VOL. LIX • NO. 4 • 2018 by Journal MSMA

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VOL. LIX • NO. 4 • APRIL 2018

EDITOR Lucius M. Lampton, MD ASSOCIATE EDITORS D. Stanley Hartness, MD Richard D. deShazo, MD

THE ASSOCIATION President William M. Grantham, MD President-Elect Michael Mansour, MD

MANAGING EDITOR Karen A. Evers

Secretary-Treasurer W. Mark Horne, MD

PUBLICATIONS COMMITTEE Dwalia S. South, MD Chair Philip T. Merideth, MD, JD Martin M. Pomphrey, MD and the Editors

Speaker Geri Lee Weiland, MD Vice Speaker Jeffrey A. Morris, MD Executive Director Charmain Kanosky

JOURNAL OF THE MISSISSIPPI STATE MEDICAL ASSOCIATION (ISSN 0026-6396) is owned and published monthly by the Mississippi State Medical Association, founded 1856, located at 408 West Parkway Place, Ridgeland, Mississippi 39158-2548. (ISSN# 0026-6396 as mandated by section E211.10, Domestic Mail Manual). Periodicals postage paid at Jackson, MS and at additional mailing offices. CORRESPONDENCE: Journal MSMA, Managing Editor, Karen A. Evers, P.O. Box 2548, Ridgeland, MS 39158-2548, Ph.: 601-853-6733, Fax: 601-853-6746, www.MSMAonline.com. SUBSCRIPTION RATE: $83.00 per annum; $96.00 per annum for foreign subscriptions; $7.00 per copy, $10.00 per foreign copy, as available. ADVERTISING RATES: furnished on request. Jill Gordon, MSMA Director of Marketing. Ph. 601-853-6733, ext. 324, Email: JGordon@MSMAonline.com POSTMASTER: send address changes to Journal of the Mississippi State Medical Association, P.O. Box 2548, Ridgeland, MS 39158-2548. The views expressed in this publication reflect the opinions of the authors and do not necessarily state the opinions or policies of the Mississippi State Medical Association. Copyright © 2018 Mississippi State Medical Association.

SCIENCE IN MEDICINE Top 10 Facts You Need to Know about the Reemergence of Syphilis 184 Lucius Lampton, MD; Desiree Pendergrass, MD, MPH; Peter Pendergrass, MD, MPH; Paul Byers, MD; Kendra L. Johnson, MPH; James D. Stewart, PhD; Matthew N. Marturano, M4; 2LT Zachary E. Schwartz, M4 Top 10 Facts You Need to Know about Stinging Insect Allergy 188 Jessica B. Perkins, MD A Survey of Early Stage Prostate Cancer: An Analysis of Treatment Modality by Race in Mississippi 190 Kevin McKay, PhD; Jessica Bailey, PhD; Lei Zhang, PhD; Ellen Jones, PhD Primary Hepatic Leiomyosarcoma 194 Mary Tucker Sessums, MD; David Ray, MD; Truman Mark Earl, MD; Charulochana Subramony, MD; Maria F. Gonzalez, MD Quality of Life in Patients with Bladder Cancer after Bladder Preservation Therapy using Chemoradiation 200 Ashley Albert, MD; Srinivasan Vijayakumar, MD Fatal Acute Sickle Cell Intrahepatic Cholestasis Despite Exchange Transfusion: A Case Report and Literature Review 204 Carter Capra, MD; L. Wesley Aldred, MD; Srikrishna Patnana, MD, MPH; Brian Borg, MD; Vincent Herrin, MD SPECIAL ARTICLES Interview with Dr. Ken Cleveland, Director of the MSBML Sid Scott Meet the MSMA Staff

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DEPARTMENTS From the Editor – Is Universal Primary Care the Answer? Lucius M. Lampton, MD President’s Page – MOC Playbook Puts Power in Your Hands William M. Grantham, MD Letters to the Editor Commentary – Healthcare is a Catch-22 for the Uninsured J. Anthony Cloy, MD; Chair, MSMA Council On Medical Service Commentary – Avoid the Social Networks: A Mobile Communication Platform Should Provide a Secure, Efficient Workflow Tracey Haas, DO, MPH; Chief Medical Officer, DocbookMD Commentary – Role of Vitamin D and NEC – An Emerging Risk Factor Parvesh Mohan Garg, MD Images in Mississippi Medicine – King's Daughter Home, Greenville, 1905 Lucius M. Lampton, MD Poetry and Medicine – Greenwood-1942 John D. McEachin, MD Una Voce: The Doctor Who “Cared Too Much” Dr. Nick and Elvis: A Forty Year Retrospective Dwalia S. South, MD

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F R O M

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Is Universal Primary Care the Answer?

novel idea of improving access to care for the nation’s millions of uninsured is being kicked around Vermont, Rhode Island, and other states across the country: universal primary care (UPC). This concept is a publicly-funded universal model for primary care and mental health services (including substance abuse but not dental services). If the country cannot afford an all-inclusive single payer health Lucius M. Lampton, MD system, proponents assert, this nation Editor can afford a primary care only system, which currently represents only 6% of the nation’s health care spending. Supporters argue that increased utilization of primary care and mental health services not only improves the quality of a population’s health but also reduces the overall cost of care for that population. As currently proposed in Vermont, the state would provide primary care services to all Vermonters, regardless of insurance coverage. Citizens would be encouraged to maintain additional insurance coverage for all other health care services and the uninsured would remain uninsured for other medical services.

There seems to be merit in the plan. Primary care, where much of health care occurs, is relatively inexpensive and benefits the health of the public enormously via prevention and early treatment. The significant financial benefits of primary care were revealed in Rhode Island from 2007 to 2011: after the state mandated an increase in primary care spending, overall health care costs dropped by 18%. UPC, proponents claim, would lower health insurance premiums and, if done correctly, reduce many of the administrative hassles which burden primary care physicians. Many of those pushing UPC perceive it as a legitimate first step towards an all-inclusive fully integrated single payer health care system. Others see it as a way to maintain the structure of the health care status quo while providing a foundation of basic medical care for all citizens in a manner the government can afford. Of course, there are many problems to be overcome, especially with how the system facilitates referrals of the uninsured for specialty or surgical care. But UPC is an idea which may gain traction in the brave new medical world in front of us! n Contact me at LukeLampton@cableone.net. — Lucius M. Lampton, MD, Editor

JOURNAL EDITORIAL ADVISORY BOARD ADDICTION MEDICINE Scott L. Hambleton, MD

EMERGENCY MEDICINE Philip Levin, MD

MEDICAL STUDENT John F. G. Bobo, M2

ALLERGY/IMMUNOLOGY Stephen B. LeBlanc, MD Patricia H. Stewart, MD

EPIDEMIOLOGY/PUBLIC HEALTH Mary Margaret Currier, MD, MPH Thomas E. Dobbs, MD, MPH

NEPHROLOGY Jorge Castaneda, MD Harvey A. Gersh, MD

ANESTHESIOLOGY Douglas R. Bacon, MD John W. Bethea, Jr., MD

FAMILY MEDICINE Tim J. Alford, MD Diane K. Beebe, MD Jennifer J. Bryan, MD J. Edward Hill, MD Ben Earl Kitchens, MD James J. Withers, MD

OBSTETRICS & GYNECOLOGY Sidney W. Bondurant, MD Darden H. North, MD

GENERAL SURGERY Andrew C. Mallette, MD

OTOLARYNGOLOGY Bradford J. Dye, III, MD

HEMATOLOGY Vincent E Herrin, MD

PEDIATRIC OTOLARYNGOLOGY Jeffrey D. Carron, MD

INTERNAL MEDICINE Daniel P. Edney, MD W. Mark Horne, MD Daniel W. Jones, MD Brett C. Lampton, MD Jimmy Lee Stewart, Jr., MD

PEDIATRICS Michael Artigues, MD Owen B. Evans, MD

CARDIOVASCULAR DISEASE Cameron Guild, MD Thad F. Waites, MD CHILD & ADOLESCENT PSYCHIATRY John Elgin Wilkaitis, MD Nisha S. Withane, MD, Fellow CLINICAL NEUROPHYSIOLOGY Alan R. Moore, MD DERMATOLOGY Robert T. Brodell, MD Adam C. Byrd, MD

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ORTHOPEDIC SURGERY Chris E. Wiggins, MD

PLASTIC SURGERY William C. Lineaweaver, MD Chair, Journal Editorial Advisory Board PSYCHIATRY Beverly J. Bryant, MD June A. Powell, MD PULMONARY DISEASE Sharon P. Douglas, MD John R. Spurzem, MD RADIOLOGY P. H. (Hal) Moore, Jr., MD RHEUMATOLOGY Shweta Kishore, MD C. Ann Myers, MD UROLOGY W. Lamar Weems, MD

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Top 10 Facts You Need to Know about the Reemergence of Syphilis LUCIUS LAMPTON, MD; DESIREE PENDERGRASS, MD, MPH; PETER PENDERGRASS, MD, MPH; PAUL BYERS, MD; KENDRA L. JOHNSON, MPH; JAMES D. STEWART, PHD; MATTHEW N. MARTURANO, M4; 2LT ZACHARY E. SCHWARTZ, M4

In the middle of the Great Depression, President Franklin Roosevelt’s Surgeon General, Dr. Thomas Parran, Jr., initiated a progressive campaign against the ancient scourge syphilis, which he termed the “shadow on the land,” publishing a landmark book with that title in 1937. Parran asserted that the disease was decimating the public health of the country and needed a coordinated plan of action for control. He commented: “There is reason to believe that if all conditions due to syphilis were reported as such it would be found to be a leading cause of death in the United States.” In that book, he quoted the legendary Sir William Osler, who called syphilis the “Great Imitator” because in its late stages it “simulates almost every disease known to man.” He further recounted Osler’s famous aphorism: “Know syphilis and the whole of medicine is opened unto you.” 1 Here in Mississippi, at the same time, State Health Officer Felix Underwood aggressively partnered with Parran’s efforts to control syphilis. Contemporary Jacksonians remember hearing Underwood discuss the disease in a medically straightforward manner, utilizing such terms as “spirochetes” and sexual transmission on the public airwaves of WJDX radio in the 1930s.2 Such was uncommon for a health officer in the South at the time. That Underwood could discuss a sexual plague so openly reveals how highly regarded and trusted he was as a medical statesman by his community and the political establishment. Although great strides have been made over the last eight decades against syphilis in Mississippi and the nation, this “shadow on the land” is rising in incidence since 2001 and reemerging as a significant public health issue in our state. The Centers of Disease Control and Prevention (CDC) dedicated April’s 2017 STD Awareness Month to syphilis prevention due to its increased incidence and broad spectrum of presenting symptoms, which often make its clinical diagnosis challenging. On a personal level, a recent syphilis case in south Mississippi was originally misdiagnosed by other providers as scabies before presentation at one of the authors’ clinics. With syphilis’s reemergence, this “Top Ten” article will cover the core facts every Mississippi physician should know to recognize, treat, and report a syphilis case.

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Syphilis is reemerging at an alarming rate. For 2016, CDC reported an 18% increase of early syphilis (primary and secondary + early latent syphilis cases) nationwide as compared to 2015. In Mississippi, 822 cases of early syphilis were reported in 2016, compared to 623 reported cases in 2015, a 32% increase statewide. Most of the cases (644) occurred in men; however, increases in the number of cases in women have been noted as well. Of note, the percentage of cases among men who have sex with men (MSM) has steadily risen over the past several years both nationally and in Mississippi and has been one of the biggest drivers for the increase in cases among men. In 2016, 70% of male cases of early syphilis in Mississippi were in MSM.3,4

African American men ages 20-29 have the highest rates of infection. Individuals aged 20-29 years account for 52% (426/822) of all cases of early syphilis reported in 2016; 36% (293/822) of the total cases reported are in African American (AA) men in this age group. In addition to age, race and gender, other risk factors for syphilis include living in an urban environment, living in the southern United States, having multiple sexual partners, MSM and persons who are HIVpositive. Among cases reported in 2016, HIV co-infection was seen in 36%.

Syphilis progresses through stages, with the first, primary syphilis, manifesting anywhere from 10-90 days (typically 21 days) after onset of infection. The first sign is a red, painless papule that ulcerates. This “chancre” occurs at the site of inoculation (i.e. genitals, anus, rectum, hands, or mouth) and is described as a firm, round, painless ulcer typically 0.5 – 2 cm in diameter and with sharp borders. Associated regional lymphadenopathy is common and the chancre resolves completely in 3-6 weeks with or without treatment.5,6,7 Typically, one chancre is present; however, multiple chancres can be seen and are more common with HIV co-infection. Males will more often present in clinic at this stage than females as the painless chancre is commonly located inside the vagina for women.8

Figure 1. Primary, Secondary and Early Syphilis Cases in Mississippi, 2007-2016

Secondary syphilis presents 4-10 weeks post-inoculation with a variety of features. The most typical feature of secondary syphilis is a generalized symmetrical maculopapular or scaly papular rash across the trunk, extremities, and on the palms and soles. Condylomata lata, raised grey-white lesions, can also be present and are highly infectious. Other common findings include malaise, fever, sore throat, lymphadenopathy, myalgia, patchy hair loss, and weight loss.9 Early neurosyphilis (headache, meningitis, cranial nerve lesions, intranuclear ophthalmoplegia, and vascular manifestations) rarely occurs during secondary syphilis but when it does is most often associated with a HIV co-infection.10 Symptoms spontaneously resolve within 3-12 weeks at which time the person enters the latency period. Refer to Figure 2 for a more detailed timeline of syphilis stages. Tertiary syphilis rarely occurs. Tertiary syphilis manifests in many different forms 2-20 years post-infection and may include neurosyphilis, cardiovascular, visceral, and gummatous disease.11 While important in understanding the disease process, most untreated cases do not develop tertiary syphilis. For more information on tertiary syphilis and its treatment, refer to the CDC’s Sexually Transmitted Diseases Guidelines, 201512 at https://www.cdc.gov/std/tg2015/tg-2015-print.pdf.

Appropriate screening is essential to stop the spread of syphilis. The Mississippi State Department of Health (MSDH) recommends syphilis screening for: • All patients who identify as MSM – screen every 6 months • All HIV positive individuals – screen every 3-6 months in conjunction with CD4 and viral load testing • All pregnant women – screen at the first prenatal visit, the beginning of 3rd trimester, and at delivery • Any high-risk individual including those using IV drugs, exchanging sex for money or other commodities, or those with previous history of other STI Providers should routinely take a complete sexual history and discuss high-risk behaviors with all patients. They should not make assumptions about their patient’s behaviors or they will fail to appropriately identify those at risk. Diagnosis of syphilis involves 2-step laboratory testing. A diagnosis of syphilis is made through the use of two types of serologic tests: • Nontreponemal tests (RPR or VDRL) • Treponemal tests (TP-PA) Nontreponemal tests are nonspecific while treponemal tests are specific for syphilis. Both are required to make the diagnosis of

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Figure 2. Timeline of Syphilis Stages

Modified from Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA. 2003; 290:1510-1514. From Bennet BE, Dolin R, Blaser MJ, Mandall, Douglas, and Bennett’s Principles and Practice of Infectious Disease. Ed 8, Philadelphia, PA: Saunders; 2015: 2684-2709.

syphilis and the use of either test alone is insufficient. Physicians should be aware that an alternate testing algorithm exists and is utilized in some situations, but the Mississippi State Department of Health (MSDH) recommends an initial RPR and if positive followup testing with a confirmatory TP-PA.13,14,15

Parenterally delivered penicillin G benzathine (Bicillin) is the treatment of choice for all stages of syphilis. Correct preparation, dosage, and length of treatment depend on the stage and clinical manifestations of the disease. Specific recommended regimens can be found on the CDC website at https:// www.cdc.gov/std/tg2015/syphilis.htm.16 Warn patients of the JarischHerxheimer reaction which is frequently accompanied by headache and myalgia within 24 hours of treatment. In patients with a skin-test positive penicillin allergy, desensitization of the patient followed by treatment with penicillin is preferred to alternate regimes when access to these services is available. There is no appropriate alternative treatment to penicillin in pregnant women. Clinical and serologic evaluation to assess response should be repeated 6 months and 12 months following treatment.17,18 Follow-up should occur more frequently in high risk groups such as those with HIV co-infection.

Identification and treatment of infected women are essential to prevent congenital syphilis. In addition to sexual transmission, syphilis can also be transmitted perinatally from mother to infant. In 2016, Mississippi had 178 cases of 186 VOL. 59 • NO. 4 • 2018

early latent and primary/secondary syphilis reported among women.3,4 Increased cases in women are generally accompanied by an increase in cases of congenital syphilis. In 2016, two cases of congenital syphilis were reported. Among infected infants, lifelong clinical manifestations can occur including facial abnormalities, ophthalmologic, CNS, cutaneous, and skeletal symptoms. Congenital syphilis is a preventable disease that can be eliminated through effective antenatal screening and treatment of infected pregnant women.19,20,21

Reporting in Mississippi. In an attempt to break the chain of transmission, Mississippi State Department of Health actively investigates any reported case of syphilis and follows up with contacts to assure testing and treatment. Syphilis is a Class 1B reportable condition in Mississippi requiring a telephone report within one business day of first knowledge or suspicion. Reports may be made to MSDH STD/HIV office (601576-7723) or the Office of Epidemiology (601-576-7725) or toll free to (1-800-556-0003).22 n References

1. Parran, Thomas. Shadow on the Land: Syphilis. Reynal and Hitchcock, New York: 1937, 3,15. 2. Lyell, Louis J. Personal Interview with Lucius Lampton, MD, October 18, 2017. 3. Centers for Disease Control and Prevention. 2016 Sexually Transmitted Disease Surveillance. Retrieved 02/20/2018 from https://www.cdc.gov/std/stats16/ tables/1.htm. 4. Mississippi State Department of Health. MS Health Alert Network (HAN) Advisory. Increases in Early Syphilis in Mississippi—Screening and Reporting Recommendation; 2017.

5. Sparling PF. Natural history of syphilis. In: Sexually Transmitted Diseases, Holmes KK, March, PA, Sparling PF, et al. New York, NY: McGraw-Hill; 1990:213. 6. Clark EG, Dan bolt N. The Oslo study of the natural course of untreated syphilis: an epidemiologic investigation based on a re-study of the Boeck-Bruusgaard material, Med Clin North Am. 1964;48:613. 7. Bennet BE, Dolin R, Blaser MJ, Mandall, Douglas, and Bennett’s Principles and Practice of Infectious Disease. Ed 8, Philadelphia, PA: Saunders; 2015: 2684-2709. 8. Chapel TA, The variability of syphilitic chancres. Sex Transm Dis 1978; 5:68-70. 9. Bop ET, Kellerman, RD, Conn’s Current Therapy 2017. Philadelphia, PA: Elsevier; 2016:886-888. 10. Moradi A, Salek S, Daniel E, Gangaputra S, Ostheimer TA, Burkholder BM, Leung TG, Butler NJ, Dunn JP, Thorne JE. Clinical features and incidence rates of ocular complications in patients with ocular syphilis, Am J Ophthalmol. 2015;159(2):334343.e1. 11. Wilks D, Farrington M, Rubenstein D, The Infectious Disease Manual. Oxford, UK: Blackwell; 2003:89-92. 12. Workowsi KA and Bolan GA. Sexually Transmitted Diseases Guidelines, 2015. MMWR. 2015: 64(3): Available at https://www.cdc.gov/std/tg2015/tg-2015print.pdf. Accessed October 24, 2017. 13. Centers for Disease Control and Prevention. Diseases Characterized by Genital, Anal, or Perianal Ulcers - 2010 STD Treatment Guidelines. Cdc.gov. 2017. Available at: https://www.cdc.gov/std/treatment/2010/genital-ulcers.htm#a5. Accessed June 12, 2017. 14. Peeling RW, Ye H. Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview. Bull World Health Organ 2004; 82:439-46. 15. Centers for Disease Control and Prevention. Discordant Results from Reverse Sequence Syphilis Screening – Five Laboratories, United States, 2006 – 2010. Cdc.gov. 2017. Available at: https://www.cdc.gov/mmwr/preview/mmwrhtml/ mm6005a1.htm?s_cid=mm6005a1_w. Accessed June 15, 2017. 16. CDC. 2015 Sexually Transmitted Disease Guidelines. Syphilis. https://www.cdc. gov/ std/tg2015/syphilis.htm. Accessed October 24, 2017. 17. Fiumara N, Serologic Responses to Treatment of 128 Patients with Late Latent Syphilis. Sexually Transmitted Diseases. 1979;6(4):243-246. doi:10.1097/00007435197910000-00003.

