorile către editor care pot avea maximum 5 autori și declarațiile de consens care nu au limită de autori, fiind obligatorie menționarea numelui grupului.

C. Rezumate şi cuvinte-cheie. Fiecare articol trebuie însoţit de un rezumat redactat obligatoriu în limbile română şi engleză. Fiecare rezumat trebuie să se încadreze în limita a 1.000 de semne tipografice fără spaţii şi va cuprinde (în cazul studiilor originale): Introducere (Introduction): prezentarea celor mai importante aspecte din domeniul studiat cu scopul susținerii studierii ipotezei şi obiectivului studiului, precum și motivul pentru care a fost întreprins acest studiu.

Metode (Methods): se vor prezenta principalele metode folosite şi tipul de studiu (studiu clinic, experimental, metaanaliză).

Rezultate (Results): principalele rezultate ale studiului.

Discuție (Discussion): semnificaţia rezultatelor; se vor sublinia aspectele noi ale studiului.

Pentru prezentările de caz se recomandă descrierea stării inițiale a bolnavului, examenului clinic şi paraclinic efectuat, discutarea diagnosticului diferențial și a tratamentului, urmată de prezentarea evoluției bolnavului până la ultimul contact cu acesta.

Pentru rezumate ale literaturii (review-uri), declarații de consens și articole de perspectivă, rezumatele vor cuprinde descrierea generală a tematicii prezentate. Scrisorile către editor nu trebuie însoțite de abstract.

Nume autori

Sub fiecare rezumat vor fi menţionate 3-5 cuvinte-cheie (în limbile română şi engleză) care vor fi afişate pentru indexare.

D. Abrevieri. Abrevierile nu sunt acceptate nici în titlu şi nici în rezumate. Unităţile de măsură vor fi exprimate conform Sistemului Internaţional, putându-se folosi abrevierile acceptate internaţional. În manuscris se vor folosi numai abrevieri standard, încetăţenite în practica medicală. În text, abrevierile vor fi explicate între paranteze rotunde la prima apariţie.

E. Text. În cazul articolelor originale în text se va respecta următoarea succesiune: Introducere - Prezentarea celor mai importante aspecte din domeniul studiat fără realizarea unui rezumat al literaturii.

Scopul acestei părți a textului este de a prezenta și susține ipoteza pe care s-a bazat realizarea studiului.

Metode - Această secțiune va cuprinde toate informațiile necesare pentru ca cititorul să poată verifica validitatea studiului, incluzând, dar nu limitându-se la subiecți, măsurători, etică și analiză statistică.

Rezultate - Vor fi prezentate rezultatele studiului, inițial cele legate de ipoteza principală, în ordinea descrescătoare a importanţei. Nu se va realiza o interpretare a rezultatelor în această secțiune.

Discuție - Se va prezenta modul în care rezultatele susțin ipoteza inițială a studiului, precum şi modul în care rezultatele sunt confirmate sau se află în contradicție cu rezultatele din literatura publicată. Este obligatorie introducerea unui paragraf care să discute limitările studiului şi a unei concluzii care să reprezinte opinia autorilor susținută de rezultatele studiului și/sau a altor articole din literatură. În cazul celorlalte tipuri de articole publicate de către revista Romanian Journal of Oncology and Hematology se recomandă folosirea unei structuri clare bazate pe capitole și subcapitole.

6. Bibliografie Pentru referinţe se va folosi stilul Vancouver. Referinţele bibliografice vor fi numerotate în ordinea în care apar în text, cu cifre arabe astfel: (1). Este obligatoriu ca toate sursele cuprinse în bibliografie să fie citate în text; nu trebuie să apară în text trimiteri la lucrări care nu sunt menţionate în bibliografie. Titlurile periodicelor vor fi abreviate conform stilului internaţional acceptat. Informaţiile provenite din surse nepublicate încă, dar acceptate spre publicare pot fi citate indicaţiile respective vor purta însă în bibliografie menţiunea “sub tipar” între paranteze rotunde. Dacă lucrarea nu este acceptată încă, menţiunea va fi “comunicare personală”, menționată între paranteze în text, nu în referințe. Nu vor fi citate decât referinţe bibliografice care au fost consultate de autorii articolului. Un articol original nu va include mai mult de 50 de referinţe bibliografice. Un review nu va include mai mult de 100 de referințe. O scrisoare către editor nu va include mai mult de 5 referințe. Celelalte tipuri de articole vor include numărul minim de referințe necesar.

