HAWAIIMEDICAL

JOURNALOctober 2003 Volume 62, No. 10 ISSN: 0017-8594

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HAWAIIMEDICAL

JOURNAL(USPS 237.640)

Puhliuhed monthly by theHawaii Medical Association

Incorporated in 1856 under the Monarchy1360 South Beretania, Suite 200Honolulu, Hawaii 9681031520

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EditorsEditor: Norman Goldstein ME)

Associate Editor: William W. Goodhue Jr., MI)News Editor: Henry N. YokoyantaMD

Contributing Editor: Russell T. Stodd MD

Editorial BoardJohn Breinich MLS, Satoru izutsu Phi).

Douglas G. Massey MD. Myron E. Shirasu MD,Frank U. Tahrah MD, Alfred D. Morris MI)

Journal StaffEditorial Assistant: Drake Chinen

OfficersPresident: Sherrel Hammer MD

PresidenrtElect: Inam Ur Rahman MDSecretary: Thomas Kosasa MDTreasurer: Paul DeMare MD

Past President: Calvin Wong MD

County PresidentsHawaii: JmAnn Saruhi MD

Honolulu: inam Er Rahman MDMaui: Joseph Kamaka MD

West Hawaii: Kevin Kuhn MDKauai: Peter Kint MD

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The Journal cannot be held responsible foropinions expressed inpapers, discussion, com.munications or adveo:is.enients, The ath•vertisin policy of the Hawaii Medical Joarnalis governed by thevales of the Council on Drugs of the A.rnerican Medical Association,The right is re.servedto reiectmateriai submitted foreditorialor advertising, columns. The Hawaii Medical Journal CUSPS•237640)is published tttonthiy by the Hawaii Medical Association(ISSN 00173(594), 1360 South Betetaria Street, Suite 200.Honolulu, Hawaii 968141520.

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Nonmember subscriptions are $23. Copyright 2.003 by theHe it M ci a A satdt or Pn”rtd ir the U S

ContentsEditorial: Report to the Hawaii Medical Association.The Journal and the Foundation.Norman Goldsteirt MD .........,...,.,,..,.,.,,,..,,,,,,,,,.,,.,.,,.,....,,...,,.....,..,..,.....,...,..,.,..,.,... 2 I 2

From the Associate Editor: Introducing... “Na Kauka 0 Hawaii”William 141 Goodhrieir. MD .....,,,,,,...,......,......,.,..,,,,...,,.,,,,,,,.......,..,.,.,.,,.,,,.....,...,,, 213

Na Kauka () Hawaii: Dwight Baldwin MD (1798-1886)Hawaii Medical Association Auxiliary ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 214

Commentary: Kimo’s RulesShav Bintli/’fMD 215

Intestinal Parasites of the PacificEthan A. Small BA, Alan 0. Tice Mi), and Xiaotian Zheng Mi), PhD 216

Lamivudine Prophylaxis for Chemotherapy Induced Reactivation Hepatitis B:A Case Report and ReviewShane J. Mills MD, Jeffrey L. Berenherg MD, and Fernando Ramos MD 220

Medical School Hotline: Student Profile: Class of 2007.John A. Burns School of Medicine (JABSOM)Satoru Izutsu PhD 223

Cancer Research Center Hotline:Targeting Oncogene Expression in a Childhood CancerMatthew C. Tuthill PhD and Randall K. Wada MD 224

Classified Notices 225

WeathervaneRussell F Stodd MD 226

ICover art by Dietrich Varez, Volcano, Hawaii All rightsreserved by the artist.

Lele Kawa

Cliff jumping was one of the favorite sports of old Hawaii,

HAWAS ME030AL JOURNAL, VOL 62, OCTOBER 2002

211

Editorial

Report to the HawaiiMedical Association

Annual Meeting

The Journal andthe Foundation

Report to the Hawaii Medical A-oclation.A.nnual_Meettng

The Journal is ver alive and dome well, thanks to the local andnationa1 advertisers and Michael Roth. our ads ertising executive:Drake Chinen. our editorial assistant: Dietrich \‘arez. our Big Islandcover artist: the many authors and peer review panel members:Russell Stodd continuing his excellent lVeathct’rune; contribLitorsfrom the Cancer Research Center. School of Medicine: and HawaiiMedical Library Staff yearly index preparation.