18. Clement M, Okeke N, Hicks C. Treatment of Syphilis: a systematic review. JAMA. 2014;312(18):1905. doi:10.1001/jama.2014.13259. 19. Walker D, Walker G. Prevention of congenital syphilis – time for action. Bulletin of the World Health Organization [serial online]. June 2004;82(6):401. 20. Centers for Disease Control and Prevention. Congenital Syphilis – United States, 1998. MMWR: Morbidity & Mortality Weekly Report [serial online]. September 3, 1999;48(34):757-761. 21. U.S. Preventative Services Task Force. Final Update Summary: Syphilis Infection in Pregnancy: Screening. July 2015. https://www.uspreventetiveservicestaskforce. org/Page/Document/UpdateSummaryFinal/syphilis-infection-in-pregnancyscreening. 22. Mississippi State Department of Health. List of Reportable Diseases and Conditions. Jackson, Mississippi; 2017.

Author information Associate Clinical Professor of Family and Community Medicine, Tulane University School of Medicine; Adjunct Clinical Professor of Family Medicine, William Carey University College of Osteopathic Medicine; JMSMA Editor; Mississippi State Board of Health; Private Practice Magnolia Clinic, Magnolia, Mississippi (Lampton). Associate Professor of Preventive Medicine and Pediatrics, University of Mississippi Medical Center (D. Pendergrass). Associate Professor, Department of Preventive Medicine and School of Population Health (P. Pendergrass). Mississippi State Epidemiologist, Mississippi State Department of Health (Byers). Mississippi State Department of Health (Johnson). Mississippi State Department of Health (Stewart). Fourth year medical student at Tulane University School of Medicine in New Orleans (Marturano). Fourth year medical student at Tulane University School of Medicine in New Orleans (Schwartz). Corresponding Authors: Desiree B. Pendergrass, MD, MPH, Department of Preventive Medicine, UMMC, 2500 North State Street, Jackson, MS 39216. (Desiree.Pendergrass@msdh.ms.gov). Lucius M. “Luke” Lampton, MD, FAAFP, Magnolia Clinic, 111 Magnolia Street, Magnolia, MS 39652. Ph: (601)-783-2374. (LukeLampton@cableone.net).

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Top 10 Facts You Need to Know about Stinging Insect Allergy JESSICA B. PERKINS, MD

Insect stings are a common cause of allergic reactions. Allergic reactions to insect stings can occur at any age. Even though an individual has an uneventful sting at one point in time, an allergic reaction may occur to a future sting. There are two categories of sting reactions: local and systemic. Immediate-type local reactions involve only the area of skin adjacent to the sting site. Immediate-type local reactions are pruritic, urticarial wheals that occur immediately and resolve within an hour. Late- type local reactions are erythematous, indurated, painful and pruritic areas at the site of the sting that appear hours later and may persist for days. Both types are an IgE mediated event.1 Immediate-type local reactions almost always occur with insect stings and large local reactions occur in 5% to 25% of adults and children.2 (Figure 1) With a systemic reaction, one will have symptoms in one or more locations not involving the sting site.1 In those patients who suffered a large local reaction, they have a 4% to 10% risk of systemic reaction.3

Insect stings Table. Symptoms of Anaphylaxis1 can cause a life threatening systemic reaction. Generally speaking, anaphylaxis is defined as an IgE mediated immediate hypersensitivity reaction that causes systemic 4 symptoms. In the United States, 3% of adults and 1% of children are reported to have had a systemic reaction to an insect sting.1 Signs and symptoms of anaphylaxis can involve several organ systems. Anaphylaxis may present with one or more clinical symptoms. (Table)

Stinging insects that cause allergic reactions belong to the insect order Hymenoptera The families of insects within the order hymenoptera include Apidae (honey bee, bumble bee, sweat bee), Vespidae (yellow jacket, yellow hornet, white-faced hornet, and paper wasp), and Formicidae (fire ant, jack jumper ant, and harvester ant). Some insects have characteristics that can help identify the culprit; however, most individuals are unable to correctly identify the stinging insect. For example, the honey bee has a barbed stinger that remains in the skin after a sting .1 Yellow jackets’ nests are usually located in the ground.1

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Hornets usually build their nests in shrubs and trees.1 Knowledge of these characteristics may also help patients avoid these insects. Fire ants are prevalent in the southeastern United States, where approximately 50% of the population is stung by fire ants each year.5,6

Specific insect venom immunotherapy is available for patients with sting anaphylaxis and can be curative. Venom immunotherapy (VIT) can prevent recurrent systemic allergic reactions to stings and is the treatment of choice.1 Venom immunotherapy is 95% to 100% effective in preventing systemic reactions to subsequent stings.1 Venom immunotherapy is similar to allergen immunotherapy to inhalant allergens like ragweed, where small amounts of antigen are injected intradermally to downregulate the production of allergen specific IgE by the immune system. Extracts of honeybee, yellow jacket, white faced and yellow face hornet, and wasp venom are available for venom immunotherapy.3 Venom immunotherapy to fire ants involves crushing the whole body of the fire ant to obtain the antigen needed instead of obtaining the fire ant venom itself like in the other hymenoptera insects. Whole body extracts for insect anaphylaxis have found to be effective to use only in fire ant venom immunotherapy.7

History is key in the Figure 2. identification of eligible patients for venom immunotherapy. Individuals who qualify for venom immunotherapy have a history of a systemic reaction to a sting and evidence of IgE antibodies to venom as demonstrated by skin testing to venom or in vitro blood testing.1,3 Patients with advanced heart disease and those taking beta blockers and ACE inhibitors may be at increased risks of complications from immunotherapy and their treatment is best discussed with the patient’s cardiologist.8 Those patients with large local reactions only do not require testing or venom immunotherapy.3 Patients younger than 16 with hives only do not require testing or venom immunotherapy.9,10 (Figure 2)

Figure 1. Large Local Reaction

bee and having an elevated basal serum tryptase are risk factors for severe anaphylaxis.3

10 A late type reaction to fire ant sting 24 hours after the sting. Note the three sterile pustules, which are specific for fire ant stings.

Venom immunotherapy requires about 5 years of therapy. Undergoing venom immunotherapy is a time commitment that can provide lifesaving protection. Typically injections are given weekly until the maintenance dose is achieved. Once at maintenance, injections are given monthly.1 There are several different schedules for venom immunotherapy administration and experts recommend treatment for 3 to 5 years.3 Caveats to 5 year therapy include those with honeybee allergy, those with a mast cell disorder, or those who had systemic reactions to stings during venom immunotherapy. For these patients, immunotherapy treatment may need to be longer.1

Venom immunotherapy’s safety profile is similar to immunotherapy to inhalant allergens. The risk of adverse reactions to venom immunotherapy is no greater than adverse reactions to inhalant allergen immunotherapy. Systemic symptoms occur in 5% to 15% of individuals during the first weeks of treatment.1 Patients with underlying mast cell disorders may be at greater risk for severe reactions to venom immunotherapy.1 Most systemic reactions observed during venom immunotherapy are mild but do require longer observation in clinic than usual.

Biting insects rarely cause systemic reactions. The immune system may become sensitized to proteins in biting insect saliva which will sometimes cause large local reactions. Systemic symptoms are less commonly reported in biting insects.1 Common biting insects include the kissing bug, mosquitos, black flies, fleas and horseflies. Kissing bugs have been reported to cause large local reactions and systemic symptoms such as pruritus, wheezing and laryngeal edema.11 Large local reactions to mosquito bites are common in children and have been called “Skeeter Syndrome.”12,13

A good history can help identify which individuals are at risk for sting anaphylaxis. Those patients who experience anaphylaxis without urticaria or angioedema may have a higher frequency of subsequent severe reactions.14 Individuals over age 45, have history of a previous severe reactions to stings, or take ACE inhibitor or beta blockers could be at greater risk for severe reactions to stings.1 Venom specific IgE to honey

All individuals with a history of anaphylaxis, including those with anaphylaxis to insects, should be given instructions and a prescription for an epinephrine auto injector and referred to an allergistimmunologist. Stinging insect avoidance measures should also be discussed. One of the leading causes of death from anaphylaxis is delayed administration of epinephrine. A consultation to an allergistimmunologist should be placed so venom testing and immunotherapy can be considered. Avoidance measures include avoiding grilling outdoors, being around flowering plants or garbage receptacles outdoors, walking barefoot outside, and watching for nests while doing yardwork.3 Treating fire ant mounds with pesticides can help prevent fire ant spread.6 These avoidance tips can be discussed with patients. n References 1. Golden DBK. Insect allergy. In: Adkinson NF, Bochner BS, Burks AW, et al. (editors). Middleton’s Allergy: Principles and Practice. 8th ed. Philadelphia: Elsevier Saunders; 2014. P. 1260-73. 2. Bilo MB, Bonifazi F. The natural history and epidemiology of insect venom allergy: clinical implications. Clin Exp Allergy. 2009;39:1467-76. 3. Golden DBK, Demain J, Freeman T, et al. Joint Task Force on Practice Parameters: American Academy of Allergy, Asthma & Immunology (AAAAI), American College of Allergy, Asthma, & Immunology (ACAAI) Joint Council Allergy, Asthma, and Immunology. Stinging insect hypersensitivity: a practice parameter update. 2016. Ann Allergy Asthma Immunol. 2017; 118: 32-49. 4. Brown, SGA, Kemp SF, Lieberman PL. Anaphylaxis. In: Adkinson NF, Bochner BS, Burks AW, et al. (editors). Middleton’s Allergy: Principles and Practice. 8th ed. Philadelphia: Elsevier Saunders; 2014. 1237-59. 5. Kemp SF, deShazo RD, Moffitt JE, et al. Expanding habitat of the imported fire ant: a public health concern. J Allergy Clin Immunol. 2000;105:683-91. 6. deShazo RD, Butcher B, Banks WA. Reactions to the stings of the imported fire ant. N Engl J Med. 1990; 323:462-6. 7. Freeman TM, Hylander R, Ortiz A, Martin ME. Imported fire ant immunotherapy: effectiveness of whole body extracts. J Allergy Clin Immunol. 1992;90:210-5. 8. Muller UR. Cardiovascular disease and anaphylaxis. Curr Opin Allergy Clin Immunol. 2007;7:337-341 9. Golden DBK, Kagey-Sobotka A, Norman PS, Hamilton RG, Lichtenstein, LM. Outcomes of allergy to insect stings in children with and without venom immunotherapy. N Engl J Med. 2004; 351:668-674. 10. Valentine MD, Schuberth KC, Kagey-Sobotka A, et al. The value of immunotherapy with venom in children with allergy to insects. N Engl J Med. 1990; 323:1601-1603. 11. Moffitt JE, Venarske D, Goddard J, et al. Allergic reactions to Triatoma bites. Ann Allergy Asthma Immunol. 2003;91:122-128. 12. Simons FER, Peng Z. Mosquito allergy: recombinant mosquito salivary antigens for new diagnostic tests. Int Arch Allergy Immunol. 2001;124:403-5. 13. Simmons FER, Peng Z. Skeeter syndrome. J Allergy Clin Immunol. 1999;104:705-7. 14. Stoevesandt J, Hain J, Kerstan A, Trautman A. Over and underestimated parameters in severe Hymenoptera venom-induced anaphylaxis: cardiovascular medication and absence of urticarial/angioedema. J Allergy Clin Immunol. 2012; 130:698-704.

Author information University of Mississippi Medical Center School of Medicine, MD and residency. Allergy and Immunology Fellow in the Division of Clinical Immunology and Allergy at UMMC (Perkins).

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Early Stage Prostate Cancer: An Analysis of Treatment Modality by Race in Mississippi KEVIN MCKAY, PHD; JESSICA BAILEY, PHD; LEI ZHANG, PHD; ELLEN JONES, PHD

Abstract Purpose: Prostate cancer is one of the most prevalent male cancers nationally, and prostate cancer incidence and mortality rates are higher in Mississippi than the national average for all racial groups. This research examines race and early stage prostate cancer treatment modality utilized by patients in Mississippi from 2007 to 2011. Methods: Data for 9,382 patients was obtained from the Mississippi Cancer Registry and analyzed with SPSS version 23. Treatment modality types included surgery, brachytherapy, and external beam radiation therapy. Results: Pearson’s Chi-square, binary logistic regression, and multinomial logistic regression showed that there was a statistically significant difference in treatment modality by race in Mississippi. Conclusion: This research provides a valuable resource that could allow for more targeted outreach to improve health care access for African American patients with early-stage (T1-T2) prostate cancer in Mississippi. Key words: early stage prostate cancer, brachytherapy, radiation therapy, racial disparities Introduction At the national level, prostate cancer is one of the most prevalent male cancers, and this trend is evident in Mississippi where prostate cancer rates are higher than the national average for all racial groups. In 2013, Mississippi had one of the highest annual incidence rates of prostate cancer at 127.2 per 100,000 persons compared to a rate of 101.6 nationally.1 The incidence rate for African Americans in Mississippi in 2013 was 184.1 cases per 100,000.2, while for Caucasians, the rate was 104.7 cases per 100,000.3 There is no “gold standard” regarding prostate cancer treatments, particularly early stage (T1-T2). Many treatment options including surgery, brachytherapy with radioactive isotope prostate seed implants, and external beam radiation therapy are widely available. Previous research has shown statistically significant differences in incidence rates

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between Caucasian and African American populations. Currently there is a dearth of information regarding the use of these prostate cancer treatment modalities in Mississippi. In examining men diagnosed with T1-T3 prostate cancer, some authors4 posit that there are issues of mistrust within the African American community that must be overcome for them to utilize the health care system to its fullest extent. Their research involving 71 African American and 125 Caucasian males treated in Philadelphia, Pennsylvania, found that there were significant effects of mistrust due to varying levels of the participants’ education, race, culture, and previous experiences within the health care system. While there were no statistically significant differences in most categories, the authors found that there were significant differences in that Caucasians had higher incomes, higher education levels, and were more likely to initiate or finish treatment for their cancer as compared to African Americans. Another study further examining race as it relates to mistrust of physicians and the medical field5 found that a subset of the African American population had much lower levels of physician trust than other African American patients; however, overall, there was not a statistically significant difference in the perception of physicians between Caucasians and African Americans. The authors suggest that a particular individual’s access to health care is the overriding factor in mistrust, as persons who do not have easy access to health care often have less knowledge of the health care system and do not have a strong rapport with their physician. As a subset of the African American population may have decreased access to the health care system, this could lead to mistrust of physicians and the medical system in general. For example, the authors found that African Americans were more likely to choose a less aggressive treatment modality, were more likely to see different physicians during their medical visits, and were less likely to seek needed medical care.5 Previous research showed4,5 mistrust within the African American population. One could argue that the issue of African American mistrust of physicians and the medical profession would be applicable in Mississippi as well. This mistrust could be a result of the African American population in Mississippi having a more limited exposure to the various aspects of the medical profession due to geographic, socioeconomic, educational, and other factors that could limit their health care access.

This could result in fewer African Americans attending prostate cancer screenings as well as regular physical examinations, which could then lead to delays in diagnosis and treatment, the possibility of refusing treatment or choosing a less aggressive treatment, and a corresponding increase in negative patient outcomes. This cycle of mistrust could then be repeated within the African American community as the patient and his family and friends experience poor patient outcomes. Other studies show6 prostate cancer has many interrelated risk factors that can include, but are not limited to, “biologic, socioeconomic, lifestyle, cultural, environmental and/or occupational factors”. As such, African Americans are more likely to be diagnosed with more advanced prostate cancer due to having lower overall education levels and inadequate access to health care, all of which leads to poorer outcomes. The authors found knowledge barriers consisting of myths, misunderstandings, and a lack of accurate information. Participants also had attitude barriers that included denial, fear, and apathy. These fears and misconceptions are considered a reality within the African American community, but the authors suggest that this could be overcome through targeted education in regards to prostate cancer. This concept is presently being implemented by the Centers for Disease Control and Prevention through their separate prostate cancer guidebook, providing information specifically tailored to the concerns of African Americans. An opposing viewpoint7 argued that a patient’s educational level rather than race was the most important factor regarding knowledge and misconceptions about prostate cancer. These misconceptions include topics such as prostate cancer screenings, causes for the cancer, patient fears, and knowledge pertaining to the prostate gland itself. The authors, in a qualitative study interviewing 65 men from socioeconomically and geographically diverse backgrounds in North Carolina, found that the knowledge of prostate cancer symptoms was equal regardless of the subject’s educational level, but knowledge regarding prostate screenings and treatments for prostate cancer was significantly different. Because of this education disparity, the authors argue that tailoring educational and screening materials should not be based on a particular patient’s racial status but according to their level of education as they found that as one’s education levels increased, knowledge of the prostate gland and associated tests, prevention, causes, and treatment increased. The authors argue that by increasing the knowledge level of prostate cancer for all races, intervention and treatment outcomes should improve over time, and this is especially true for those with the lowest educational levels.7 Another study using federal income levels from the 1990 census and mortality rates from the National Center for Health Statistics stated that, “At some cancer sites, the highest SES group for minorities had worse trend results than the trends for the lowest SES white group”.8 This research indicated an excess cancer burden for African Americans regarding prostate cancer. Although the prostate cancer mortality rates for both Caucasians and African Americans have been decreasing, the rate of decrease for African Americans has not been as rapid as that of

Caucasians, leading to increased disparities over the time frame of this study. Due to the data gleaned from their research, the authors suggest that early detection and treatment would reduce the disparity in mortality rates within the African American community as compared to Caucasians. In an examination of race and prostate cancer9 the authors analyzed 524 African American and 396 Caucasian men from 1982 to 1992 who were diagnosed with prostate cancer at the Veterans Affairs Medical Center in Jackson, Mississippi. The authors found that mortality rates for African Americans were higher than for Caucasians for localized prostate cancer. A patient’s race was also linked to the clinical stage, specifically Gleason score, at time of diagnosis, with African Americans having a much higher incidence of metastatic disease.9 A follow-up study from 1992 through 2000 at the same facility examined 745 African American and 522 Caucasian males.10 The majority of African American (62%) and Caucasian (79%) patients in the study had prostate cancer staged T1c-T2. The authors posit that differences in outcomes for African Americans and Caucasians with early-stage (T1-T2) prostate cancer are tied to the Gleason score. The authors state that, “Gleason score is a powerful predictor of malignant potential and underscore the clinical and biologic significance of racial differences in the prevalence of poorly differentiated cancer in men with local stage disease”.10 This research provides insight into prostate cancer treatment in this facility that was unavailable to this author in the analysis of the Mississippi Cancer Registry data set. An analysis of cancer registries from the states of Florida, Kentucky, Georgia, and Maryland found that after controlling for patient and area characteristics, African Americans were less likely than Caucasians to be diagnosed with localized prostate cancer in only Florida.11 A qualitative study involving 52 African American men residing in either Alabama or Mississippi examined perspectives of these men in regards to their prostate cancer.12 The Mississippi residents were from either Forrest County (33.6 % African American) or Humphreys County (70% African American). The authors argued that African American males living in the Deep South are a unique subset of the population that needs to have prostate cancer information specifically tailored to them. Specifically, the author’s results showed that these particular African American men wanted more information about prostate cancer, the risks of developing prostate cancer, and increased information regarding various prostate cancer treatment modalities. However, the participants also stated that increased information regarding prostate cancer would likely “bring about anxiety/fear, it would be costly or inconveniencing, and that the information received from physicians would not be trustworthy”.12 An examination of Cancer of the Prostate Strategic Urologic Research Endeavor database13 found that there was a statistically significant difference between treatment modality usage by Caucasians and

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Table 1. Pearson’s Chi Square Results for Race and Treatment Type in Mississippi

Table 1. Pearson’s Chi Square Results for Race and Treatment Type in Mississippi. Radiation No Radiation

Total Race White Black

N 3960 2416

% 73.5 70.2

Radiation External Beam p-value N 0.004

% 835 598

15.5 17.4

Radiation Brachytherapy p-value N 0.004

596 426

Surgery No Surgery

% p-value 11.1 12.4

<0.0001

N 2833 2078

Surgery Surgery

% p-value 52.5 60.2

<0.0001

N 2565 1371

% p-value 47.5 39.8

<0.0001

African Americans with similar prostate cancer status. African Americans were more likely to be treated with hormone therapy or radiation therapy than Caucasians.13

sixteen (70.2%) African Americans received no radiation treatment, 598 (17.4%) received external beam radiotherapy, and 426 (12.4%) received brachytherapy.