Exemple de citare corectă - Pentru reviste: autorii, titlul original al articolului, revista cu prescurtările internaţionale, anul, volumul, numărul revistei, pagina de început şi de sfârşit. Exemplu: Skalsky K, Yahav D, Bishara J, Pitlik S, Leibovici L, Paul M. Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials. BMJ. 2008; 336(7646):701-4.

- Pentru articole nepublicate încă în reviste (publicate doar online): Evans JD, Gomez DR, Chang JY, Gladish GW, Erasmus JJ, Rebueno N, Banchs J, Komaki R, Welsh JW. Cardiac 18F-fluorodeoxyglucose uptake on positron emission tomography after thoracic stereotactic body radiation therapy. Radiother Oncol. 2013 Sep 6. [Epub ahead of print] http://dx.doi. org/10.1016/j.radonc.2013.07.021.

- Pentru cărţi: autorii, titlul original, oraşul, editura, anul, numărul paginii. Exemplu: Cheers B, Darracott R, Lonne B. Social care practice in rural communities. Sydney: The Federation Press; 2007.

- Capitol de tratat: autorii capitolului, numele capitolului, editorii, numele tratatului, ediţia, oraşul, editura, anul publicării. Exemplu: Rowlands TE, Haine LS. Acute limb ischaemia. In: Donnelly R, London NJM, editors. ABC of arterial and venous disease.

2nd ed. West Sussex: Blackwell Publishing; 2009.

- Pentru un site web: Autor (dacă este cunoscut). Denumirea paginii web [internet]. Anul publicării [data ultimei schimbări a paginii, data citării]. Adresa web exactă. Exemplu: Atherton, J. Behavior modification [Internet]. 2010 [updated 2010 Feb 10; cited 2010 Apr 10]. Available from: http:// www.learningandteaching.info /learning/behaviour_mod. htm. În text citările se vor introduce înainte de punct sub forma (1).

Exemplu: ‘conducând la limfocitoza observată în periferie (1).

7. Figuri, imagini, tabele Figurile (desene, scheme) vor fi reprezentate grafic profe­ sional şi vor fi trimise separat (şi nu incluse în cadrul documentului). În document se citează numai figurile, consecutiv, cu cifre arabe, cu un titlu şi o legendă. Imaginile şi figurile trebuie să fie trimise în format jpg, png sau tiff la minimum 300 dpi. Toate figurile vor fi numerotate cu cifre arabe. Autorii vor indica în text unde trebuie plasate ilustraţiile. Se va preciza sursa imaginii (colecţia proprie etc.). Toate imaginile vor trebui însoţite de o declaraţie conform căreia autorul manuscrisului este titularul drepturilor de autor pentru imaginea respectivă şi este de acord cu publicarea acestora. Nu se acceptă fotografii luate de pe internet.

Tabelele vor fi incluse în document şi în mod obligatoriu fiecare tabel va fi numerotat şi însoţit de o scurtă explicaţie şi (dacă este cazul) de legendă.

8. Drepturi de autor Prin transmiterea către redacţie a manuscriselor spre publicare, autorii: - îşi asumă răspunderea integrală pentru conţinutul ştiinţific al manuscrisului transmis şi acurateţea datelor prezentate; - îşi asumă calitatea de (co)autor al manuscrisului (orice eventuală acuzaţie ulterioară de plagiat adresându-se exclusiv autorului/autorilor care au semnat manuscrisul respectiv); - declară că sunt proprietarii de drept ai imaginilor şi/sau informaţiilor propuse spre publicare sau că au permisiunea de reproducere în vederea publicării în revista „Romanian Journal of Oncology and Hematology” pentru materialele ale căror drepturi de proprietate intelectuală nu le aparţin; - declară pe propria răspundere că mesajul/conţinutul manuscrisului nu este influenţat şi/sau dictat de interese comerciale, de angajamente prealabile sau de orice alte relaţii cu terţe persoane care ar putea fi considerate conflicte de interese; - transferă integral drepturile de autor către Media Systems Communication.

9. Alte precizări Limitările expuse anterior pot fi ignorate în situaţii deosebite, cu acceptul prealabil al Editorului-şef şi/sau al Publisherului.

Materialele publicate nu se restituie. Redacţia îşi asumă dreptul de a republica materialele în aceeaşi revistă şi/sau de a aviza favorabil republicarea manuscriselor în alte reviste.

Versiunea oficială şi integrală a recomandărilor pentru revistele biomedicale se poate consulta la adresa: www.ICMJE. org. Nerespectarea recomandărilor de mai sus poate duce la întârzieri în publicarea materialelor sau la decizia de nepu­ blicare a acestora.