After a sabbatical. Henry Yokoyama has resumed his popularNews and Notes with the July 2003 issue.

The big news at the Journal is the appointment of William V.Goodhue. Jr. MD. as Associate Editor. With Bill’s experience as ateacher and s riter. and his boundless energs, the Journal is expanding its neighbor island coverage, native l-lawaiian medical subjectsand special issues.

On apersonal note. lam not retiring. M\ wife. Ramsas ,and I ha\ emoved to Maui, where I used to see patients monthly (as well as onKauai and the Big Island). We maintain our Historic Tan SingBuilding in Chinatown, where Ramsay has the Ramsay Museumand I have my Dermatology practice. where I see patients three daysper week. I then travel to Maui for four days. is ing upcountr in

Kula. where I can sside. read. and with the benefits of phones. faxesand c—mails, continue m many medical and non-medical activities.I will also host an internet radio proeram on Voice America. the ShinYou Livc In from my studio on the slopes of Haleakala.

The Hawaii Medical Journal is the sole publication of. by and forHawaii physicians, researchers, residents and students. Nowhereelse can one find the activities of the John A. Burns School ofMedicine, the Cancer Research Center of Has au, and the Flass auMedical Lihi’ar in one publication.

For more than 60 years the Journal has been sent to every memberof the Hasvaii Medical Association, The bylaws of the HMAmandates that members reeeis e the Journal as a benefit of membership. At the annual meeting of the HMA in 2002. subscription to theJournal was made voluntary. This year funding for the Journal wasleft out of the HMA proposed budget for ‘04.

At the [louse of Delegates Pat BlanchetteMD, president of theBoard ofDirectors oftheHawaii Medical Foundation. formally calledthe Reference Bureau.proposed that the Journal he administered hthe Foundation and thatfunding be included inthe HMA ‘04 budget forone mote year. whiledetails of fundingthrough the foundationare svorked out, The future dueS. str[icture svi Ilinclude subscription tothe Journal, in order toremain in compliancewtth the h\la\ss.

As u e co to press. theJournal is in prelirninardiscussions with theHawaii Medical Foundation and sve welcomeyour comments,

Norman Goldstein MDEditor, Hawaii Medical Journal

Aloha Laboratories, Inc.When results count

A CAP accredited laboratoryspecializing in Anatomic

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Phone: (8438) 842-6600Fax: (808) 848-0663

E-Mail: results @alohalabs.comhttp://www.alohalalm.c urn

212

From the Associate Editor

William W Goodhue Jr MDAssociate Editor, Hawaii Medical Journal

lance B. Taylor’s “Tales about Hawaii” column in theterritonal Honolulu Star-Bulletin commemorated people,events and institutions shaping the history of Hawaii nei.

Although the column generally appeared on the last page of thenewspaper, it was often the item many readers turned to first. Ournew column, to be included in every other issue of the HawaiiMedical Journal (HMJ). will focus on commemorating physiciansof Hawaii (Na Kauka a Hawaii) from the early I 800s to the present,by providing biographical sketches and, when available, photographs.

Principal source materials are twofold: the In lYleinoriam—Doctors ofHawaii seven volume collection at The Mamiya MedicalHeritage Center at Hawaii Medical Library (HML) describingdoctors practicing in Hawaii and now deceased, and the HawaiiMedical Association’s (KMA) Senior Physicians Committee listingof living, retired physicians.