A study of14 prostate cancer outcomes for 12,081 men found the difference in prostate cancer incidence between African Americans (8.3%) and Caucasians (3.3%) who were less than 50 years of age to be statistically significant. The authors argue that as a result of earlier detection, both African American and Caucasian males would have more favorable outcomes for their prostate cancer.

Pearson’s Chi-square (Table 1) showed race (p-values = 0.004) to be statistically significant with regard to having no radiation therapy treatment or external beam radiation therapy. For race and choice of brachytherapy, the p was <0.0001.

Materials and Methods Patient data was obtained from the Mississippi Cancer Registry after institutional review board approval. This quantitative research used SPSS to analyze race and treatment modality for early-stage (T1-T2) prostate cancer within the state of Mississippi from 2007-2011. Data were analyzed using Pearson’s Chi square, binary regression analysis, and multinomial regression analysis. Because some treatment categories were not required to be reported to the Mississippi Cancer Registry, several treatment types were combined. Intensity-modulated radiation therapy and three dimensional conformal radiation therapy were combined into a single external beam radiation therapy category. Surgical intervention modalities were also combined into a category that included any treatment that would either surgically excise the prostate or destroy the prostate through surgical intervention. The final treatment categories analyzed were surgery, external beam radiation therapy, and brachytherapy.

As for the analysis of race and surgical intervention, there were 535 cases (5.7%) with missing data which allowed the analysis of 8,847 (94.3%) cases. Of the 8,847 cases, 5,398 (61%) were Caucasian and 3,449 (39%) were African American. For Caucasians, 2,833 (52.5%) received no surgical intervention, and 2,565 (47.5%) received surgical intervention for their early stage prostate cancer. For African Americans, 2,078 (60.2%) did not receive surgical intervention, and 1,371 (39.8%) received surgery. A Pearson’s Chi-square analysis showed a statistically significant difference in race and surgical intervention (p <0.0001). Therefore, there is a statistically significant difference with regard to race and treatment modality utilization whether it is brachytherapy, external beam radiation therapy, or surgery. Limitations of this study include the exclusion of patients who had been treated at the Veterans Affairs hospital facility in Jackson, Mississippi; Keesler Air Force Base in Biloxi, Mississippi; Mississippi residents who received their prostate cancer treatments outside of the state of Mississippi; and the relatively short five-year time period that was examined.

Results

Discussion

The data set contained 9,382 unique prostate cancer cases with patients divided into two racial categories: African American or Caucasian. For the analysis of race and radiation therapy treatment modality utilization, 551 cases (5.9%) had missing data resulting in an analysis of the remaining 8,831 (94.1%) cases. Of these 5,391 (61.0%) were Caucasian and 3,440 (39.0%) were African American. For Caucasians, 3,960 (73.5 %) received no radiation treatment, 835 (15.5 %) received external beam radiation therapy, and 596 (11.1 %) received brachytherapy. Two thousand four hundred and

The analysis of race and radiation therapy treatment modality utilization with Pearson’s chi-square showed race (p-values = 0.004) to be statistically significant with regard to having no radiation therapy treatment or external beam radiation therapy. For race and choice of brachytherapy, p<0.0001. For the analysis of race and surgical intervention, Pearson’s Chi-square analysis showed a statistically significant difference (p<0.0001). Therefore, there is a statistically significant result with regard to race and treatment modality utilization whether it is brachytherapy, external beam radiation therapy, or surgery.

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This result allowed the use of binary and multinomial regression analysis for further analysis (Table 2). For surgery, the binary logistic regression analysis with regards to race (p<0.0001), the odds ratio of 0.616 (95% CI: 0.560, 0.678) indicated that African Americans were 0.616 times less likely to have surgery than Caucasians. The multinomial logistic regression analysis with regard to race and external beam radiation therapy resulted in a p-value of less than 0.0001 and an odds ratio of 0.800 (95% CI: 0.708, 0.904). This result was highly significant and showed that Caucasians were less likely to choose external beam radiation therapy than no treatment. Multinomial logistic regression analysis of race showed that Caucasians were less likely to choose brachytherapy (p-value of 0.003) and an odds ratio of 0.808 (95% CI: 0.703, 0.929).

References 1. Centers for Disease Control and Prevention. Age-Adjusted Invasive Cancer Incidence Rates and 95% Confidence Intervals by State 2013. https://nccd. cdc.gov/USCS/cancersrankedbystate.aspx?Year=2013&Variable1=Mississippi. Accessed April 1, 2017. 2. Cancer.gov. Incidence rates for United States prostate, 2013 Black, male, all ages. 2013. https://statecancerprofiles.cancer.gov/map/map.withimage. php?00&001&066&02&1&01&1&1&5&0#results. Accessed April 1, 2017. 3. Cancer.gov. Incidence rates for United States prostate, 2013 White NonHispanic, male, all ages. 2013. https://statecancerprofiles.cancer.gov/map/map. withimage.php?00&001&066&07&1&01&1&1&5&0#results. Accessed April 1, 2017. 4. Halbert CH, Weathers B, Delmoor E, et al. Racial differences in medical mistrust among men diagnosed with prostate cancer. Cancer. 2009;115(11):2553-2561.

Conclusion

5. Do YK, Carpenter WR, Spain P, et al. Race, healthcare access and physician trust among prostate cancer patients. Cancer Causes Control. 2010;21(1):31-40.

The statistical analysis indicated that in Mississippi, a patientâ&#x20AC;&#x2122;s race had a statistically significant difference in the treatment modality utilized for the treatment of their early stage (T1-T2) prostate cancer. To address this issue nationally, there are two separate Centers for Disease Control and Prevention prostate cancer screening guides specifically tailored for African Americans or Caucasians. This research could provide a valuable resource that could allow for more concrete planning with regards to improving health care access for patients with early-stage (T1-T2) prostate cancer through increased emphasis on early screening and diagnosis, equipment purchasing decisions for treatment providers, coverage decisions for insurance providers, and individual patients with prostate cancer having more information available to them and their family members to make informed decisions. n

6. Richardson JT, Webster JD, Fields NJ. Uncovering myths and transforming realities among low-SES African-American men: Implications for reducing prostate cancer disparities. J Natl Med Assoc. 2004;96(10):1295-1302. 7. Winterich JA, Grzywacz JG, Quandt SA, et al. Men's knowledge and beliefs about prostate cancer: Education, race, and screening status. Ethn Dis. 2009;19(2):199203. 8. Chu KC, Miller BA, Springfield SA. Measures of racial/ethnic health disparities in cancer mortality rates and the influence of socioeconomic status. J Natl Med Assoc. 2007;99(10):1092-1100, 1102-1094. 9. Fowler JE, Jr., Bigler SA, Bowman G, Kilambi NK. Race and cause specific survival with prostate cancer: influence of clinical stage, Gleason score, age and treatment. J Urol. 2000;163(1):137-142. 10. Fowler JE, Jr., Bigler SA. Racial differences in prostate carcinogenesis. Histologic and clinical observations. Urol Clin North Am. 2002;29(1):183-191. 11. Oliver MN, Stukenborg GJ. Race and the likelihood of localized prostate cancer at diagnosis among men in 4 southeastern states. J Natl Med Assoc. 2009;101(8):750757.

Table 2. Bivariate and Multinomial Results for Race and Treatment Type 12. Ross L, Kohler CL, Grimley DM, Green BL, Anderson-Lewis C. Toward a in Mississippi Table 2. Bivariate and Multinomial Results for Race and Treatment Type in Mississippi. 95% C.I. for EXP(B)

model of prostate cancer information seeking: Identifying salient behavioral and normative beliefs among African American men. Health Educ Behav. 2007;34(3):422-440.

Significance

Exp(B)

Lower

Upper

13. Moses KA, Paciorek AT, Penson DF, Carroll PR, Master VA. Impact of ethnicity on primary treatment choice and mortality in men with prostate cancer: Data from CaPSURE. J Clin Oncol. 2010;28(6):1069-1074.

Race

<0.0001

0.616

0.560

0.678

14. Parker PM, Rice KR, Sterbis JR, et al. Prostate cancer in men less than the age of 50: A comparison of race and outcomes. Urology. 2011;78(1):110-115.

External Beam Race

<0.0001 <0.0001

Brachytherapy

<0.0001

Race

0.003

Variable Surgery

Author Information 0.800

0.708

0.904

0.808

0.703

0.929

Medical Dosimetrist, St. Dominic Cancer Center; Assistant Faculty School of Health Related Professions, University of Mississippi Medical Center (McKay); Dean, School of Health Related Professions, University of Mississippi Medical Center (Bailey); Professor, School of Nursing, University of Mississippi Medical Center; Director, Office of Health Data and Research, Mississippi State Department of Health (Zhang); School of Health Related Professions, University of Mississippi Medical Center (Jones). Corresponding Author: Kevin McKay, 565 Turtle Lane, Brandon, MS 39047.

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Primary Hepatic Leiomyosarcoma MARY TUCKER SESSUMS, MD; DAVID RAY, MD; TRUMAN MARK EARL, MD; CHARULOCHANA SUBRAMONY, MD; MARIA F. GONZALEZ, MD

Abstract We report a rare case of primary hepatic leiomyosarcoma in a 51-yearold female and discuss the differential diagnosis. Primary hepatic sarcoma is a rare diagnosis and accounts for less than 1% of liver malignancies. The main histopathological differential diagnosis of a hepatic sarcoma includes leiomyosarcoma, angiosarcoma, epithelioid hemangioendothelioma, undifferentiated embryonal sarcoma, synovial sarcoma, and malignant solitary fibrous tumor. Of these rare tumors, leiomyosarcoma and angiosarcoma are the two most commonly reported histological types. The evaluation of liver masses must start with a good clinical history, laboratory exams, and radiologic correlation. However, most of the findings of primary hepatic sarcomas are nonspecific. The final diagnosis is made based on morphology, immunohistochemistry, and in some cases cytogenetics. Keywords: hepatic, liver, primary, sarcoma, leiomyosarcoma Introduction Primary hepatic sarcoma is a rare diagnosis and accounts for less than 1% of liver malignancies. Of these rare tumors, leiomyosarcoma and angiosarcoma are the two most commonly reported histological types.1 We present a patient with primary hepatic leiomyosarcoma and discuss the differential diagnosis of a primary hepatic sarcoma, which includes leiomyosarcoma, angiosarcoma, epithelioid hemangioendothelioma, undifferentiated embryonal sarcoma, synovial sarcoma, and malignant solitary fibrous tumor. Primary hepatic leiomyosarcoma (PHL) arises from the smooth muscle of intrahepatic vascular structures, bile ducts, or ligamentum teres. In 2011, less than 30 cases of PHL had been reported in the English literature.2 In 2012, Chi et al identified 109 cases of PHL, including cases reported in the literature and cases at their institution.3 The median age at diagnosis was 58, and there was no clear gender predominance.2,4 In patients with PHL, liver function tests may be normal or mildly elevated.5,6 No serological marker has been identified to aid in detection of PHL.1 On histology, PHL is characterized by spindle cells with cigar-shaped hyperchromatic nuclei. The diagnosis is confirmed by immunohistochemistry studies that are positive for smooth muscle actin, desmin, and vimentin, and negative for cytokeratin and S-100 protein.5 Due to the rarity of this malignancy, a standard treatment has not yet been established. Treatment options

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include chemotherapy, surgical resection, and liver transplantation.7 Resection of leiomyosarcoma with tumor-free margins has been associated with encouraging disease-free 5-year survival rates.8 Case Report A 51-year-old female was transferred to our hospital for surgical evaluation of a newly diagnosed hepatic mass. She presented with a chief complaint of bloating and worsening right-sided abdominal pain for four months. Her medical history was significant for hypertension and diabetes mellitus type II. She had no history of alcohol abuse, liver disease, or intravenous drug use. Family history was unremarkable. Laboratory analysis revealed elevated total and direct bilirubin and elevated alkaline phosphatase. Liver transaminases and prothrombin time were within normal limits. Computed tomography (CT) of the abdomen revealed a necrotic mass which measured 12.8 cm in greatest dimension and ruptured through the liver capsule. Hemoperitoneum was also identified. The radiologic appearance of this mass was highly suspicious for a primary liver neoplasm. No active extravasation of contrast was present to Figure 1. 1A (left): Coronal contrast enhanced computed tomographic (CT) image of the patient’s liver showing a large mass in the enlarged right hepatic lobe. The mass is centrally hypodense (blue arrow), suggesting necrosis, with peripheral enhancement (green arrow). Note the peripheral enhancement of the mass is different than the normal liver parenchyma. Also, the capsule of the liver is indistinct (red arrow) on the lateral margin of the mass suggesting this is the site of capsular rupture. 1B (right): Axial contrast enhanced CT through the mass showing perihepatic and subcapsular fluid causing mass effect on the right hepatic lobe (red arrow). Hemoperitoneum noted posterior to the liver which extended into the pelvis (blue arrow).

suggest active bleeding at that time (Figure 1A and 1B). There was no lymphadenopathy or evidence of distant metastasis. Hepatic steatosis and cholelithiasis without cholecystitis were also noted. She underwent partial hepatic lobectomy of segments 5 and 6, along with cholecystectomy. On histology, the liver revealed macrosteatosis and necrotic tumor. The tumor cells showed pleomorphic, hyperchromatic, cigar-shaped nuclei with prominent perinuclear cytoplasmic vacuolation (Figure 2A and 2B). Immunohistochemistry stains with adequate controls showed that the tumor cells were positive for desmin (Figure 3A) and smooth muscle actin (Figure 3B). The tumor cells were negative for hepatocyte specific antigen, broad spectrum cytokeratin, cytokeratin 7, HMB-45 (homatropine methylbromide 45), S-100 protein (solubility in a 100%-saturated solution with ammonium sulphate at neutral pH-protein), and CD34 (cluster of differentiation 34). One year prior to this presentation for the newly diagnosed hepatic mass, the patient had undergone hysterectomy with bilateral salpingooophorectomy for fibroids. The pathology report was obtained from an outside hospital. Gross description revealed an 8 cm yellow-red nodule with some degenerative areas that composed the majority of the uterus, along with a second 4 cm nodule that consisted of homogenous gray tissue. The report suggested no evidence of malignancy, and the final diagnosis was leiomyomas. Figure 2. 2A (left): Intermediate-magnification photo of the tumor of our patient composed of pleomorphic hyperchromatic spindle cells and necrosis (hematoxilin & eosin, original magnification 100X). 2B (right): High magnification of the tumor cells showing the characteristic cigar-shaped nuclei and intracytoplasmic vacuoles (hematoxilin & eosin, original magnification 600X).

Discussion Primary hepatic leiomyosarcoma (PHL) arises from the smooth muscle of intrahepatic vascular structures, bile ducts, or ligamentum teres.2 The literature varies regarding the number of reported cases of PHL, from <30 to 109. The median age at diagnosis is 58, with rare cases occurring in the pediatric population.2,3 The gender ratio in PHL is approximately equal.2 The nonspecific signs and symptoms often delay diagnosis. Clinically, PHL symptoms include abdominal pain, weight loss, jaundice, and vomiting. However, patients may be asymptomatic until the tumor becomes large in size, and hepatomegaly may be noted on physical exam.5 The radiologic appearance of PHL

is not pathognomonic either. Prior reports of primary hepatic leiomyosarcoma have described a hypodense mass on CT with some peripheral enhancement.2,5

Figure 3. Immunohistochemistry stains were performed on a representative section of the patientâ&#x20AC;&#x2122;s tumor. The tumor cells are positive for desmin (Figure 3A, top photo below) and smooth muscle actin (SMA) (Figure 3B, bottom photo) antibodies. (Desmin and SMA respectively, original magnification 60X).

However, since PHL is such a rare entity, there are no imaging findings that enable this diagnosis to be made by imaging alone. Occasionally, PHL may present with tumor rupture and intraperitoneal bleeding.3 Liver function tests may be normal or mildly elevated, but tumor markers such as alpha-fetoprotein (AFP) are within normal limits.5 PHL has been reported in association with EpsteinBarr virus and acquired immune deficiency syndrome.7 Histologically, PHL is characterized by spindle cells arranged in intersecting bundles with hyperchromatic and atypical nuclei. On immunohistochemistry, PHL is immunoreactive to desmin, vimentin, and smooth muscle actin (SMA). Tumor cells are negative for cytokeratin and S-100 protein.5,7 Primary leiomyosarcomas in other sites have been shown to be positive for caldesmon, a marker for smooth muscle differentiation.9 Soft tissue leiomyosarcomas show multiple gene alterations and very complex karyotypes, including numerous gains and losses.10 The differential diagnosis of hepatic masses in adults is extensive and includes metastasis and primary tumors (most commonly hepatocellular carcinoma and cholangiocarcinoma, and rarely mesenchymal tumors). Clinical history is an important tool that might help us to rule out some of the diagnostic possibilities. Per electronic medical records, our patient had a hysterectomy with leiomyomas. Before making the diagnosis of PHL, we ruled out the possibility of metastasis. The pathology report of the patientâ&#x20AC;&#x2122;s hysterectomy was requested. According to the report, the specimen was well sampled and no malignancy was identified. Radiologic studies, in some circumstances, can also help to differentiate metastatic disease from primary tumors. However, there is no a pathognomonic imaging finding or laboratory study that can help us to suspect a sarcoma, especially PHL. Therefore, the final diagnosis relies on the histologic examination of the specimen. The differential diagnosis of PHL on histology includes other sarcomas. The most common primary hepatic sarcomas include angiosarcoma, epithelioid hemangioendothelioma, undifferentiated embryonal sarcoma, synovial sarcoma and solitary fibrous tumor (Table).11-32 Primary hepatic angiosarcoma (PHA) arises from endothelial cells of blood vessels within the liver.11 Like other primary hepatic sarcomas, PHA is rare, accounting for <5% of all angiosarcomas and 0.1-2% of JOURNAL MSMA