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49

o f

j o u r n a l

o f

Doresc să mă abonez la O n c o l o g y & H e m at o l o g y 90 RON 160 RON

R o m a n i a n

q Abonament pentru 1 an 4 numere ale revistei q Abonament pentru 2 ani 8 numere ale revistei

j o u r n a l

R o m a n i a n

JURNAL DEDICAT REZIDENȚILOR, REZIDENȚILOR Ț , SPECIALIȘTILOR Ș ȘI Ș CERCETĂTORILOR DIN DOMENIUL ONCOLOGIEI, ONCOLOGIEI HEMATOLOGIEI, HEMATOLOGIEI MEDICINEI PALIATIVE ȘI TERAPIEI TERA DURERII

Oncology & Hematology

TALON DE ABONAMENT

www.romjoh.com

REVISTĂ PUBLICATĂ SUB EGIDA

N r . 1 / V o l . II / 2 0 1 4 www.medsysc.com

ROLUL COMISIEI DE TUMOR BOARD ÎN CHIRURGIA ONCOLOGICĂ

‰ ‰ ‰

detalii în pagina 16

Nume:................................................................................... Prenume: ...............................................................................

Dna Dl Dra Adresă domiciliu: .....................................................................................................................................................................

Municipiu: ........................................................................ Sect.: ................ Judeţ:............................................................

Oraş:................................................................. Comună: ......................................................................................................

Cod poştal: ............................................... Telefon: ...............................................................................................................

Specialitate ................................................................................................................................................................................ student rezident medic specialist medic primar Competenţă ............................................................................... Denumire instituţie: .......................................................

Domeniu de activitate: Privat Public Secţie: ................................................................................................. Funcţie: ......................................................................

Specialitate: ................................................................. Adresă instituţie: ............................................................................ .................................................... Municipiu: ....................................................Sect.: ........... Judeţ:.................................

Oraş:................................................................. Comună: ......................................................................................................

Cod poştal: ............................................... Telefon: .......................................... Mobil: ......................................................

E-mail: ........................................................................ Web: ...................................................................................................

CUI instituţie: da nu Plătitor de TVA: Factură - vă rugăm să completaţi cu coordonatele necesare emiterii facturii: Denumire persoană: ...................................................... Denumire instituţie: ..................................................................

Adresa pentru primirea revistelor Media Systems Communication: Domiciliu Instituţie Data:

/

/

Semnătură:…..………….….......…

După completare, vă rugăm să trimiteţi talonul însoţit de dovada efectuării plăţii la adresa: Media Systems Communication S.R.L., Calea Rahovei nr. 266-268, corp 2, etaj 2, camerele 22-23, Sector 5, Bucureşti, cod poştal 050912, prin fax (031) 432.82.30 sau scanate prin e-mail la office@mediasyscom.ro. Mulţumim!

Adeverinţa pentru abonarea la revistă se eliberează în maximum 5 zile lucrătoare de la exprimarea solicitării dvs.

Plata abonamentului se va efectua prin mandat poştal sau prin ordin de plată pe coordonatele: Media Systems Communication S.R.L., Calea Rahovei nr. 266-268, corp 2, etaj 2, camerele 22-23, Sector 5, Bucureşti, cod poştal 050912, CUI RO31922876, J40/8111/2013.

Cont RON IBAN: RO05BACX0000000912742000, deschis la Unicredit Țiriac Bank, Sucursala Rahova.

Doresc să primesc o copie a facturii abonamentului: q Da, la adresa de e-mail: ..................................................................... q Da, la fax: .....................................................................

SC MEDIA SYSTEMS COMMUNICATION cu sediul în București, Calea Rahovei nr. 266-268, corp 2, etaj 2, camerele 22-23, CUI RO31922876, J40/8111/2013 prelucrează datele cu caracter personal furnizate de dumneavoastră prin acest document în scopul actualizării bazei de date.

Pe viitor, datele menționate ne permit să vă ţinem la curent cu activitatea noastră. În cazul în care nu doriţi această informare, bifaţi

NU

!

Conform Legii nr. 677/2001, beneficiaţi de dreptul de acces, de intervenţie asupra datelor, dreptul de a nu fi supus unei decizii individuale.

Aveţi dreptul să vă opuneţi prelucrării datelor personale care vă privesc şi să solicitaţi ştergerea datelor. Pentru exercitarea acestor drepturi, vă puteţi adresa cu o cerere scrisă, datată şi semnată la sediul social din Calea Rahovei nr. 266-268 corp 2 etaj 2 camerele 22-23, București.

De asemenea, vă este recunoscut dreptul de a vă adresa justiţiei. Media Systems Communication este înregistrată la Autoritatea Națională de Supraveghere a Prelucrării Datelor cu Caracter Personal sub numărul 29878/7.11.2013.

Nume autori

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