In Memoriam—Doctors of’ Hawaii’s compilations come fromsource materials including HMA archival listings, newspaper clippings. Who’s Who and Men of Hawau listings and when possiblecontact with the doctor’s family, close personal friends and professional associates. This seven volume series began in the early 1 950sas a project of the HMA Auxiliary, with the first two volumes beingcompleted in time for presentation to the HMA in 1956, on theoccasion of its 1 00th anniversary, Mrs. Betty Katsuki, widow ofRobert Y. Katsuki, M.D.. worked with other HMA uxi1iaryvolunteers for more than 3(3 years to complete the collection ofbiographical sketches of 621 doctors and 407 photographs listed inthe 1986 Index to: Jji,Me,noda,n:De4orso Hawaii. The projectwas resumed in the mid-90s by HML volunteers Ann Catts, Ml).,and Florence Chinn, M.D., with 63 additional biographical sketches,and is again ongoing. Work is currently overseen by John A.Breinich, MS. Executive Director. HML, and Laura E. Oerwitz,MA, MLIS, Reference Librarian/Archives, Online access to thisdat ihasc is aailahlc through links at http //hml org/nnnhc/

____

Introducing...“Na Kauka 0 Hawaii”

Members of the HMA Senior Physicians Committee will also beapproached from time to time for interviews as a basis for biographical sketches in Na Kauka o Hawaii. Many of these doctors alreadyhave video and oral histories in the FIML Medicine in Hawaii: OralHistory Series.

Biosketches will bepresented with certainthemes: for example,doctors who took careof Hawaii’s kings,queens and alii; missionary doctors; doctors whoplayed significant rolesin combating epidemics(plague, cholera, typhus,typhoid fever) in theI SOOs and other infectious diseases (tuberculosis. leprosy); plantation doctors: doctors ofKauai, of Oahu, of Maui.of Molokai, of Lanai, ofthe Big Island. Therewill he overlaps amongthese themes. Our inaugural hiosketch in thisissue is of DwightBaldwin, M.D., becausewith a hirthdate of 1798he is one of the earliestof physicians practicingin Hawaii on whom datais available,

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MED VEAL JOURNAL, VOL LV. OCTOBER RUED

23

Na Kauka 0 Hawaii

Dwight Baldwin MD1798- 1886

by Hawaii Medical AssociationAuxiliary

wight Baldwin as horn at Durham, Connecticut, on Sep

• J tember 29. 179$. the son otSe th and Rhoda (Hull) Baldwin.I His first two \ ears of college work were done at Williams

College, X\ilhamstown. Massachusetts, and from there he went toYale from which he graduated in 1821. From 1821 to 1824 he taughtschool in Kingston and Catskill, New York, and in 1824 he began thestudy of medicine while teaching at Durham. New York. Droppingthe study of medicine in I 826, he entered the Auburn TheologicalSeminary, graduating in I 829.

As a minister young Baldwin volunteered to join the FourthMissionary Company being made up to go to Hawaii, but thedemand for doctors outweighed the need for ministers, so hereturned to Harvard in I $28- I $29 and attended a course of medicallectures. However, he did not have time to wait for his officialmedical diploma and, at the advice of’ the Prudential Committee ofthe Mission Board, accepted a diploma as Master of Science. In theyears to come, Dr. Baldwin’s lack of a medical diploma was to causehim great embarrassment Although he was obviously as wellqualified as any of his professional peers and practiced for some 27years. the Hawaii Medical Society refused to grant him a licenseuntil he could produce documentary proof of a medical degree. In1859 he belatedly received word from Dartmouth College in NewHampshire that they had granted him an honorary medical degree.

Dr. Baldwin married Charlotte Fowler at Northford. Connecticut.on December 3. I 830. On December 28 the young couple sailedfrom New Bedford. Massachusetts. as members of the FourthMissionar Compan After a ‘ ovage of 161 da s aboard the ‘NewEngland”. they arrived in 1-lonolulu on June 7. 1831.