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primary hepatic malignancies.12,13 PHA shows a male to female ratio of 3:1 and usually develops during the sixth and seventh decades of life.13 Symptoms of PHA are variable, nonspecific, and may include abdominal pain, fatigue, anorexia, and weight loss.1,13 PHA has been described as hypodense to the surrounding liver parenchyma on unenhanced and contrast enhanced imaging studies.14 PHA may rarely present with tumor rupture and intraperitoneal bleeding.11 In patients with PHA, laboratory tests may show thrombocytopenia, anemia, and moderately elevated liver enzymes. Tumor markers such as AFP, cancer antigen 19-9, and carcinoembryonic antigen are within normal limits or only mildly elevated.13 PHA has been associated with exposure to environmental carcinogens (thorium dioxide, arsenical insecticides, or polyvinyl chloride) in case-control studies.15 Histologically, PHA demonstrates spindle-shaped and polyhedral cells with nuclear atypia and mitoses, which proliferate in hepatic sinusoids and form vascular channels.12,13,16 The tumor may demonstrate a wide range of vascular patterns, from dilated cavernous spaces or sinusoids to slit-like anastomosing vessels.13 PHA is positive for endothelial markers such as CD34, CD31 (cluster of differentiation 31), Ulex europaeus agglutinin I, and factor VIII-related antigen.16 The most sensitive and specific marker for hepatic angiosarcoma is erythroblast transformation-specificrelated gene (ERG).17 A subset of primary angiosarcoma is known to be associated with amplification of MYC, a regulator gene that codes for a transcription factor.18 Epithelioid hemangioendothelioma (EHE) is a rare tumor of low to intermediate grade malignant potential which arises from vascular origin.19 EHE shows a slight female predominance and usually occurs in the soft tissue. The age range is 40 to 66 years, with a mean age of 52 years.20 Approximately 200 cases of primary hepatic EHE have been reported in the literature.19 Histologically, EHE is composed of spindle-shaped or epithelioid cells that grow along the hepatic sinusoid endothelium with intracytoplasmic vascular lumens containing red blood cells. The stroma is mucoid or fibrous, and mitotic figures are rarely observed. On immunohistochemistry, tumor cells are positive for CD34, CD31, Fli-1 (Friend leukemia integration 1 transcription factor), ERG, and Podoplanin (D2-40).20,21 A characteristic translocation t(1;3) (p36;q23-25) resulting in the gene fusion protein WWTR1-CAMTA1 has been identified in EHE in all anatomic sites.22 Undifferentiated embryonal sarcoma of the liver (UESL, also known as malignant mesenchymoma of the liver) is a malignant neoplasm that is composed of undifferentiated mesenchymal cells.23 UESL usually occurs in childhood, but it can occasionally be seen in middle-aged and elderly adults. Sixty cases in adults have been reported in the past fifty years. The tumor is usually a single, large, well-circumscribed mass which may display hemorrhage, necrosis, and cystic degeneration. Microscopically, UESL is composed of medium to large pleomorphic spindle cells that are loosely arranged and have poorly defined cell borders. Most are diffusely positive for vimentin and alpha-1 antitrypsin.24 The tumor may be focally positive for cytokeratin, desmin, SMA, muscle-specific actin, CD68 (cluster of differentiation 68), myoglobin, non-specific enolase, S-100, and CD34, demonstrating the undifferentiated nature of this neoplasm.23, 24 Multiple cytogenetic studies of sporadic cases demonstrated that UESL frequently harbors 196 VOL. 59 â&#x20AC;˘ NO. 4 â&#x20AC;˘ 2018

chromosomal rearrangements of 19q13.4, including the translocation t(11;19)(q11;q13.3/13.4) and add(19)(q13.4).25 Synovial sarcoma (SS) is a malignant tumor that arises from primitive mesenchymal cells and is usually located close to large joints such as the knee.26 Primary intra-abdominal synovial sarcomas are rare, with approximately 33 cases reported in the literature. While intraabdominal synovial sarcomas usually occur in the retroperitoneum, SS has been reported in sites throughout the body, including the liver.27,28 These tumors are usually diagnosed at middle age, and have no gender predilection.27 Histologically, SS demonstrates spindle cells within a collagenous background and a hemangiopericytomalike vascular pattern.26 SS can be subclassified into three morphologic types, including monophasic, biphasic, and poorly differentiated. Immunohistochemistry reveals positivity for vimentin, keratin, and/or epithelial membrane antigen (EMA). The cytogenetic and molecular analysis of SS is perhaps more useful for diagnosis, especially when SS occurs in unusual anatomic sites. The t(X; 18)(p11.2;icq11.2) translocation and the chimeric gene SYT-SSX are specific for SS and are usually present in the monophasic and biphasic morphologic types.28 Solitary fibrous tumor (SFT) is also included in the differential diagnosis of hepatic spindle cell lesions. SFT is a mesenchymal neoplasm which is usually benign, but may behave aggressively in 10-15% of cases.29 SFT most commonly occurs in the thoracic cavity, affecting the pleura and mediastinum.30 As of 2015, only 44 cases of hepatic SFT have been described in the English-language literature, four of which were malignant.30,31 The median age at diagnosis is 60 years, with a female predominance of 2:1. The neoplasm is characterized by fibroblast-like spindle cells that proliferate in a patternless architecture, separated by thick collagen bundles. The collagenous stroma may contain angulated hemangiopericytic staghorn-shaped vessels.31 Malignant SFTs may display pleomorphic spindle cells with increased cellularity, mitoses, and necrosis.29 Immunohistochemically, SFT is positive for CD34, Bcl2 (B-cell lymphoma 2), vimentin, and signal transducer and activator of transcription 6 (STAT6). The tumor cells are negative for S100, cytokeratins, and EMA.31 A NGFI-A binding protein 2 (NAB2)-STAT6 gene fusion has been shown to be a consistent finding in SFT.32 â&#x20AC;&#x192; Conclusion We conclude that primary hepatic sarcomas are rare tumors. Angiosarcoma and leiomyosarcoma are the most commonly reported types of hepatic sarcoma. The differential diagnosis also includes rarer entities such as epithelioid hemangioendothelioma, undifferentiated embryonal sarcoma, synovial sarcoma, and malignant solitary fibrous tumor (see table 1). Additionally, metastases must be considered in the differential diagnosis as primary hepatic sarcomas are very rare, and the liver is a common site of metastasis from gastrointestinal or retroperitoneal leiomyosarcoma.33,34 Evaluation of a malignant spindle cell lesion of the liver must start with clinical history, laboratory exams, and radiologic correlation. On histology, a morphological examination of the tumor formulates a differential diagnosis, which can be narrowed down by the morphologic appearance and the immunohistochemical profile of the tumor cells. n

Table. Differential Diagnosis of Primary Spindle Cell of theSpindle Liver35* Table. Differential Diagnosis of Tumors Primary

IHC STAINS

LEIOMYOSARCOMA

ANGIOSARCOMA

Cell Tumors of the Liver35*

EPITHELIOID HEMANGIOENDOTHELIOMA

UNDIFFERENTIATED EMBRYONA L SARCOMA

SYNOVIAL SARCOMA

SOLITARY FIBROUS TUMOR

Usually occurs in childhood, but rarely may be seen in middle-aged and elderly adults.

Middle age

60 years; Range 16-84

No gender predilection

Female predominanc e of 2:1

MEAN AGE OR AGE RANGE

58 years

60-70 years

40 to 66 years, with a mean age of 52 years

SEX

No gender predilection

Male: female ratio: 3:1

Female predominance of 3:2

SYMPTOMS

Nonspecific

RADIOLOGIC FINDINGS ON CT SCAN OR ULTRASOUND

Hypodense Hypodense mass with mass with peripheral peripheral enhanceme enhancent ment

In some cases, a vasogenic tumor can be suspected.

Large hypodense mass with septations, solid and cystic components

Hypodense mass

Heterogeneously enhancing mass

LFTs & AFP are normal or slightly elevated

LFTs are normal or mildly elevated. Rare cases with elevated AFP.

LFTs are normal or mildly elevated. AFP is normal

No clear associations

Mesenchymal hamartoma

No clear associations

Hypoglycemia

Spindle cells cells Spindle within aa within collagenous collagenous background background and aa and hemangioperihemangioperic cytoma-like y vascular toma-like pattern vascular pattern

Fibroblast-like spindle cells that proliferate in a patternless architecture, separated by thick collagen bundles. The collagenous stroma may contain angulated hemangioperi cytic staghornshaped vessels

LABORATORY EXAMS

ASSOCIATIONS

HISTOLOGIC FINDINGS

LFTs are normal or mildly elevated; AFP is normal

Rare cases are associated with EBV and AIDS.

Hypodense

Thrombocyto penia, anemia, moderately elevated liver enzymes. AFP, CA19-9, CEA: normal or midly elevated. Exposure to environmental carcinogens (thorium dioxide, arsenical insecticides, or polyvinyl chloride)

SpindleCigar-shaped Cigarshaped and hyperchroshaped polyhedral matic nuclei hyperchrom cells with aticwith nuclei nuclear atypia with cytoplasmic and mitoses, cytoplasmic vacuolizaforming vacuolizatio tion vascular n channels.

SpindleSpindle-shaped or orshaped epithelioid epithelioid cells cells that grow along the hepatic sinusoid endothelium endothelium with with intracytoplasintracytoplasmi mic vascular c vascular lumen lumen containing red containing red blood cells a in a blood cells in mucoid or mucoid or fibrous fibrous stroma. stroma.

Pleomorphic spindle cells that are loosely arranged and with poorly defined cell borders. Numerous mitosis

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Table. Differential Diagnosis of Primary Spindle Cell Tumors of the Liver35* Continued

POSITIVE IHC STAINS:

CYTOGENE TIC FINDINGS

Desmin, SMA, vimentin

Karyotype often highly complex with genomic instability10

CD31, CD34, Ulex, Factor VIII, ERG.

MYC amplification

CD34, CD31, Fli-1, ERG, and D2-40

Vimentin and alpha-1 antitrypsin. The tumor may be focally positive for cytokeratin, desmin, SMA, musclespecific actin, CD68, myoglobin, non-specific enolase, S100, and CD34

t(1;3)(p36;q2325) resulting in the gene fusion protein WWTR1CAMTA1

Chromosomal rearrangemen ts of 19q13.4, including the translocation t(11;19)(q11;q 13.3/13.4) and add(19)(q13.4 ).

Vimentin, keratin, EMA

The t(X; 18)(p11.2;icq1 1.2) translocation and the chimeric gene SYT-SSX usually present in the monophasic and biphasic variants N.i.a. - (99%) - (86%) - (98%) - (100%)

CD34, Bcl-2, vimentin, STAT6.

NAB2STAT6 gene fusion

H-CALDESMON + (100%) N.i.a. N.i.a. DESMIN + (70%) - (100%) - (100%) + (71%) - (94%) SMA + (89%) - (80%) - (69%) + (100%) - (87%) CD34 - (92%) + (75%) + (78%) +/+ (94%) CD31 - (98%) + (87%) + (90%) N.i.a. - (100%) ULEX EURO PAEUS - (93%) + (74%) + (88%) N.i.a. - (90%) N.i.a. AGGLUTININ I FACTOR VIII - (100%) + (82%) + (100%) - (100%) - (100%) N.i.a. ERG - (100%) + (97%) + (98%) N.i.a. - (100%) - (100%) FLI-1 - (100%) + (95%) + (97%) N.i.a. - (87%) - (100%) D2-40 + (56%) + (61%) N.i.a. N.i.a. CYTOKERATIN - (88-100%) - (71%) - (88%) +/+ (68%) - (100%) MUSCLE SPECIFIC + N.i.a. N.i.a. N.i.a. ANTIGEN CD68 - (67%) - (69%) - (100%) + (100%) - (90%) - (100%) MYOGLOBIN - (100%) +/- (100%) - (100%) NON SPECIFIC + N.i.a. N.i.a. ENOLASE S100 - (95%) - (93%) - (97%) +/- (74%) - (93%) VIMENTIN + (93%) + (99%) + (95%) + (100%) + (99%) + (95%) ALPHA-1 - (86%) N.i.a. N.i.a. + (100%) N.i.a. N.i.a. ANTITRYPSIN EMA - (85%) - (90%) N.i.a. - (100%) + (73%) - (98%) BCL2 - (69%) N.i.a. N.i.a. + (91%) + (95%) STAT6 - (100%) N.i.a. N.i.a. - (100%) + (100%) N.i.a.: No information available; *Immunohistochemistry profiles obtained from ImmunoQuery; +: positive staining; -: Negative staining; IHC: Immunohistochemistry stains LFT: Liver function tests; AFP: Alpha feto protein; CA 19-9: cancer antigen 19-9; CEA: carcinoembryonic antigen EBV: Epstein Barr virus; AIDS: Acquired immune deficiency syndrome; SMA: smooth muscle actin; CD34: Cluster of differentiation 34; CD31: Cluster of differentiation 31; ERG: erythroblast transformation-specific-related gene ; Fli-1 (Friend leukemia integration 1 transcription factor); Podoplanin: D2-40; CD68: Cluster of differentiation 68; S100: solubility in a 100%-saturated solution with ammonium sulphate at neutral pH-protein; EMA: Epithelial membrane antigen; BCL2: B-cell lymphoma 2; STAT6: signal transducer and activator of transcription 6

198 VOL. 59 • NO. 4 • 2018

References

27. Rao L, Jaiprakash P, Palankar N, Gowda V. Intra-abdominal primary monophasic synovial sarcoma with hemangiopericytoma-like areas. J Cancer Res Ther. 2013;9(1):102-4. 28. Srivastava A, Nielsen PG, Dal cin P, Rosenberg AE. Monophasic synovial sarcoma of the liver. Arch Pathol Lab Med. 2005;129(8):1047-9. 29. Silvanto A1, Karanji ND, Bagwan IN. Primary hepatic solitary fibrous tumor with histologically benign and malignant areas. Hepatobiliary Pancreat Dis Int. 2015;14(6)665-8. 30. Liu Q, Liu J, Chen W, Mao S, Guo Y. Primary solitary fibrous tumors of liver: a case report and literature review. Diagn Pathol. 2013;8:195. 31. Makino Y, Miyazaki M, Shigekawa M, et al. Solitary fibrous tumor of the liver from development to resection. Intern Med. 2015;54(7):765-70. 32. Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol. 2014;27(3):390-5. 33. Lang H, Nussbaum KT, Kaudel P, Frühauf N, Flemming P, Raab R. Hepatic metastases from leiomyosarcoma: A single-center experience with 34 liver resections during a 15-year period. Ann Surg. 2000;231(4):500-5. 34. Stavrou GA, Flemming P, Oldhafer KJ. Liver resection for metastasis due to malignant mesenchymal tumours. HPB (Oxford). 2006;8(2):110-3. 35. ImmunoQuery | Get it Right, Right Now. ImmunoQuery | Get it Right, Right Now. https://app.immunoquery.com/view/panel/dx?dxgroups=796. Accessed August 23, 2016.

1. Lin YH, Lin CC, Concejero AM, Yong CC, Kuo FY, Wang CC. Surgical experience of adult primary hepatic sarcomas. World J Surg Oncol. 2015;13:87. 2. Shivathirthan N, Kita J, Iso Y, et al. Primary hepatic leiomyosarcoma: Case report and literature review. World J Gastrointest Oncol. 2011;3(10):148-52. 3. Majumder S, Dedania B, Rezaizadeh H, Joyal T, Einstein M. Tumor rupture as the initial manifestation of primary hepatic leiomyosarcoma. Gastrointest Cancer Res. 2014;7(1):33-4. 4. Shamseddine A, Faraj W, Mukherji D, et al. Unusually young age distribution of primary hepatic leiomyosarcoma: case series and review of the adult literature. World J Surg Oncol. 2010;8:56. 5. Lv WF, Han JK, Cheng DL, Tang WJ, Lu D. Imaging features of primary hepatic leiomyosarcoma: A case report and review of literature. Oncol Lett. 2015;9(5):2256-2260. 6. Tsai PS, Yeh TC, Shih SL. Primary hepatic leiomyosarcoma in a 5-month-old female infant. Acta Radiol Short Rep. 2013;2(7):2047981613498722. 7. Chelimilla H, Badipatla K, Ihimoyan A, Niazi M. A rare occurrence of primary hepatic leiomyosarcoma associated with epstein barr virus infection in an AIDS patient. Case Rep Gastrointest Med. 2013;2013:691862. 8. Hamed MO, Roberts KJ, Merchant W, Lodge JP. Contemporary management and classification of hepatic leiomyosarcoma. HPB (Oxford). 2015;17(4):362-7. 9. Milanetto AC, Liço V, Blandamura S, Pasquali C. Primary leiomyosarcoma of the pancreas: report of a case treated by local excision and review of the literature. Surg Author Information: Case Rep. 2015;1(1):98. 10. Yang J, Du X, Chen K, et al. Genetic aberrations in soft tissue leiomyosarcoma. House Officer, Anatomic & Clinical Pathology (Sessums); House Officer, Radiology Cancer Lett. 2009;275(1):1-8. (Ray); Assistant Professor, Transplant and Hepatobiliary Surgery Program Director, 11. Cawich SO, Ramjit C. Herald bleeding from a ruptured primary hepatic General Surgery Residency, Department of Surgery (Earl); Professor, Anatomic angiosarcoma: A case report. Mol Clin Oncol. 2015;3(5):1063-1066. Pathology, Director, Autopsy Pathology, Department of Pathology (Subramony); 12. Chen G, Li J, Wan R, Wang G, Shi J. Primary hepatic angiosarcoma in a 64-yearAssistant Professor, Department of Pathology (Gonzalez); The University of old man: A case report. Oncol Lett. 2016;11(4):2445-2448. doi:10.3892/ Mississippi Medical Center, Jackson. ol.2016.4277. 13. Zhu YP, Chen YM, Matro E, et al. Primary hepatic angiosarcoma: A report of two Corresponding Author: Maria F. Gonzalez, MD. The University of Mississippi cases and literature review. World J Gastroenterol. 2015;21(19):6088-96. Medical Center, Department of Pathology. 2500 North State Street. Jackson, MS. 14. Koyama T, Fletcher JG, Johnson CD, Kuo MS, Notohara K, Burgart LJ. 39216. Ph: (601) 984-1876 (mfgonzalez@umc.edu). Primary Hepatic Angiosarcoma: Findings at CT and MR imaging. Radiology. 2002;222(3):667–673. Journal of the Mississippi State 15. Chi M, Dudek AZ, Wind KP. Primary hepatic leiomyosarcoma in adults: analysis of prognostic factors. Onkologie. 2012;35(4):210-4. 16. Chaudhary P, Bhadana U, Singh RA, Ahuja A. Primary hepatic angiosarcoma. Eur 1 J Surg Oncol. 2015;41(9):1137-43. InfectiousDiseases Diseases• Clinical 2 Infectious Clinical Physician 17. Wang ZB, Yuan J, Chen W, Wei LX. Transcription factor ERG is a specific and Physician The University Mississippi The University of MississippiofMedical Center sensitive diagnostic marker for hepatic angiosarcoma. World J Gastroenterol. 3 Medical Center Infectious Division 4 Infectious Disease DivisionDisease is seeking (2) BC/is 2014;20(13):3672-9. seeking (2) Physicians. BC/BE Clinical Physician. Faculty BE Clinical Faculty candidates should 18. Italiano A, Thomas R, Breen M, et al. The miR-17-92 cluster and its target THBS1 5 are differentially expressed in angiosarcomas dependent on MYC amplification. 6 submit a CVshould via faxsubmit to: 601-815-4014. candidates a CV via fax to: Genes Chromosomes Cancer. 2012;51(6):569-78. EOE, M/F/D/V. 601-815-4014. EOE, M/F/D/V. 7 19. Singh A, Sood N, Puri HK, Selhi PK, Garg B. Primary Hepatic Epithelioid Journal of the Mississippi State 8 Hemangioendothelioma: Diagnostic Dilemmas in Cytology and Histology. J Oncol Pract. 2016;12(4):394-6. 9 20. Dong K, Wang XX, Feng JL, et al. Pathological characteristics of liver biopsies 1 10 in eight patients with hepatic epithelioid hemangioendothelioma. Int J Clin Exp Ob/Gyn Hospitalists 2 11 Pathol. 2015;8(9):11015-23. 12 21. Sardaro A, Bardoscia L, Petruzzelli MF, Portaluri M. Epithelioid 3 Join an established academic medical center! hemangioendothelioma: an overview and update on a rare vascular tumor. Oncol 4 13 University of Mississippi Medical Center, Rev. 2014;8(2):259. 514 Department of Obstetrics and Gynecology is 22. Jo VY, Fletcher CDM. WHO classification of soft tissue tumours: An update 615 based on the 2013 (4th) edition. Pathology. 2014;46(2):95–104. currently accepting applications for Ob/Gyn 16 23. Jia C, Zhao W, Dai C, et al. Undifferentiated embryonal sarcoma of the liver in 7 Hospitalists. Candidates will work with residents a middle-aged adult with systemic lupus erythematosus. World J Surg Oncol. 8 17 and students and care for a diverse population. 2013;11:244. 918 Support is available for research if desired. 24. Li XW, Gong SJ, Song WH, et al. Undifferentiated liver embryonal sarcoma 19 in adults: a report of four cases and literature review. World J Gastroenterol. 10 Competitive compensation. If interested, please 11 20 2010;16(37):4725-32. contact Bretta Blackman, BS, MSM 25. Hu X, Chen H, Jin M, et al. Molecular cytogenetic characterization of 12 21 Department Business Administrator at 601-984undifferentiated embryonal sarcoma of the liver: a case report and literature 13 22 5391 or submit CV to bcblackman@umc.edu. review. Mol Cytogenet. 2012;5(1):26. 23 26. Kritsaneepaiboon S, Sangkhathat S, Mitarnun W. Primary synovial sarcoma 14 Equal Opportunity Employer, M/F/D/V of the abdominal wall: a case report and literature review. J Radiol Case Rep. 15 24 2015;9(7):47-52. 16 25

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Quality of Life in Patients with Bladder Cancer after Bladder Preservation Therapy using Chemoradiation ASHLEY ALBERT, MD; SRINIVASAN VIJAYAKUMAR, MD

Abstract Radical cystectomy with urinary diversion is considered the standard treatment for muscle-invasive bladder cancer in the United States. Bladder preservation therapy using transurethral resection (TUR) and chemoradiation is another treatment option. Many studies have assessed the efficacy of bladder conservation therapy in terms of overall survival; however, less data concerning quality of life after bladder preservation therapy are available. The few studies that have been performed indicate that this treatment modality may offer an acceptable quality of life for patients with bladder cancer. Furthermore, advancements in radiation therapy may prove to offer an even higher quality of life for these patients than was previously possible. Examining quality of life issues related to the treatment of bladder cancer is important for the overall well-being of the patient. This review serves to present the available data to assist physicians and patients in the decision-making process regarding bladder cancer treatment modalities. Key Words: bladder cancer, bladder preservation, quality of life Introduction

can be removed along with the tumor. However, this approach is not considered standard and may be used in patients with significant comorbidities.2 In addition, many patients may also need chemotherapy. Neoadjuvant chemotherapy is recommended for patients with cT2-T4a disease without nodal involvement. Adjuvant chemotherapy is recommended for patients with pT3 or pT4 disease or positive lymph nodes.2 Although cystectomy has traditionally been considered as the standard of care, radiotherapy with concurrent chemotherapy is an option for patients who are unable to undergo an operation and for those who opt not to have a radical cystectomy. Radiation without concurrent chemotherapy has been proven to be inferior to concomitant chemoradiation.4,5 Thus, patients who can tolerate concurrent chemotherapy should be treated with this approach. Radiosensitizing regimens using Cisplatin and 5-FU, Cisplatin and Paclitaxel, or 5-FU and mitomycin are considered standard.5,6,7 Patients with unifocal tumors, no lymph node involvement, no carcinoma-in-situ, no tumor-related hydronephrosis, and good bladder function are candidates for bladder preservation therapy.8,9 Radiation for bladder cancer involves treatment of a small pelvic field to include lymph nodes to 45-50 Gy, a whole or partial bladder field to 54-60 Gy, followed by a tumor boost to 64-66 Gy.10 The decision to treat regional lymph nodes should be based on patient comorbidities and potential toxicities.

Bladder cancer is the sixth most common cancer in the United States.1 The management of bladder cancer differs depending on whether the disease is non-muscle-invasive or muscle-invasive. For nonmuscle invasive bladder cancer, transurethral resection of the bladder tumor (TURBT) with or without Bacillus Calmette-Guérin (BCG) intravesicular therapy is the primary treatment. Patients are followed Table 1. Overview of Treatment Options for Bladder Cancer with cystoscopy and undergo maintenance therapy BCG for 1 to 3 Table 1. Overview of Treatment Options for Bladder Cancer years. The standard treatment for muscle-invasive bladder cancer is radical cystectomy with pelvic lymph node dissection. In males, radical cystectomy includes the removal of the bladder, prostate, seminal vesicles, and distal ureters. For female patients, radical cystectomy includes removal of the bladder, entire urethra and adjacent vagina, uterus, and distal ureters. A partial cystectomy can be performed when an adequate margin of soft tissue and noninvolved urothelium

Non-muscle invasive (Stage Ta, Tis, T1)

1. TURBT+/- intravesical BCG or intravesical chemotherapy 2,3

Muscle invasive (Stage T2-T4)

1. Cystectomy (radical or partial) with pelvic lymph node dissection 2,3 2. Neoadjuvant chemotherapy + cystectomy and pelvic lymph node dissection 2,3 3. Cystectomy and pelvic lymph node dissection + adjuvant chemotherapy 2,3 4. Definitive chemoradiation 2,3

200 VOL. 59 • NO. 4 • 2018 Table 2. Survival Outcomes Following Curative Therapy for Muscle-Invasive

4. Definitive chemoradiation

Table 2. Survival Outcomes Following Curative Therapy for Muscle-

Table 2. Survival Outcomes Following Curative Therapy for Muscle-Invasive InvasiveCancer Bladder(Stages CancerT2-T4a) (Stages T2-T4a) Bladder Series

Number of Patients

5-year Overall Survival

Cystectomy USC 200111

633

48%

MSKCC 200112

181

36%

SWOG/ECOG/CALGB 200213

317

49%

U. Erlangen 200214

326

45%

RTOG 19989

123

49%

MGH 20127

348

52%

BC2001 20125

182

48%

RTOG 201415

57%

Chemoradiation

Currently, there are no randomized trials comparing radical cystectomy and radiotherapy with concurrent chemotherapy. However, results from treatment with aggressive bladder-preservation approaches using concurrent chemoradiation are comparable to those results of cystectomy as summarized in Table 2. Furthermore, up to 80% of patients who are treated with bladderpreserving therapy maintain an intact bladder.16 Additionally, aggressive bladder-conserving therapies for non-surgical candidates may be underused, especially among elderly patients and racial minorities.17 Therefore, understanding of the side effects and resultant quality of life is important for patients and physicians in order to prevent further underutilization of this treatment approach.

Despite these aforementioned side effects, data concerning quality of life after radiation therapy for bladder cancer indicate that the side effects of conservative therapy may possibly be more acceptable than those caused by traditional surgical management. Yet, patients have reported that they would not be willing to undergo bladder preserving treatment if it will potentially decrease survival even as little as 1%.21 The possibility of having a bladder that potentially still harbors disease may be stress-inducing for some patients and thus affect the quality of life after treatment of bladder cancer. However, as previously mentioned, patients who cannot or choose not to undergo cystectomy may benefit from bladder preservation therapy and remain free from invasive recurrence as survival rates are comparable to radical cystectomy.7,8,14,22,23 Therefore, patients may not have to sacrifice survival for an increased quality of life after treatment for bladder cancer and can be reassured about the outcomes of aggressive treatment strategies involving bladder preservation. Retrospective Quality of Life Studies When assessing symptoms after radiotherapy for bladder cancer, Henningsohn et al. compared radiated patients to patients who underwent cystectomy as well as to population controls.21 The results from 48 radiated patients were compared to 175 patients who underwent radical cystectomy with urostomy and 261 controls. Symptoms of urinary tract dysfunction, bowel dysfunction, and sexual dysfunction were assessed with a questionnaire. The results are summarized in Table 3. Table 3. Summary of survey results regarding distressful symptoms after radiotherapy bladder cancer Table 3. Summaryfor of Survey Results Regarding Distressful Symptoms after Radiotherapy

for Bladder Cancer Body System Urinary tract dysfunction

Complications After Aggressive Treatment

Bowel dysfunction

Cystectomy with urinary diversion, the more established treatment for muscle-invasive bladder cancer, may cause physical distressful symptoms for the patient as well as issues with body image. After cystectomy, patients may experience altered bowel and sexual function and a decreased sense of physical attractiveness.18 Furthermore, the mortality rate after cystectomy is about 3% and the complication rate is approximately 28%.19 Yet, bladder preservation therapy with chemoradiation is not without negative effects on the patient. Intestinal function, urinary tract function, as well as sexual function can all be altered by radiation therapy.20 The dose per radiation fraction and the radiation technique may be the most important influential factors for the development of radiation side effects.20 Additionally, radiation side effects may complicate operative interventions if the tumor relapses or progresses and cystectomy is later needed.

Sexual dysfunction (men)

Symptoms Presence of urinary tract infections Urinary incontinence Presence of odor Distress from urinary symptoms Abdominal pain Diarrhea Stool incontinence Distress from problems involving GI tract Dissatisfaction with sexual life Erectile dysfunction No ejaculate during orgasm

Radiation 22% 33% 3% 26% 22% 35% 17% 32% 36% 75% 43%

Cystectomy 12% 28% 10% 24% 67% 92% 100%

Control 10% 19% 2% 13% 9% 12% 2% 9% 28% 49% 7%

The authors highlight that 74% of patients treated with radiation had little to no distress from the urinary tract. Sexual dysfunction and dissatisfaction in men were higher after cystectomy. However, distress from gastrointestinal symptoms was slightly higher in the radiated group. The authors of this study postulate that the ability to avoid radiation to the sphincter area and bowel with the older techniques may be less than that with modern techniques and thus current radiation techniques may cause less distress from bowel symptoms than was found in this study. Furthermore, newer radiation techniques which allow for more sparing of normal tissue may result in lower

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bladder toxicity. In a study performed by Zietman et al., patients with invasive bladder cancer were evaluated for both quality of life as well as quality of bladder function after chemoradiation.24 The quality of life evaluation involved a questionnaire, and bladder function was assessed with urodynamic studies evaluating voided volume, maximum and average urinary flow rates, post-void residual volumes, abdominal pressure, volume at first sensation, volume at first and maximal urge, bladder compliance during filling, presence or absence of involuntary contractions, presence of stress incontinence and or prolapse. This evaluation found that at a median of 6 years after bladder conservation therapy, the majority of conserved bladders functioned normally. Despite these detected side effects of radiation, few patients reported significant levels of distress and the level of bladder, bowel, and general functioning was acceptable for most patients. The authors did note that the patients that did not return for urodynamic studies may have had worse urinary function which may have potentially led to a selection bias in the study population. An investigation by Caffo et al. compared quality of life in patients who had conservative therapy with radiotherapy, with or without chemotherapy, to the quality of life in patients after cystectomy with a stoma.25 The two groups reported differences in quality of life with scores higher in the conservative treatment group in all seven subscales of the questionnaire used in the study. Decreased quality of life after cystectomy, marked by stoma presence, was due to lack of sexual activity and worsened physical condition. Yet, social and recreational life were only minimally affected. In the conservative therapy group, there was a low incidence of urinary symptoms and an acceptable sexual adjustment. Overall, the quality of life in the conservative therapy group was consistently better than in the group that underwent surgery. Prospective Quality of Life Studies While several retrospective studies have examined the quality of life after chemoradiation for bladder, fewer numbers of prospective studies are available. In one prospective study performed by Lagrange et al., overall quality of life who underwent chemoradiation for bladder cancer was maintained over 70% for all patients alive without relapse for 36 months.26 Improvement of global bladder function was observed after treatment and maintained at 36 months. Additionally, sexual function was preserved in 79% of patients at 18 months. The most frequently reported sequela in this study was an increase in moderate urinary frequency. The authors concluded this prospective evaluation supports published retrospective data suggesting good quality of life for cancer patients managed by bladder preservation. Herman et al. also performed a prospective study that found similar results to other bladder preservation quality of life studies.27 This Phase I study specifically examined gemcitabine as chemotherapy agent. All the patients in this study had clinical Stage T2-T3 lesions and were all cystectomy candidates. This may have eliminated a selection

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bias because patients did not receive bladder preservation therapy simply because they were not candidates for surgery. No statistically significant differences were found before, during, or after treatment indicating that concurrent gemcitabine and conformal radiation therapy may not have a substantial impact on quality of life and thus offer an acceptable form of treatment for patients with bladder cancer. Disadvantages of Bladder Preservation Therapy Although it is possible to have a higher quality of life with bladder preservation therapy compared to undergoing surgery, disadvantages to this conservative approach do exist. Bladder preserving strategies require high compliance as well as close coordination between clinical specialties. Additionally, conservative treatment may involve higher costs than surgery.28 Furthermore, those patients that have an incomplete response to therapy or have tumor progression will need surgery and may consequently experience higher morbidity and mortality than if they had undergone a primary cystectomy.28 Advancements in Treatment Advancements in both surgical techniques and radiotherapy may allow for better quality of life in both treatment options. For example, a preliminary series with sixteen patients demonstrated that IntensityModulated Radiation Therapy (IMRT) reduced the radiation dose administered to normal tissue compared to traditional techniques and no severe gastrointestinal side effects were reported.29 In a series of 25 patients using Proton Beam therapy, no grade 3 or 4 gastrointestinal or genitourinary adverse event was observed and only one patient required a salvage cystectomy.30 Furthermore, patients undergoing robotic cystectomy have been shown to have less postoperative complications than those undergoing open cystectomy.31 However, a more recent trial demonstrated similar ninety day complication rates, hospital stay, pathologic outcomes, and 3- and 6-month quality of life outcomes regardless of surgical technique.32 Conclusion Several studies have shown an acceptable quality of life after bladder preservation therapy and in some cases even better quality of life when compared to cystectomy. The overall survival rate of bladder preserving therapy approaches that of cystectomy. Advancements in both forms of treatment may lead to a better quality of life in either group. Thus, there seems to be a need for more prospective studies that take into account these newer developments in treatment so that physicians and patients can be well informed about the potential outcomes and side effects when deciding between these two treatment modalities for patients who opt not to pursue cystectomy. Until then, the current data concerning quality of life issues should be taken into consideration when making a decision about bladder cancer treatment or when counseling patients who are not surgical candidates about treatment so that patients and physicians can work towards achieving the best possible outcome in terms of overall wellbeing for the patient. n

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin.2017;67:730. 2. National Comprehensive Cancer Network. Bladder Cancer. Version 5.2017. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed September 29, 2017 3. Efstathiou JA , Zietman AL. Bladder Cancer. In: Gunderson LL, Tepper JE, eds. Clinical Radiation Oncology. Philadelphia, PA: Elsevier Health Sciences; 2015:10961120. 4. Coppin CM, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1996;14:2901-7 5. James ND, Hussain SA, Hall E, et al. Radiotherapy plus Chemotherapy in MuscleInvasive Bladder Cancer. N Engl J Med. 2012;367:379-381. 6. Mitin T, Hunt D, Shipley WU, et al. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): A randomised multicentre phase 2 trial. Lancet Oncol. 2013;14:863-872. 7. Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-Term Outcomes of Selective Bladder Preservation by Combined-Modality Therapy for Invasive Bladder Cancer: The MGH Experience. Eur Urol. 2012;61:705-711. 8. Shipley W, Kaufman D, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urology. 2002;60:62-67. 9. Shipley WU, Winter KA, Kaufman DS, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998;16(11):3576-3583. 10. Adams B, Diaz AD, Pollack A, et al. Bladder Carcinoma. In: Lee NY, Riaz N, Lu JJ, eds. Target Volume Delineation for Conformal and Intensity-Modulated Radiation Therapy. New York: Springer; 2015: 377-386. 11. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001;19:666-75. 12. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol. 2001;19:89-93. 13. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349:859-66. 14. Rödel C, Grabenbauer GG, Kühn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol. 2002;20:3061-71. 15. Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscleinvasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014;32:3801-9. 16. Kaufman DS, Shipley WU, Griffin PP, Heney NM, Althausen AF, Efird J. Selective Bladder Preservation by Combination Treatment of Invasive Bladder Cancer. N Engl J Med. 1993;329:1377-1382. 17. Fedeli U, Fedewa SA, Ward EM. Treatment of Muscle Invasive Bladder Cancer: Evidence From the National Cancer Database, 2003 to 2007. J Urol. 2011;185:7278. 18. Henningsohn L, Wijkström H, Dickman PW, Bergmark K, Steineck G. Distressful Symptoms after Radical Cystectomy with Urinary Diversion for Urinary Bladder Cancer: A Swedish Population–Based Study. Euro Urol. 2001;40:151-162. 19. Konety BR, Allareddy V, Herr H. Complications after radical cystectomy: Analysis of population-based data. Urology. 2006;68:58-64. 20. Jahnson S, Pedersen J, Westman G. Bladder carcinoma — a 20-year review of radical irradiation therapy. Radiother and Oncol. 1991;22:111-117. 21. Henningsohn L, Wijkström H, Dickman PW, Bergmark K, Steineck G. Distressful symptoms after radical radiotherapy for urinary bladder cancer. Radiother Oncol. 2002;62:215-225. 22. Fung CY, Shipley WU, Young RH, et al. Prognostic factors in invasive bladder carcinoma in a prospective trial of preoperative adjuvant chemotherapy and radiotherapy. J Clin Oncol. 1991;9:1533-1542. 23. Liu M, Zietman A, Shipley W. Organ Preservation Approaches With Radiation Therapy in Muscle-Invasive Bladder Carcinoma. J Urol. 1998;159:605-606. 24. Zietman AL, Sacco D, Skowronski U, et al. Organ Conservation in Invasive Bladder Cancer by Transurethral Resection, Chemotherapy and Radiation: Results of a Urodynamic and Quality of Life Study on Long-term Survivors. J Urol. 2003;170:1772-1776.

25. Caffo O, Fellin G, Graffer U, Luciani L. Assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma: A survey by a self-administered questionnaire. Cancer. 1996;78:1089-1097. 26. Lagrange JL, Bascoul-mollevi C, Geoffrois L, et al. Quality of life assessment after concurrent chemoradiation for invasive bladder cancer: results of a multicenter prospective study (GETUG 97-015). Int J Radiat Oncol Biol Phys. 2011;79:172-8. 27. Herman JM, Smith DC, Montie J, et al. Prospective quality-of-life assessment in patients receiving concurrent gemcitabine and radiotherapy as a bladder preservation strategy. Urology. 2004;64:69-73. 28. Kuczyk M, Turkeri L, Hammerer P, Ravery V. Is There a Role for Bladder Preserving Strategies in the Treatment of Muscle-Invasive Bladder Cancer? Euro Urol. 2003;44:57-64. 29. Søndergaard J, Høyer M, Petersen JB, Wright P, Grau C, Muren LP. The normal tissue sparing obtained with simultaneous treatment of pelvic lymph nodes and bladder using intensity-modulated radiotherapy. Acta Oncol. 2009;48:238-244. 30. Hata M, Miyanaga N, Tokuuye K, et al. Proton beam therapy for invasive bladder cancer: A prospective study of bladder-preserving therapy with combined radiotherapy and intra-arterial chemotherapy. Int J Radiat Oncol Biol Phys. 2006;64:1371-1379. 31. Ng CK, Kauffman EC, Lee M-M, et al. A Comparison of Postoperative Complications in Open versus Robotic Cystectomy. Euro Urol. 2010;57:274-282. 32. Bochner BH, Dalbagni G, Sjoberg DD, et al. Comparing Open Radical Cystectomy and Robot-assisted Laparoscopic Radical Cystectomy: A Randomized Clinical Trial. Euro Urol. 2015;67:1042-1050.

Author Information

Resident physician in the Department of Radiation Oncology at the University of Mississippi Medical Center (Albert). Chairman and Program Director of the Department of Radiation Oncology at the University of Mississippi Medical Center (Vijayakumar). Corresponding Author: Ashley Albert, MD; Department of Radiation Oncology, University of Mississippi Medical Center, 350 West Woodrow Wilson Drive, Suite 1600, Jackson, MS 39213 (AAlbert@UMC.edu).