For the first six months the Baldwins were stationed at Honolulu.and on November 26. 1 X3 I. their lirsi child, David Dwight. sasborn. Seven other children ‘ crc horn to the doctor and his x ife:Abigail Charlottet Mrs. William D .Alcxanderi. Mary Clark. CharlesFowler. Douglas Hoapili. Henry Pcrrine. Emily Sophronia (Mrs.William 0. An atcr. and Harriet Nlelindat Mrs. Samuel NI. Damon).Mary and Douglas died in eul childhood.

In Januar\ . 1832. the Bald ins were assigned to Waimea. Hawaii.where the remained until February, I X35. when the famii movedto Lahaina. Maui. hopeful that the drier climate there would provebeneficial to the throat ailment troubling Dr. Baldwin. When thechance brought little improvement, the doctor took a trip to theSociety Islands. He as cone for six months, returning in Septemher, 1 836. completely cured.

During his years at Lahaina Dr. Baldwin preached every Sundayin Hawaiian at the \Vainee Church and often preaching assignmentstook him to other parts of Maui, He supervised all the church schoolsnumbenng 22 in I 549 md s is instrument il in building m seaman 5

chapel. During the smallpox epidemic of 1853 Dr. Baldwin workedso effecti\ el that out ota total of 10,000 deaths in the Islands. therewere ouR 25t) fatal cases on Maui. In an attempt to cure the cases ofleprosy which he treated on Maui, he became intensely interested inthe disease and experimented with many types of drugs. He was alsoan advocate of all movements to diminish the sale and use of liquorand tobacco, and as the author of an essay on the subject which wona prize offered in the United States .Somehow the doctor found timefor agricultural and horticultural experiments and was a chartermember of the Royal Hawaiian Agricultural Society when it wasorganized in 1850.

In 1856 Dr. and Mrs. Baldwin revisited New England, going byway of Cape Horn and returning on January 8, 1858, via the PanamaCanal. The doctor also made a trip to the Marquesas in 1862 as amission delegate.

Forced to resign in September, 1868, due toparalysis, Dr. Baldwinmoved to Flonolulu in I $70 and he and Mrs, Baldwin made theirhome with their daughter. Abigail. In spite of his disability, thedoctor taught at the native Theological School in Honolulu from

872 to 1177.On January 3. I $86. Dr. Baldwin (lied in Honolulu at the age of$7.

Mrs. Baldwin predeceased him on October 2. 1873.

AWAH MEDCAL. JOURNAL, VOL 62, OCTOBEF..U.UJ

214

Here/i. Baldwin, Dwight. A-8H(. Physicians File.Man,iya tlediea/ Heritage Center, Hawaii Medical Library,

C Commentary

Kimo’s Rulesby Shay Bintliff MD

e eral ears ago, a very popular tee shirt s as printed inHawaii. There were no sandt beaches. beautiful women in

i bikinis or exciting surf scenes No, it was quite simply a

‘iherap shirt”... andit soldlike hotcakes! Kimo’s Rulesconnnuesto he a very popular item, notonlv torthe humor in some of the rules.but mainl\ for the wisdom so simply expressed. See if you don’tagree ith me. Here are Kimo’s Rules:

I. Never Judge a Day by the Weather2. The Best Things in Life aren’t Things3. Tell the Truth,., There is Less to Remember4. Speak Sol’tly and Wear a Loud Shirt5. Loosen Up... The Unaimed Arrow Neer Misses6. He Who Dies with the Most Toys, Still Dies7 Age is Relative... When You’re Over the Hill... You Pick upSpeed8. There are Two Ways to Get Rich... You (‘an Make More or You(‘an Require Less9. What You Look Like Doesi’t Matter... Beauty is Internal10, No Rain... No Rainbows