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Fatal Acute Sickle Cell Intrahepatic Cholestasis Despite Exchange Transfusion: A Case Report and Literature Review CARTER CAPRA, MD; L. WESLEY ALDRED, MD; SRIKRISHNA PATNANA, MD, MPH; BRIAN BORG, MD; VINCENT HERRIN, MD

Introduction Sickle cell intrahepatic cholestasis (SCIC) is a rare, devastating and often fatal complication of sickle cell disease (SCD). It is a clinical syndrome of right upper quadrant abdominal pain, hepatomegaly, and striking hyperbilirubinemia associated with bleeding and multi-organ failure. Red blood cell exchange transfusion has become the mainstay of therapy. We report what we learned from a fatal case of SCIC despite the use of exchange transfusion. Case description A 19-year-old African American male with known homozygous hemoglobin S disease (SCD) presented with confusion, lethargy, and abdominal pain worsening over the previous two weeks. Physical exam was significant for hypotension, obtundation, tender hepatomegaly and severe jaundice. Laboratory data revealed severe anemia with

a hemoglobin of 3.0 g/dL, bilirubin level of 38 mg/dL, and multiorgan failure with metabolic acidosis (Table 1). He was intubated for airway protection after an episode of hematemesis and immediately transfused 4 units of packed red blood cells (pRBCs). He was admitted to the medical intensive care unit for hypovolemic shock and started on continuous veno-venous hemodialysis. Initial Hemoglobin S level was only 14.2%, making sickle cell hepatopathy an unlikely differential diagnosis. This low level was presumed to be due to recent blood transfusions. Nearly two weeks prior he was admitted to an outside institution for a sickle cell pain crisis with a severe direct hyperbilirubinemia. He was treated supportively and then sent for liver biopsy (Figures 1 and 2). This biopsy revealed diffuse sinusoidal congestion with abundant erythrophagocytosis, striking Kupffer cell hyperplasia, mild macrovesicular steatosis, and moderate interstitial fibrosis without significant inflammation—findings consistent with sickle cell intrahepatic cholestasis. We performed an exchange

Table 1:

Table 1. Selected Labatory Data from Hospitalization Selected Laboratory Data from Hospitalization Hospital Day

-13

1 (ET)

Total Bilirubin (mg/dL)

37.7

38.0

47.3

47.9

46.9

52.1

50.5

48.3

62.9

68.6

60.3

Serum Creatinine (mg/dL)

0.96

10.38

4.14

3.0

1.71

1.34

2.42

2.53

3.27

4.52

2.33

Alkaline phosphatase (U/L)

309

142

114

135

132

125

128

201

257

182

128

ALT (U/L)

164

776

642

430

275

112

AST (U/L) 213 728 INR 1.10 3.85 Hemoglobin S - 14.2 (%) 204 VOL. 59 • NO. 4 • 2018

4000 2.19 -

2539 1.45 -

1131 1.36 -

384 1.28 -

135 1.64 -

118 1.59 -

- - 5.1

228 2.21 -

240 1.69 -

- - 8.1

127 - -

Figure 1. Trichrome stain demonstrates sickled red blood cells (A) with striking Kupffer cell hyperplasia (B).

Figure 2. Hematoxylin and eosin (H&E) stain demonstrates the sickled red blood cells (A) causing sinusoidal congestion and dilatation with resultant bile stasis (B).

transfusion (ET) on the night of admission with six units of pRBCs to a post-ET Hemoglobin S level of 5.3% (Table 1). After initial stabilization, a non-contrasted computed tomography (CT) and abdominal ultrasound demonstrated hepatomegaly and patent portal and hepatic veins with appropriate direction of flow. No focal mass was identified. The patient was deemed a poor candidate for liver transplantation due to multi-organ failure. Despite ET and optimal supportive care, he demonstrated no improvement in hyperbilirubinemia or renal function and expired.

Discussion Previous Experiences Sickle cell intrahepatic cholestasis is a clinical syndrome of right upper quadrant abdominal pain, hepatomegaly, and extreme hyperbilirubinemia. The earliest report of this condition came from the Johns Hopkins Hospital in 1953. It described a patient with a fatal case of acute liver failure with extremely elevated bilirubin. At autopsy, the liver showed distorted sinusoidal architecture, plugged from engorged Kupffer cells that had phagocytized sickled red cells causing bile stasis.1 The next case series came from the University of Mississippi Medical Center in 1963 and reported five patients, ages twelve to twenty-three, with homozygous sickle cell disease who succumbed to liver failure after developing hepatomegaly, progressive jaundice and high direct bilirubin levels. Liver tissue from four of the five patients demonstrated sludged and sickled red cells within the sinusoids and engorged Kupffer cells causing sinusoidal obstruction and bile stasis.2 Sickle cell intrahepatic cholestasis is felt to be a variant of acute sickle hepatic crisis. In acute sickle hepatic crisis, patients present with right upper quadrant pain, tender hepatomegaly, and jaundice; however, they rarely have a bilirubin level greater than 15 mg/dL. In SCIC, there is widespread sickling within the sinusoids causing vascular stasis and hepatic ischemia. The resultant hypoxia causes Kupffer cell hypertrophy associated with phagocytosis of debris causing intracanalicular cholestasis. The presentation consists of tender hepatomegaly and striking jaundice, and as seen in our patient can be accompanied by bleeding diathesis, encephalopathy, renal failure, and shock. The extreme hyperbilirubinemia is postulated to be from hemolysis, intrahepatic cholestasis, and renal impairment. Death typically occurs from resultant fulminant hepatic failure and bleeding.3-4 Exchange Transfusion Exchange transfusion (ET) is currently the first line treatment for acute SCIC. This is based on the first patient to survive reported in 1980. That patient had a typical presentation of increasing liver impairment with hyperbilirubinemia and was initially treated conservatively. On day 7 of admission, the patient appeared to be deteriorating with development of asterixis and extensive purpura. The treatment team decided to utilize a partial blood-plasma ET, and the patient received 8 units of FFP and type O Rh positive pRBCs over the next 24 hours. After that, the asterixis resolved by 24 hours, and bilirubin, transaminases, and coagulation parameters all began to improve by 48 hours. The patientâ&#x20AC;&#x2122;s initial hemoglobin S level was not reported (though it is mentioned that the initial electrophoresis was consistent with SS hemoglobinopathy). After ET the hemoglobin S level was noted to be 30%4 â&#x20AC;&#x201C; the level now accepted as the ideal target for this therapy. A Spectrum of Disease Including our own, it appears there have been at least fourteen adult patients with acute SCIC that have been treated with ET since 1980

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Table 2: Table 1. Selected Labatory Data from Hospitalization Previously Reported Patients and Outcomes of Acute Sickle Cell Intrahepatic Cholestasis since 1980 Age/Sex SCD Genotype Total Bilirubin on Treatment modality presentation 21/M SS 23.0 mg/dL Partial ET 48/M S/B+ 59.7 mg/dL ET thalassemia 40/M S/B+ 26.0 mg/dL ET thalassemia 37/M SCD* 61.5 mg/dL ET 41/M SS 39.0 mg/dL ET 29/M SS 106.5 mg/dL ET 48/M SS 48.9 mg/dL ST 21/F SS 20.3 mg/dL TEA 22/M S/B0 50.2 mg/dL ET followed by OLT thalassemia 27/F SCD* 34.0 mg/dL ET followed by OLT 49/M SCD* 48.7 mg/dL ST followed by combined Liver and Kidney transplant 31/M SCD* 50.0 mg/dL ET SCD: Sickle Cell Disease; ET: Exchange Transfusion; ST: Simple Transfusion; OLT: orthotopic liver tranplant * Genotype of SCD was not specified in article ** patient died more than 1 year later from complications related to transplant

(Table 2).4-12,14,16,17 Ten of these fourteen have survived. In reviewing the available case reports of SCIC survival with ET, we note there are common themes and important differences.4, 6-9,11,12 The presentation of each was typical of SCIC, no inciting factor was identified, and improvement occurred within 48 hours of initiation of ET. Important differences include time to presentation (one week vs one month), SCIC presenting in SCD versus hemoglobin S/beta-thalassemia, and degree of multi-organ dysfunction. Treatment modalities also differed. There is a single case report where therapeutic erythrocytapheresis was employed. The patient’s blood was removed and separated into erythrocytes and plasma while simultaneously replacing it with normal saline and three units of pRBCs, ultimately leading to a favorable outcome.11 As in our patient, the three prior patients that did not survive received ET to maintain the Hemoglobin S level < 30%, though they did not show any improvement in the hyperbilirubinemia or coagulopathy.5,14,16 Two of these patients had concomitant hepatic comorbidities, including compensated cirrhosis due to hepatitis C virus5 and autoimmune hepatitis,14 while the third, like ours, was a young man without other comorbidities. It is evident that exchange transfusion does not always remedy the hepatic insult.

Three patients have been reported to survive SCIC with supportive care alone. More recently, a patient was reported who refused ET for SCIC. This patient presented very similarly to ours, with abdominal pain and extreme hyperbilirubinemia, normal renal function and coagulation parameters, but quickly developed an acute kidney injury (AKI) and coagulopathy within one week. His bilirubin trended up to 78 mg/ dL, though improved with simple transfusion and was noted to have trended down to 4 mg/dL by 3 months. His AKI was felt to be related to a delayed-transfusion reaction and did not require hemodialysis.10 We

206 VOL. 59 • NO. 4 • 2018

Outcome Survival4 Fatal5 Survival6

Survival7 Survival8 Survival9 Survival10 Survival11 Survival12

Fatal14 Survival16** Survival17

have observed a spectrum of the severity of illness in acute SCIC and feel that those who have survived without ET may represent the less severe end of this spectrum. These few positive outcomes also likely reflect an improvement in the supportive care available as compared to those prior to 1980. Liver Transplantation There is scant data on liver transplantation for any indication in SCD, and even less so in acute SCIC. In 2002, acute SCIC was reported in a 22-year-old patient with S/β0–thalassemia. The patient presented with jaundice, abdominal pain, and itching and was found to have total bilirubin > 50 mg/dL, normal renal function, and no coagulopathy. He was treated acutely with ET and maintained on a chronic ET program to keep the Hemoglobin S below 30%. He successfully received orthotopic liver transplant nine months later. To our knowledge, this was the first reported successful liver transplant for SCIC in an adult, though it was not utilized in the acute phase.12 This experience proved that liver transplantation is possible for SCIC, though warned there was still a high chance of graft loss if the underlying hematologic problem was not adequately controlled. Prior to this, a child with SCIC was treated with liver transplantation but shortly afterward developed veno-occlusive disease. He died of graft vascular complications and sepsis after a second and third transplantation.13 In another case report from 2002, a combined liver-kidney transplant was performed on a 49-year-old man with acute SCIC. This patient did well but died 22 months post-transplant of causes unrelated to the transplant. There was no mention of ET prior to transplantation.15 Overall, it appears that two of the three patients with acute SCIC that received liver transplant survived, though most are precluded from surgery due to the severity of illness at onset.

cholestasis in sickle cell disease: a case report. Anemia. 2011;2011:975731. PMID: 21490769 PMCID: PMC3065851 DOI: 10.1155/2011/975731. 9. Shao SH, Orringer EP. Sickle cell intrahepatic cholestasis: approach to a difficult problem. Am J Gastroenterol. 1995 Nov;90(11):2048-2050. PMID: 7485022. 10. Hosiriluck N, Rassameehiran S, Argueta E, et al. Reversal of liver function without exchange transfusion in sickle cell intrahepatic cholestasis. Proc (Bayl Univ Med Cent). 2014 Oct;27(4):361-363. PMID: 25484513 PMCID: PMC4255868. 11 Tiftik N, Altintas E, Kiykim A, et al. Long-term red blood cell exchange can be used to successfully treat sickle cell intrahepatic cholestasis: a case report. J Clin Apher. 2004;19(1):17-19. PMID: 15095397 DOI: 10.1002/jca.10077. 12. Gilli SC, Boin IF, Sergio Leonardi L, et al. Liver transplantation in a patient with S(beta)0 â&#x20AC;&#x201C;thalassemia. Transplantation. 2002 Sep 27;74(6);896-898. PMID: 12364877 DOI: 10.1097/01.TP.0000028445.23375.FA. 13. Emre S, Kitibayashi K, Schwartz ME, et al. Liver transplantation in a patient with acute liver failure due to sickle cell intrahepatic cholestasis. Transplantation. 2000 Feb 27;69(4): 675-676. PMID: 10708131. 14. Baichi MM, Arifuddin RM, Mantry PS, et al. Liver transplantation in sickle cell anemia: a case of acute sickle cell intrahepatic cholestasis and a case of sclerosing cholangitis. Transplantation. 2005 Dec 15;80(11):1630-1632. PMID: 16371935. 15. Ross AS, Graeme-Cook F, Cosimi AB, et al. Combined liver and kidney transplantation in a patient with sickle cell disease. Transplantation. 2002 Feb 27;73(4):605-608. PMID: 11889439. 16. Chitturi S, George J, Ranjitkumar S, et al. Exchange transfusion for severe intrahepatic cholestasis associated with sickle cell disease? J Clin Gastroenterol. 2002 Oct;35(4):362-363. PMID: 12352306. 17. Malik A, Merchant C, Rao M, et al. Rare but lethal hepatopathyâ&#x20AC;&#x201D;sickle cell intrahepatic cholestasis and management strategies. Am J Case Rep. 2015 Nov 28;16:840-843. PMID: 26613743 PMCID: PMC4671447.

Conclusion We know that acute SCIC is a very rare and potentially fatal hepatic complication of a very common hematologic disease with varying degrees of severity. We observe that recognition of SCIC is improving, an inference made from the number of recently reported cases. The nearly two-week delay in recognition and diagnosis in our patient is felt to be a significant contributor to the poor outcome. By this time, the patient was in multi-organ failure and shock. There currently are no guidelines for SCIC, though prompt recognition and initiation of treatment are integral to survival. Each case should be immediately evaluated by both Hematology and Hepatology to initiate ET and determine candidacy for liver transplantation. n References 1. Green TW, Conley CL, Berthrong M. The liver in sickle cell anemia. Bull J Hopkins Hosp. 1953;92(2):99-127.PMID: 13009339. 2. Owen DM, Aldridge JE, Thompson RB. An unusual hepatic sequela of sickle cell anemia: a report of five cases. Am J Med Sci. 1965 Feb;249:175-185. PMID 14257309. 3. Banerjee S, Owen C, Chopra S. Sickle cell hepatopathy. Hepatology. 2001 May;33(5):1021-1028. PMID: 11343226 DOI: 10.1053/jhep.2001.24114. 4. Sheehy TW, Law DE, Wade BH. Exchange transfusion for sickle cell intrahepatic cholestasis. Arch Intern Med. 1980 Oct;140(10):1364-1366. PMID 7425771. 5. Costa DB, Miksad RA, Buff MS, et al. Case of fatal sickle cell intrahepatic cholestasis despite use of exchange transfusion in an African-American patient. J Natl Med Assoc. 2006 Jul;98(7):1183-1187. PMID: 16895293 PMCID: PMC2569475. 6. Tsimpoukas F, Goritsas C, Kotsanis A, et al. Successful outcome of acute sickle cell intrahepatic cholestasis in a patient with sickle/beta+ thalassemia and chronic hepatitis C virus infection. J Hepatology. 2004 Jun;40(6):1046-1047. PMID: 15158356 DOI: 10.1016/j.jhep.2004.02.003. 7. Kurshid I, Anderson L, Downie GH, et al. Sickle cell disease, extreme hyperbilirubinemia, and pericardial tamponade: case report and review of the literature. Crit Care Med. 2002 Oct;30(10):2363-2367. PMID: 12394969 DOI: 10.1097/01.CCM.0000026323.65745.1B. 8. Brunetta DM, Silva-Pinto AC, do Carmo Favarin de Macedo M, et al. Intrahepatic

Author Information Department of Internal Medicine, University of Mississippi Medical Center (Capra, Aldred); Division of Digestive Diseases, Department of Internal Medicine, University of Mississippi Medical Center (Patnana, Borg); Division of Hematology/Oncology, Department of Internal Medicine, University of Mississippi Medical Center (Herrin). Corresponding Author: C. Capra, MD; Department of Internal Medicine, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216. (CCapra@UMC.edu).

PHYSICIANS NEEDED Internists, Cardiologists, Ophthalmologists, Pediatricians, Orthopedists, Neurologists, Psychiatrists, etc. interested in performing consultative evaluations according to Social Security guidelines.

OR Physicians to review Social Security disability claims at the

Mississippi Department of Rehabilitation Services (MDRS) in Madison MS.

DISABILITY DETERMINATION SERVICES 1-800-962-2230

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An Interview with new MSBML Executive Director: Dr. Kenneth Cleveland SID SCOTT

uilding bridges is job one for the new executive director of the State Board of Medical Licensure. “I really want to build bridges between the community of physicians across the state and the medical board,” said Kenneth Edwards Cleveland, MD, FACS. Protecting patients is the agency’s top priority, and Dr. Cleveland said the best way to do that is to work hand-in-hand with the medical community. “I’m very optimistic about the work ahead,” he said. “I look forward to working with MSMA and other advocates to help patients in Mississippi.” For Dr. Ken Cleveland, life is all about challenges. A veteran surgeon, Dr. Cleveland’s latest challenge may be his biggest yet. In February he was appointed by the State Board of Medical Licensure to serve as the agency’s executive director, and he started the job March 1, 2018. As a physician who has practiced in Mississippi for nearly 20 years, Dr. Cleveland said that he knows the importance of the Licensure Board. “I didn’t take the position lightly,” Dr. Cleveland said. “I understand the value of the Licensure Board and how vital it is to healthcare in Mississippi. Let’s just say I think I can bring insight and measured, experienced leadership to the role.” An Alabama native, Dr. Cleveland attended the University of Alabama continuing to medical school at the UA School of Medicine and completed surgery residencies at Mercer University School of Medicine and the University of Mississippi School of Medicine. He closed his bariatric practice and opened a weight loss clinic in Ridgeland in 2011, providing weight loss counseling and hormone replacement therapy. While the business was successful, he said there was just something missing. “Nothing against the work,” Dr. Cleveland said, “but, I missed the pressure of surgery. I wanted something that rivaled the challenges of being a surgeon.” This desire led him to the Licensure Board. The state agency had been without an executive for several few months and the executive director position seemed to be a challenging venue where his experience and leadership could be utilized.

208 VOL. 59 • NO. 4 • 2018

Kenneth Edwards Cleveland, MD, FACS

Director, Mississippi State Board of Medical Licensure “For a couple of years I had been considering a move into an administrative role,” Dr. Cleveland said. “When the executive director post became available, I felt like it was a job that I would be good at and a place where I could make a difference.” Dr. Cleveland brings leadership experience to the position from years of service on the Central Mississippi Medical Center Board of Trustees and on the Board of Directors of the Mississippi Society for Disabilities. His family includes his wife, Jackson oncologist Dr. Nikki Cleveland, and their three daughters. n

“Building bridges is job one.”

Dr. Kenneth Edwards Cleveland with his wife, Dr. Nikki Cleveland, and their daughters.

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Meet the MSMA Staff Charmain Kanosky, Executive Director The leader of MSMA for the last 10 years, Charmain focuses on the Association’s longterm mission and its day-to-day operations. As manager of strategy, vision and more, Charmain juggles the needs of staff and membership. For 23 years at MSMA, she has been a source of innovative thinking, welcoming new ideas and opportunities. From the legislative session to the annual Charmain Kanosky House of Delegates session, Charmain leads Executive Director the staff through example and with a focus on end goals. Under her leadership, MSMA is a thriving, healthy voice for organized medicine in uncertain, ever-changing time.

Deborah D. Batzing, CPA, Chief Financial Officer Deborah has over 25 years of accounting experience, primarily in the healthcare field. She manages the accounting, human resources and administration functions of the Association and its subsidiaries. Deborah prepares all facets of the Association’s budget as well as the financial statements for the Association and subsidiaries. She oversees the audit activities and reviews the Association’s and subsidiaries' audited financial Deborah D. Batzing statements and tax returns. Her job is also to Chief Financial Officer ensure internal controls are in place to safeguard the assets of MSMA.

Jill Gordon, Director of Marketing Jill works on bringing valuable business partners to the Association to benefit you. She is using her talents to increase membership and expand advertising which in turn will greatly benefit all MSMA members. She is also working to develop some MSMA exclusive member offers as extra benefits for your membership. Jill joined MSMA in 2017 after 18 years in the banking and financial services Jill Gordon industry. Her expertise and enthusiasm for her Director of Marketing work have earned her a place as a top ten finalist for Mississippi Business Journal Top 50 Business Leaders. She prides herself in the relationships she has built over her career and enjoys helping others both personally and professionally.

Sheryl Ashley, Data and Technology Manager Sheryl has been with MSMA over 16 years. Her primary focus is keeping you informed of what’s going on at MSMA. Sheryl is the one keeping the data current for our physicians, residents and students. This is important so that she can share advocacy efforts, events, and who is doing what. She is also MSMA’s in-house IT person. Her knowledge is what allows us to provide you the smartphone app Sheryl Ashley that provides you with information from the Data & Technology Manager House of Delegates meeting. According to Sheryl, "Our goal is to increase awareness of MSMA work and events to our membership and we are working every day to add value to our membership."

Virginia Jackson, Executive Office Manager Virginia joined MSMA over seven years ago and is an integral part of the operations at MSMA. She works closely with the Executive Director to ensure smooth and accurate operations. In addition, to all this Virginia coordinates the meeting schedule for the MSMA President whether that be across the state meeting with component and specialty societies, at the Capitol meeting with legislative Virginia Jackson leaders, or with congressional members at the Executive Office Manager federal level. She keeps us all where we need to be. Her knowledge of all things MSMA ensures all functions of MSMA work smoothly.

Joseph “Trell” Tucker, Mail Clerk Trell is an integral part of the day-to-day functions of MSMA. Simply put, he is our go-to guy for keeping our operations running smoothly, having been with us for over 14 years. He has a wide variety of tasks from assisting our accounting department with weekly filing to assisting the executive office manager with setups (and take-downs) for many, many meetings and helping MSMA staff with any projects they may be working on by transporting supplies and meeting materials to various locations throughout the city.

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Joseph "Trell" Tucker Mail Clerk

MISSISSIPPI STATE MEDICAL ASSOCIATION MSMAonline.com

Karen Evers, Managing Editor of the Journal MSMA Karen Evers is managing editor of the Journal MSMA. With the Committee on Publications, Karen oversees and coordinates the publishing process from content acquisition, editing, and production to the printed magazine and online epub distributed in members’ mailboxes. Since 1995, Karen has produced over 20 bound Journal volumesover 250 issues. She is the recipient of several Karen Evers APEX awards including Best One-PersonManaging Editor, JMSMA Produced Magazine, an Association Trends All-Media Contest Silver Award for Most Improved Magazine, and a Lantern award for a special issue “From Doc on Horseback to Managed Care.” Becky Wells, Director of Events and Association Management Becky has been a part of MSMA for over 20 years. Her knowledge of all things MSMA is unsurpassable. Her work as Director of Membership for many years and understanding the needs of the members led to her current role as Director of Events and Association Management. Becky focuses on the coordination Becky Wells of all MSMA events for the Association including Director of Events and CME in the Sand, CME with Mickey and House Association Management of Delegates meeting and many other meetings between. She also coordinates events and handles requests of the various specialty and component societies managed by MSMA. Becky is dedicated to providing assistance and support to all members. Kim Mathis, Director of Education Kim has been with MSMA for almost 5 years serving as the CME coordinator for over 3 years and over the last year full time as the Director of Education. Kim loves her work here at MSMA and strives to offer quality CME programs to all our physicians. She also accredits 16 other healthcare providers in the state of MS and TN who provide CME within their communities. Her goal is to increase CME activities that are both beneficial and enjoyable to our members.

Kim Mathis Director of Education

David Roberts, Director of Government Affairs David Roberts is Director of Government Affairs for MSMA. An experienced, veteran lobbyist, David advocates strongly for members in the realm of public policy in the state legislature and beyond. He serves the Association in lobbying, strategic planning and vision. David leads the effort with our Doctor of the Day program at the Capitol. He often delivers results of hearings and reports to our members and community leaders. He makes sure David Roberts members are kept informed on upcoming legislative Director of issues and the physicians of Mississippi are strongly Government Affairs represented at the Capitol. David completed his undergraduate degree at Mississippi College and his graduate studies at MSU in public policy and administration. David and his wife Mindy live in Madison with their 3 children. Sid Scott, Director of Communications Sid Scott serves as Director of Communications for MSMA. A seasoned journalist, advertising creative director and public relations specialist, Sid helps guide the Association’s efforts in external and internal communications, keeping MSMA’s reputation solid and unassailable. Sid attended the University of Mississippi and the Sid Scott American Film Institute. He and his wife have Director of Communications two sons and live in Madison. Phyllis Williams, Director of Practice Strategies After 23+ years with working with the Medicaid program, Phyllis was ready for a reprieve. She loves working with physicians to support and improve the non-clinical side of their practices. This includes serving as a payer advocacy resource to help resolve issues with healthcare payers whether that is one-on-one or by coordinating educational opportunities for medical practices and their staff. Phyllis also coordinates our Physician Leadership Program to prepare physicians to thrive in the new world of medicine Phyllis Williams by helping doctors understand their leadership Director of style and collaborating more effectively with Practice Strategies others – the things not taught in medical school.

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Conner Reeves, General Counsel Conner serves as General Counsel for MSMA and is an integral part of the Government Affairs team. He also monitors the healthcare regulatory landscape and ensures MSMA’s members are up to date on changes affecting their practices. When not at the Capitol, Conner assists the Association with business development, marketing, and strategic Conner Reeves planning. He often works with MSMA’s General Counsel student and resident members and developed the Student Advocacy Training (STAT) program for medical students to become advocates for their profession by participating in organized medicine. He is a graduate of Mississippi State University and Mississippi College School of Law and was recognized as a 2017 Leader in Law by the Mississippi Business Journal. Conner and his wife just welcomed their first child and live in Jackson.

and various other reports and accounting functions. She enjoys a number of hobbies such as painting, crocheting, gardening and nature walks.

Dominica Thames, Controller Dominica, known as “Dom”, has been with MSMA for over 19 years. Dom is the hub of the accounting department and the CFO’s right hand. She oversees the daily accounting operations regarding, accounts payable, accounts receivable, payroll, expense reimbursement, account reconciliation, new projects and events. Dom prepares the MSMA Lobbyist’s Client report, MS Medical Political Action Committee reports

Apphia McCollough Apphia serves as the Capitol nurse during the legislative session, approximately January through April. She provides clinical/emergent care to the legislators and staff. She works with rotating Doctors of the Day and together they are able to provide multi-specialty care and up-todate advice and counseling for legislators and staff.

Dominica Thames Controller

Jenny White Jenny has been with MSMA since January 2011. She manages the Mississippi Society of Otolaryngology, Mississippi Gastroenterology Society, American College of Surgeons, Mississippi Chapter, and American College of Cardiology, Mississippi Chapter. Jenny works with Kim Mathis with other MSMA CME activities and Becky Wells with the planning of CME in the Sand. She recently relocated to the Washington, DC, area and is grateful for the opportunity to still serve the members of MSMA.

Jenny White

Apphia McCollough

Navigating the Business of Healthcare 2018 iPASS

Insurance Payment Advocacy Solutions Summit MSMA will help you navigate the business of healthcare at our annual iPASS summit. Topics include:

• Challenges of MACRA • Issues with healthcare payers and handling prior authorization denials • Changes to Medicaid and MississippiCAN • Networking and open forums to answer your questions See www.MSMAonline.com/iPASS for more information.

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iPASS Summit Dates Hattiesburg: Friday, May 4 Jackson: Wednesday, May 9 Oxford: Friday, May 11

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Jackson, MS • Oxford, MS • Madisonville, LA • 877-759-5765 • www.MWGEmployerServices.com JOURNAL MSMA

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Maintenance of Certification Playbook Puts Power in Your Hands WILLIAM GRANTHAM, MD

s physicians, we all struggle with the challenges of practicing in a complex time. Regulations, procedures and processes are interwoven into our practices every day, often putting barriers between us and our patients. One of the most intrusive of these is the burden of Maintenance of Certification requirements. These rules have distorted board certification into a hardship for physicians instead of a proud accomplishment. To help doctors work toward changing burdensome MOC requirements, MSMA staff has a solution—the MOC Playbook. The Playbook gives you communication templates that you can use along with your state and national specialty society to help change their MOC requirements. The Playbook also has sample medical staff bylaws that you can use to help your hospital bylaws protect physicians from intrusive MOC. MSMA staff also included new developments in specialty board testing requirements and CME program accreditation. Physicians in other states have turned to legislation to alleviate the MOC problem. But these laws have not been put to the test. MSMA staff investigated the issue, calling on the AMA, national specialty societies and other state medical associations about these laws. Our staff has told us they agree with other policy experts that laws are not a viable option for the protection physicians want. More importantly, in our current political environment, a legislative fix isn’t realistic. So, we must follow the lead of medical policy experts who believe a better way to reduce the burdens of MOC is to change the game by arming physicians with tools that empower them to influence their specialty boards and hospitals. That’s where the MOC Playbook comes in. Find it on the MSMA

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William M. Grantham, MD MSMA President 2017-2018 website and use the tools put in place there. Only by organizing and communicating with policy makers of specialty boards and hospitals will we get the change we all need. n

William M. Grantham, MD MSMA President 2017-2018

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Letters to the Editor Opioid issue praised for quality content Dear JMSMA Editor, I want to congratulate you on the recent MSMA journal issue on opioids. You certainly provided a broad perspective and lots of food for thought. I particularly liked the piece by Dr. South, “The Painkiller Panic: From Pandemic to Pandemonium.” [South D. The painkiller panic: From pandemic to pandemonium. J Miss State Med Assoc. 2018;59(1):70-72]. First of all, the title is wonderful! Great alliteration, and certainly summarizes her attitude. And I loved the content. I also liked the article on end-of-life care by Dr. Merkelz. [Merkelz, K. “The Other Side of the Opiate Crisis: Why Increasing Opiate Hurdles May Negatively Impact End of Life Patient Care.”] – Jennifer Schneider, MD, PhD Tucson, AZ Moth in a human ear: A special report of non-bacterial, fishing-associated external otitis Dear JMSMA Editor, Insects are known to occasionally enter the human ear. In fact, one study showed that out of 164 foreign bodies removed from people’s ears, 17 (10.4%) were insects.1 Usually, this type of infestation causes only minor annoyance, but the arthropod's movements within the ear canal and against the sensitive eardrum can be painful, potentially leading to tympanic membrane perforation. Live insects inside a human ear may present in dramatic ways such as otalgia, restlessness, and great discomfort which may confuse an inexperienced physician.1-3 A report from one clinic indicated that all foreign bodies seen in human ears and noses were successfully removed in their clinic without the need for general anesthesia. In that report, live insects were killed first by drowning in olive oil before manual extraction or ear syringing.1 Although most cases can be treated/resolved in the local clinic, sometimes it may be necessary to refer patients to an otorhinolaryngologist who can safely remove the insect using a microscope, sometimes under general anesthesia.2,3 Canal wall lacerations have been reported in patients following attempts at removal by other healthcare professionals.2 Herein we describe a case of a moth entering a patient’s ear and remaining there for approximately 37 hours. On Saturday, September 30, 2017, several friends were night fishing offshore near Grand Isle, Louisiana, when their boat broke down leaving them stranded with the boat lights still on. One of the fishermen, a graduate student at Mississippi State University (MSU), reported seeing numerous insects flying around the lights before one flew into his left ear. He could feel the insect moving inside his ear but was unable to get it out. One of his companions suggested 216 VOL. 59 • NO. 4 • 2018

they pour whiskey in his ear, which they did, and the insect ceased moving. From Figure. Moth removed from human ear, a member of the that point on, the patient could feel family Crambidae. discomfort in his ear but no pain. On Monday morning (approximately 32 hours later), the patient went to college and told his fellow graduate students about the incident. Using a flashlight and a pair of small forceps, they removed the moth from his ear. The specimen was identified by MSU entomologists as a member of the family Crambidae, which are small, pale, yellowish-brown specimens (see Figure) whose larvae feed in a wide array of grasses and stems, including sugarcane which is common in Louisiana. Monday afternoon, the patient went to the MSU Student Health Center where they flushed his ear, recovering moth legs and a piece of a wing. The patient recovered uneventfully with one exception – he still occasionally feels the moth in his ear, even though it is not there. Interestingly, even though the patient’s fellow graduate students “removed” the offending specimen, flushing of the patient’s ear revealed that they had not completely removed the foreign body, demonstrating the need for medical follow-up after crude removal efforts. – Jerome Goddard, PhD, and John H. North Mississippi State University Department of Biochemistry, Molecular Biology, Entomology, and Plant Pathology, 100 Twelve Lane, Clay Lyle Entomology, Mississippi State University, Mississippi State, MS 39762, U.S.A. E-mail: jgoddard@entomology.msstate.edu. References 1. Adedeji TO, Sogebi OA, Bande S. Clinical spectrum of ear, nose and throat foreign bodies in North Western Nigeria. Afr Hlth Sci. 2016;16:292-297. 2. Bressler K, Shelton C. Ear foreign-body removal: a review of 98 consecutive cases. Laryngoscope. 1993;103:367-370. 3. Krauss BS, Green SM. Removal of foreign bodies from the ear and nose. N Engl J Med. 2016;375:194.

Dr. South’s truth-telling essay is applauded Dear JMSMA Editor, I enjoyed the revisit to Spoon River in your poetry section very much. I applaud your truth-telling article in the January issue of the Journal. [South D. The painkiller panic: From pandemic to pandemonium. J Miss State Med Assoc. 2018;59(1):70-72] The powers that be having failed miserably in the decades-long war on illegal drugs have started a new war on legal drugs. The MSMA leadership seems to have said “Mea Culpa” and joined them. Good luck in your battle for your patients! – Robert Ray “Bob” McGee, MD, FACP Clarksdale

C O M M E N T A R Y

Healthcare is a Catch-22 for the Uninsured J. ANTHONY CLOY, MD; CHAIR, MSMA COUNCIL ON MEDICAL SERVICE

ealthcare in Mississippi can be much like Joseph Heller’s Catch-22. In the novel Heller writes about the conundrum a WW II bombardier faced: one must be crazy to fly such extremely dangerous missions and one who is crazy gets grounded. Healthcare in Mississippi is just such a Catch-22 for the uninsured patient. J. Anthony Cloy, MD Insurance coverage is often the single factor that makes the most difference in whether a patient gets medical care when he/she seeks care and ultimately how healthy the patient is. The uninsured patient is far more likely to postpone health care than is the patient with insurance. Consequences of delaying care can be severe, particularly when preventable conditions or chronic diseases go undetected.

Because a patient without health coverage is less likely than one with insurance to have regular medical care, he/she is also more likely to be hospitalized for health problems that have worsened or could have been avoided. The uninsured patient is up to four times less likely to have a regular source of health care and is more likely to die from health-related problems. Studies repeatedly demonstrate that uninsured patients are less likely to receive preventive care and services for major health conditions and chronic diseases than are those patients with insurance.1,2 One in five (20%) nonelderly adults without coverage say that he/she went without care in the past year because of cost. That compares to 3% of adults with private coverage and 8% of adults with public coverage who agreed. Part of the reason for poor access among the uninsured is that nearly half do not have a regular place to go when they are sick or need medical advice. The pool of uninsured patients is a diverse group that includes people who cannot afford private health insurance, work in a small business that does not offer insurance, simply choose not to purchase health insurance even though they can afford it, are eligible but not enrolled in governmentsponsored programs such as Medicaid/CHIP and immigrants. According to national data summarized by the Congressional Budget Office, groups with a high propensity to lack health insurance include people in families with income below 200% of the Federal Poverty Level (FPL), Hispanics, young adults age 19 to 34, those in a family in which the adults work part-time or only part of the year or employed individuals with fair or poor health status. Medicaid and CHIP are available for low-income children, but coverage for adults is more limited. The District of Columbia and 31 states had expanded Medicaid eligibility for adults under the Affordable Care Act (ACA) by January 2017. However, coverage for adults remains limited in the 19 states that did not expand Medicaid. In those states, the median eligibility level for parents was 44% of FPL and adults without dependent children were often not eligible at all. Millions of poor uninsured adults fall into the “coverage gap” because they earn too much to qualify for Medicaid but not enough to qualify for the marketplace premium tax credit created by the ACA. Kaiser Family Foundation Health Facts published statistics for 2016 revealing that 42% of Mississippians had employment-based group health insurance coverage and another 3% had coverage not based on an

employer’s group policy. Medicare, Medicaid or another public health care program covered 41%, and 12% were uninsured. The MSMA president and other Association leaders frequently meet with state policy makers and the topic of Medicaid expansion has been an ongoing discussion. However, House and Senate leaders have held steadfast with the position that expanding Medicaid is not an option. Therein lies the Catch-22: Medicaid expansion is the only program available to provide health coverage for the uninsured in Mississippi and it’s a program that policy makers refuse to consider. Federally Qualified Health Centers (FQHCs) are one resource for the medically uninsured. Strictly speaking, an FQHC is a non-profit health center that provides comprehensive primary care for patients of all ages, regardless of their ability to pay and receives grant funding under Section 330 of the Public Health Service Act. FQHCs also receive a host of benefits that include cost-based reimbursement from Medicare and Medicaid, access to National Health Service Corp programs, participation in the Public Health Act 340B drug discount program and malpractice insurance under the Federal Tort Claims Act. The Community Health Center (CHC) is one type of FQHC available to patients that typically have low family income, live in a medically underserved community and have complicated health conditions. Mississippi has 20 CHCs with 187 service sites covering 69 of the 82 counties. CHCs offer sliding-fee discounts to all income eligible under or uninsured patients based on family size and annual household income; the health center can waive the fee for a patient who truly has no other resource. In 2016, CHCs in Mississippi documented $34 million in Sliding Fee Discounts. CHCs primarily provide health care to patients who are uninsured or covered by Medicaid and 33% of all 2016 CHC patients lack insurance. In 2016 at least 68% of patients reported family incomes less than 100% of the federal poverty level. More than 90% of patients had family incomes at or below twice the poverty level. Health Center patients tend to be younger in age and are more likely to be female. In 2016, 31% of all CHC patients were children, and almost three in five patients were female. Over 57,000 (20%) were women of childbearing age. Statewide, our CHCs are not at capacity, thus presenting a potential avenue for health care amongst at least some of these underinsured/uninsured patients. Thus, just like Heller’s pilots in Catch-22, the medical community may be “crazy” to keep pushing for Medicaid expansion under the ACA. Likewise, some think the state may be “crazy” not to take advantage of a federal solution. Nonetheless, physicians always put the patient first which leaves medicine to answer another conundrum: Mississippi must find a politically palatable method to get medical care for the working poor. As chair of the Council on Medical Service, I welcome your thoughts and suggestions regarding promotion of CHCs as well as other ways to expand service to those in need. n References 1. Hadley J. Insurance Coverage, Medical Care Use, and Short-term Health Changes Following an Unintentional Injury or the Onset of a Chronic Condition. JAMA. 2007;297(10):1073-1084. doi:10.1001/jama.297.10.1073. 2. McMorrow S, Kenney GM, Goin D. Determinants of receipt of recommended preventive services: Implications for the Affordable Care Act, Am J Public Health. 2014;104(12):2392-2399. doi: 10.2105/AJPH.2013.301569.

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Avoid the Social Networks: A Mobile Communication Platform Should Provide a Secure, Efficient Workflow TRACEY HAAS, DO, MPH; CHIEF MEDICAL OFFICER, DOCBOOKMD

obile communication is an integral and growing part of every aspect of modem life, including healthcare. Fast and secure communication among care team members can measurably improve clinical efficiency as well as patient outcomes – this is a given. In addition, federal and state requirements for electronic health recordkeeping are pushing many medical professionals to aggressively begin updating and integrating their electronic health records and communications. However, many physicians and health care organizations still rely on multiple technologies and information systems for their communications. The time it takes to monitor multiple communication portals can take away from time spent with patients and can allow important messages to slip through. The Problem Several products are on the market to address the need for HIPAA-compliant mobile messaging among medical professionals. However, many of these solutions have serious flaws: they are social networks that make their money by selling physicians' information to recruiters or they are siloed solutions that only help those who work inside a hospital system. Physicians need a mobile communication solution that is not only HIPAA-secure but also shields their personal information and works regardless of practice type or location. The Solution The ideal messaging application for health care providers should include: • Efficient and instantaneous physician-to-physician communication; • A secure community to share patient information and collaborate with medical colleagues, in a HIPAA-secure manner; • Ability to send medical images securely between

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physicians; • Built-in local physician and pharmacy directories; • Ability to scale from small groups to hospitals, all the way to large multi-enterprise organizations like A COs; • Widespread adoption among medical professionals; • Availability across platforms including smartphones, tablets and the Web; • Data that reside on secure servers, not users' devices; • Ability to remotely disable the app on a device that has been lost or stolen; • Long-term message archive compliant with HITECH recommendations; and • Ability to integrate with other health IT solutions. When all the information is at a physician's fingertips, faster and richer discussions on patient treatment and care can result. Also, with local physician and pharmacy directories built into a secure messaging app, the time physicians spend finding colleagues or tracking down a local pharmacy is cut from hours to minutes. A Secure Gateway The only HIPAA-secure instant messaging application that meets all these requirements is DocbookMD. Designed by physicians for physicians, it creates a secure community to share patient information and collaborate with medical colleagues as well as third-party services such as radiology, labs, answering services, even health plans. Dr. Tim Gueramy and I began developing DocbookMD out of our own need for more efficient and instantaneous physician-to physician and physician-to-care team communication. Since then, DocbookMD has experienced incredible growth, now serving more than 25,000 physician users across 42 states, including Mississippi.

In addition, DocbookMD offers CareTeam, a feature that allows physicians to invite members of the patient's direct care team – including nurses, PAs, administrators, care coordinators and other staff - to join them on DocbookMD to communicate in a secure, fast and efficient way through their mobile devices. DocbookMD is a free benefit of membership in the Mississippi State Medical Association.

health IT solutions? Answering these questions and others will help physicians evaluate messaging apps and select the right fit for their organizations. A HIPAA-secure mobile medical communication solution should put physicians firmly in control of whom they connect with and who can send messages to them. Any other model opens physicians up to unwanted contacts and wasted time.

Use Cases With DocbookMD, health care providers of all kinds can communicate with colleagues rapidly and securely with the confidence that their privacy and data integrity will be maintained. Here are some exemplary use cases based on users' testimonials: • A dermatologist can send the ENT surgeon an image of a complicated skin lesion to be removed. The surgeon is able to make a more efficient plan for surgery and reconstruction ahead of time. • A family doctor in a rural area can collaborate over X-rays with an orthopedic surgeon in the nearest city. The specialist is able to determine if an urgent surgery or just a cast is necessary, saving the patient time, extra office visits and travel.

DocBookMD partners with MSMA to bring members a free, HIPAA-secure messaging app that uniquely provides extra security to Mississippi physicians. For more information on the mobile app, visit www.DocBookMD.com or call tollfree 888-930-2048. To join MSMA, visit MSMAonline.com or call 601-853-6733. DocBookMD is available in Mississippi only to actively practicing MSMA members. Membership is open to any MD or DO licensed to practice in Mississippi. n

• A radiologist can communicate test results immediately to the ordering physician, who can in tum notify the patient and bring in for treatment, if needed, much more quickly. • An emergency physician is able to rapidly receive and send messages, images and test results to consultants and referring doctors during a busy shift. They are also able to coordinate transfer of care with outpatient primary care, or inpatient hospitalists, thereby streamlining transitional patient care and closing the loop on any ER visit. Physicians report improved workflow with the ability to do the same work in far less time. For example, a traveling cardiologist's assistant can send the doctor lower extremity Doppler studies and EKGs for a patient who may be hundreds of miles away. The cardiologist is able to make treatment decisions without having to return, and the patient receives much quicker and more responsive care. Selecting a Platform Ultimately, when choosing a secure instant messaging application for medical communications, physicians and health care organizations must carefully consider their professional needs as well as the potential to improve patient care. What features are absolute must-haves? What app characteristics would eliminate an app from consideration? Is the solution scalable? Is it cost-effective? Can it be integrated into existing

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Role of Vitamin D and NEC – An Emerging Risk Factor PARVESH MOHAN GARG, MD

ecrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in low birth weight infants. NEC is an acute inflammatory disease resulting in intestine necrosis, systemic sepsis and multi-system organ failure. NEC likely has a multifactorial etiology and an unclear pathogenesis. Low Vitamin D is emerging as a potential risk for NEC. In United States, preterm delivery (<32 weeks) is more than twice as common among black infants (3.9%) as compared with white infants.1 Infants born <32 weeks gestation are at higher risk than more mature infants for low 25(OH) D levels. The study has shown that infants had lower mean umbilical cord plasma 25(OH)D levels if they were born in the winter or spring (vs. summer or fall) and if their mothers were black (vs. white).2 A study done by Cetinkaya M et al in 2017 showed that among 145 enrolled patients ( less than 36 weeks), 26 (18%) developed NEC. Maternal/neonatal 25-OHD levels in the NEC group were significantly lower than those of the no-NEC group (P=0.001 and 0.004, respectively).3

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A recent report by Yongyan Shi et al suggests that Vitamin D ameliorates neonatal necrotizing enterocolitis via suppressing Toll-like receptors 4 in a murine model.4 The role of vitamin D levels as a potential risk factor for NEC is still to be investigated fully in preterm infants to prevent mortality and morbidity due to this life-threatening disease. References 1. Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, Kirmeyer S, Mathews TJ, et al. Births: final data for 2009. Natl Vital Stat Rep. 2011;60(1):1-70. 2. Burris HH, Van Marter LJ, McElrath TF, Tabatabai P, Litonjua AA, Weiss ST, et al. Vitamin D status among preterm and full-term infants at birth. Pediatr Res. 2014;75(1-1):75-80. 3. Cetinkaya M, Erener-Ercan T, Kalayci-Oral T, Babayigit A, Cebeci B, Semerci SY, et al. Maternal/neonatal vitamin D deficiency: a new risk factor for necrotizing enterocolitis in preterm infants? J Perinatol. 2017;37(6):673-8. 4. Shi Y, Liu T, Zhao X, Yao L, Hou A, Fu J, et al. Vitamin D ameliorates neonatal necrotizing enterocolitis via suppressing TLR4 in a murine model. Pediatr Res. 2018.

Author Information

Department of Pediatrics/ Division Neonatology, University of Mississippi Medical Center, Jackson, MS, 39216 (gargparvesh@hotmail.com)

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I M A G E S

I N

M I S S I S S I P P I

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ING'S DAUGHTERS HOME, GREENVILLE, 1905 – Situated on the corner of Smith (later Arnold Avenue) and Walker Streets, on the current site of the Bessie J. Taylor Retirement Home, the King’s Daughters Home, seen above and erected in 1904-5, was the first hospital in Greenville and the first King’s Daughters hospital built in the state. In March 1892, a group of civic-minded “gentlewomen” rented a two-room cottage to use as a charity “hospital” for the disease-ridden, poor river population, called “shanty boaters.” By 1894, the group applied for a charter of incorporation to the International Order of The King’s Daughters, one of the oldest Christian service organizations in the world. Their charter was received January 14, 1895, as The King’s Daughters and Sons Circle No. 2, which continues today as a charitable foundation for the Delta. With monthly dues of only twenty-five cents, the Circle somehow managed to operate a series of small cottages as hospitals. It is said that the first surgery (an appendectomy) to be performed in one of these cottages was in 1894 by Dr. Jefferson Davis Smythe. (Prior to this, all surgery in the area had been performed in a patient’s home.) Mrs. LeRoy Percy led the drive to build a “real” hospital, which would be supported by monthly contributions of the citizenry as a benevolent institution. The Circle contracted in 1904 with J. F. Barnes to construct the hospital for $16,500. (Total project costs would end up being $40,000.) The new 35-bed hospital was a 2½ story stone building, with the stone supplied by the Mississippi Stone Manufacturing Company in Greenville. The ceremony to lay the cornerstone occurred May 18, 1905, with Governor J. K. Vardaman and Congressman John Sharp Williams among those in attendance. The first patient (who was suffering from typhoid fever) was admitted June 1, 1905, by Dr. R. S. Toombs. A school of nursing was associated with the hospital beginning in 1906. By 1913, a brick annex was added as a home for nurses. By 1924, the Home’s average census had increased sizably, and Circle leaders embarked on an ambitious drive to build a larger modern hospital. The $450,000 project would result in the construction and opening by February 1927 of a new Mediterranean-style hospital, with patients moved from the Home at that time. When this new hospital opened, the 1905 hospital was converted into a home for nurses, and in 1937, it was razed and replaced with a companion structure (nurses home) for the 1927 hospital. See previous issue and future issues for related Images of Greenville hospitals. If you have an old or even somewhat recent photograph or image which would be of interest to Mississippi physicians, please send it to me at lukelampton@cableone.net or by snail mail to the Journal. n Lucius M. “Luke” Lampton, MD; JMSMA Editor

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Greenwood – 1942 ... [This month, we print an elegant and graceful poem by John D. McEachin, MD, FAAP, a Meridian pediatrician and the Journal’s unofficial poet laureate. “Greenwood-1942” reaches back to the days of McEachin’s youth, recalling a Mississippi Delta community during World War II. He writes the editor: “My family moved from Grenada to Greenwood in 1942. My father was a Greenwood cotton factor (buyer for the mills in North Carolina), and with gas and tire rationing during the war, commuting was no longer an option. I started first grade in Greenwood, and moved back to Grenada in 1944. I have wonderful memories of my 2½ years in Greenwood – witness the poem.” For more of Dr. McEachin’s poetry, see past JMSMAs. Any physician is invited to submit poems by slow mail for publication in the Journal, attention: Dr. Lampton or email me at lukelampton@cableone.net.] — Ed.

Alligator gar, Yalobusha – Yazoo,

Cottonfields, row on row

Sand bags stacked high on the banks;

Flat “Delta” land--- green, aglow,

Mimosas leaning in the breeze

Gaunt black faces, straining backs,

To set pink powder puffs free.

White fat fluffs, stuffing burlap sacks.

Clickety-clacking down Carrollton’s brick

Books of rations--- food, gas, and tires---

‘Round the bend over railroad tracks,

“You Are My Sunshine;” “Don’t Set the World on Fire;”

Then spinning, curling back over the bridge,

“Praise the Lord and Pass the Ammunition;”

And down by Hamrick’s Motors.

“Mares eating oats, and lambs, ivy?”

Cotton exchange with doors wide open,

Over the Tallahatchie and on to Money,

Chalk dust mounting, stack upon stack;

Twisting up the sunburned trail,

Fifty two cards, dominoes, and checkers

Little bitty boy, way down South,

Gliding through smoke with skillful plans.

Reliving the ’42 Greenwood days.

Wading in water up to the knees,

– John D. McEachin, MD Meridian

Down Grand Boulevard and onto Cleveland, Being careful not to cut the feet. Hoping the car will start again!

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U N A

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The Doctor Who “Cared Too Much” Dr. Nick and Elvis: A Forty Year Retrospective DWALIA S. SOUTH, MD

Elvis was heart-poundingly beautiful. He was heart-achingly talented and charismatic. Sadly, he was apparently also heartbreakingly gullible. According to his biographical information, his high school tested I.Q. was 70 which placed him in the ‘moderately impaired cognition’ category. But, like the fictional Forrest Gump, he possessed miraculous gifts and abilities, a generous heart of gold and an amazing amount of luck. Although his manager, “Colonel” Tom Parker took extreme financial advantage of Presley (by taking half of most his earnings),1 he propelled him from a life of poor white trash to millionaire in one year. It seems Elvis was not prepared for what such rapid success would mean in his life and the deadly excesses it would soon foster. At Elvis’ sudden passing, the Shelby county medical examiner listed his cause of death to be “coronary arrhythmia resulting from hypertensive heart disease.” Later toxicology results rightly fueled speculation about the role prescription drug abuse had played in his demise. There were about 14 different prescription drugs, “uppers, downers, and all arounders” in Elvis’ post-mortem blood sample. It showed ‘significant’ levels of Codeine, Ethinamate (a sedative), Quaaludes and barbiturates. Lesser amounts of Morphine, Demerol, Placidyl (a sleeping pill), Valium and antihistamines were found. But who gave him these dangerous drug combinations and why? Here then is our subject of discussion, Elvis’ long time personal physician Dr. George Nichopoulos. Elvis and Dr. Nick met 50 years ago now on a Sunday afternoon in 1967 at Elvis’ Circle G Ranch in Horn Lake, Mississippi. Nichopoulos was taking calls that day for another physician who had been treating Elvis and the doctor was summoned to Elvis’ DeSoto country home 226 VOL. 59 • NO. 4 • 2018

he “Tupelo Daily Journal” arrived in my box on Wednesday, August 16, bearing the headline “REMEMBERING THE KING.” The story paid homage to the 40th anniversary of the shocking premature death of one of northeast Mississippi’s favorite native sons, Elvis Presley. Elvis was a superstar so famous he didn’t need a last name, an icon so alive during his 42 years that some people are insistent that he still is.

to treat his complaint of severe saddle soreness from too much horseback riding the previous day.2,4,5 At the time, Dr. Nichopoulos belonged to a well-respected east Memphis internal medicine group with five other physicians.3 This proved to be a lifechanging house call for the doctor, a professional segue that ultimately destroyed his career.

George C. Nichopoulos Died: February 24, 2016

From this encounter, Nichopoulos and Elvis struck up a close relationship and for the next ten years Dr. Nick was his ‘go to’ man for every real or perceived ailment. When Elvis returned home to Graceland permanently in 1970 Dr. Nick became something more than just his primary care physician. Dr. Nick told investigative reporter Gerald Posner that “at times I was his father, his best friend and his doctor. Whatever role I needed to play at the time, I did.” Dr. Nick quit his day job to become the full time physician for Elvis and his entourage who were dubbed the “Memphis Mafia.” Presley had since the 60’s already become dependent on a daily cocktail of amphetamines (an effort to maintain his weight and to keep him going during his punishing touring schedule), sedatives to treat the insomnia caused by the stimulants, and narcotics to treat his gyration induced joint pains.6,7 He spent a great deal of time either personally seeking drugs or having his close friends obtain them for him. Presley didn’t touch a drop of alcohol or illicit drugs but believed that if a physician prescribed the many meds he took that there was nothing to fear.6 There is no way to know how many doctors in Memphis he had sought out for treatment prior to George Nichopoulos becoming his official full time “Dr. Feelgood.”4,5

Elvis and his entourage who were dubbed the Memphis Mafia - Dr. Nick (kneeling) immediately to the left of Elvis.

The rapport and true affection between the silver-haired doctor and patient was instant, and Nichopoulos was apparently unable to say ‘no’ to any of Elvis’ requests.5,6 In multiple later interviews after Presley’s death, Dr. Nick said, “Elvis was a firm believer that there was a medicine for everything…He was always childlike with these things… I don’t think he ever realized how harmful these things could be to him… Elvis was convinced he needed these drugs.” Nichopoulos observed that “If he had a scratchy throat, he wanted penicillin tablets. I would give him twenty and tell him to take four a day.” Then, Elvis would take the entire prescription in two days because he believed he would get well faster.7 Nichopoulos freely admitted that Elvis’ consumption of numerous medications was dangerous but could never bring himself to simply stop enabling him.5 He claims that he tried several times to cure Presley of his addictions and even manufactured placebo capsules for him in an effort to curtail his abuse but to no avail.5 Three years after Elvis’ death in 1980, the finger of blame was pointed at Dr. Nick; he was indicted on 14 counts of

“unlawfully, willfully and feloniously” prescribing a cornucopia of narcotics, amphetamines, and sedatives to Presley in the months prior to his death. He persisted that he had prescribed only two of the drugs in Presley’s system at the time of his death. At that time, Nichopoulos was found ‘not guilty’ of the charges of unethical conduct, but the medical board suspended his license for three months and put him on probation for three years. The Tennessee Board of Medical Examiners permanently suspended his license fifteen years later in 1995, stating that he had been overprescribing to numerous patients for decades. Dr. Nick appealed to the board admitting that he had overprescribed medications to Elvis but had thought they were for his entire family, his band, production crew and all his employees. In 1977 alone it is documented that he wrote more than 10,000 doses of meds for Elvis including opiates, amphetamines, barbiturates, tranquilizers, some various injectable drugs, antihistamines, anti-hypertensives, steroids, hormones and laxatives.3,7 He speculated in his memoir, “The King and Dr. Nick: What Really Happened to Elvis and Me,” that Presley’s medical problems, not his drug addiction, were to blame for his death. He listed diabetes, glaucoma, obesity (350

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pounds), migraines, allergies, adrenal insufficiency and arthritis as factors but theorized that his actual cause of death was a toxic megacolon in light of his death on the toilet while attempting to have a bowel movement. He had in the past been treated multiple times for obstipation (a complete inability to pass solid waste) at the Baptist Memorial Hospital in Memphis. This chronic severe constipation was, of course, opiate induced. Stripped of his medical license and unable to make a living as a practicing physician, Dr. Nick worked for a time as a road manager for Jerry Lee Lewis and as a disability claims consultant for Federal Express.4 Nichopoulos actually even had his own traveling road tour for a while. I was able to meet Dr. Nick and view his “Memories of Elvis” exhibition at a medical conference held at one of the Tunica casinos several years ago. I regretfully cannot recall which pharmaceutical company sponsored him but remember that his exhibit included a good deal of Elvis memorabilia collected during his ten years with him and his own medical bag which contained empty Dilaudid prescription bottles with Elvis’ name on the labels. Ultimately his exhibit was deemed in poor taste and his tour ended after a few Las Vegas Casino showings. Elvis was not the first superstar to die as a result of his addictions and excesses. Where do you go after you reach the pinnacle of a fantastic career? Some people cannot deal with the emotional pain that is a side-effect of mega-stardom. Can you think how physically punishing it must be for a middle aged man to try to keep his aging body doing impossible dance moves night after night? Multi-millionaire celebrities have the money to buy whatever services they can imagine, and yes, can also ‘buy’ the people capable of providing them. Think of other recent similar horrible and unnecessary deaths that have been aided by Doctor Feelgoods…Michael Jackson died while his personal physician, Dr. Conrad Murray, had him hooked up to a propofol drip with several other heavy prescription drugs present in his system.8 Prince died primarily from fentanyl but also had countless other narcotics in his home, bottles written in the names of other patients, and prescribed by at least nine medical practitioners.9 George Nichopoulos knew that if Elvis wasn’t getting what he wanted from him, he would get it elsewhere as he had done before. Dr. Nick truly at some level felt that he was protecting Elvis from his personal demons.10 There is no doubt they felt a deep brotherly love for each other, but a great portion of their relationship was based on codependency. Until his own death in Memphis in February of 2016 at age 88, Dr. Nick denied being Elvis’ “Doctor Feelgood” or bearing any blame for his untimely demise. He lamented that “They always wanted a scapegoat for Elvis’ death. They never stopped going after me ... I just cared too much.”

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References 1. The Dark Side of Colonel Parker. Elvis Information Network https:// www.elvisinfonet.com/spotlight_thedarksideofcolonelparker.html. Accessed March 9, 2018. 2. English edition of Elvis-History.com. February 1967 page. February 26 entry. http://www.elvis-history.com/english/year1967/februar.html. Accessed March 9, 2018. 3. Higginbotham A. Doctor Feelgood. The Observer. August 11, 2002. 4. Grimes W. George C. Nichopoulos, Elvis’s Last Doctor, Dies at 88. The New York Times. February 26, 2016. https://www.nytimes. com/2016/02/27/us/george-c-nichopoulos-elviss-last-doctor-diesat-88.html. Accessed March 9, 2018. 5. George Nichopoulos, Elvis's doctor – obituary. The Telegraph. March 1, 2016. https://www.telegraph.co.uk/news/obituaries/12178962/GeorgeNichopoulos-Elviss-doctor-obituary.html Accessed March 9, 2018. 6. New York Daily News. Thursday, February 25, 2016, U.S. Section:.'Doctor Feelgood' physician to Elvis Presley and Jerry Lewis accused of over-prescribing pain meds, dead at 88. http://www. nydailynews.com/news/national/doctor-feelgood-physician-elvis-diedarticle-1.2544068. Accessed February 28, 2018. 7. Pleasance C. The Daily Mail February 25, 2016. Elvis Presley's physician George Nichopoulos known as 'Dr Nick' dies aged 88. Daily Mail Online. http://www.dailymail.co.uk/news/article-3464926/Elvis-Presley-sphysician-George-Nichopoulos-known-Dr-Nick-accused-helping-causeKing-s-death-prescribing-drugs-dies-aged-88.html Accessed March 9, 2018. 8. Avila J, Ng C. ABC News. Michael Jackson's Doctor Guilty. November 7, 2011. http://abcnews.go.com/US/michael-jacksons-doctor-guilty/ story?id=14880567. Accessed March 9, 2018. 9. Hayes A. WebMD. Prince Died From Fentanyl Overdose. https://www. webmd.com/mental-health/addiction/news/20160602/prince-fentanyloverdose#1 Accessed March 9, 2018. 10. Williamson J. Salon. The Elvis Presley cover-up: What America didn’t hear about the death of the King. November 16, 2014. https://www. salon.com/2014/11/16/the_elvis_presley_coverup_what_america_ didnt_hear_about_the_death_of_the_king/. Accessed March 9, 2018.

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