Ah, such v isdom... and so little time. Mv family will likely neverforgive me. but I startedreading Kimo’s Rules to m granddaughter.lleiana. when she was five years old. When she didn t completelunderstand a rule, she would ask the most profound questions. LikeRule #4... she asked, “why do I ha\e to speak softly if I have a redshirt on, Granny. .. maybe I want to shout... hut maybe that will

scare people. yes.”?” And question #2, my all time favorite: “Is a hug

a thing. Granny’? Or like camping out ith daddy on the beach, is thata thing? Cause you knos. those are the best! !“ Nv at age 8. she

constantly reminds us all to ‘tell the truth.’’ and to “alw avs look forrainbow s!” We even made tip a game called “Naine thatrule Oneofus writes down a number, and the other has to guess what rule yourai’e thinking of. If you are wrong, you have to tell a story about thatrule. WOW,,, have I heard some “out of the mouth of babes”Stories!!!

Bringing closure to this moment of joyful sharing for me, I cansum it all up with these words: Kinio has real clarity on what isimportant in our lives. The “Rules” reflect what we all know aboutthe “Aloha Spirit”.., that to be generous and loving, especially withnurseR es, will go a long wa. Kimo’ s Rules are like a large dose ofpositive energy and thinking, the kind of focus that builds strengthand resilience,

Editorial Comment:

Sho,’on SLav [Put/ill ,iD. La CEP, F.4.4P. is Emeritus Profes car 0/

.S’iii’gerv and J—’edioi,’,es at 1/ic John .4. Bu,’,i s .5 c/tool of .Wedieine. Sin’ still

prai licec Emergent-v Medicine a., the lietheiiI Director of the Lmerc’encv

Deparmnient at the Jauio ‘,ele,’aiis lJe,itoria/ Hospi al on Katioi.

Di-. Ilintlit/precented “Kinto ‘s Rules “at the recent Hot .Sjors in Dei’nia—

iol(i gv YtU.’ (0 tutu. ito/i he,’ pert u sion. ne n/c pre.ceniing the Rule us

i’eade,’s ‘1 the it ‘urnal, She has used in Ka,niu’ln oii the Big tc/amul fin’ the

pits! JO VC(if’3 autil continues “to hate a [till liii’ canoe path/hog, golfing.hi/mt g. and it orking on her Saiidoln-o, l Tree Form,

Until there’s a cure, there’s the American Diabetes Association.

- Until there’s a cure, there’s the American Diabetes Association.

i-AWAH 040DC21 .2uRN0... 0) 2002215

Intestinal Parasites of the PacificA Sm.ai I BA Al an P TI a a A LI*. ‘ a MD PhD’

Authors:*John A Burns School ofMedicine, Honolulu, Hawaii

LaboratoryServIces, Inc., Honolulu, Hawaii“(Preseth atflllationl ChildrensMemorIal Hospital, NorthwesternUniversity, Chicago, llllnols

Cc:rres.ccndevc.eto:

H’-

Abstractobo: ‘-‘cs. “u’ oa.ac’es ‘ Ha::a;

I%cc s [(Cr1 Cu’’O’7. L’c reve:’eo reoor[s on feca3 C dL C r

rocoor)’ “ares ci’ 9.3% ‘ Hau’aU 1-1.2% n Sa;ba”.18% ‘cRora a’d95% Guam Tiverncsr&eouenflv,aenrnr000aras’tes nere Biastocvs S flOnnflS 1/ 6%).Gard:a Iambha (1 2%u. 3r0 Entarnc.eoa cof ‘u, 7%.)..nimo.:ign lire %cdencu 300 ivpes of organthn’rs naeeonanaeo itr Urre. ohvsic:ans Han an snould conhone !ookng for nrestn’ra: rnaras!tes.

IntroductionIntestinal parasites has e been a scourge of mankindfor millennia. The’ has e adapted to numerous habitatsand hosts ss hue spreading throughout the world. Improvements in sanitation and medications, however.has e interrupted their life cycles in man\ instances.Consequently. they have lost their foothold in mimer—otis countries. While the impact of modern medicinehas been dramatic in Hawaii. intestinal parasites remain a common cause of disease. Continued immigration of Pacilic Island and Asian peoples and travelersbring strongvloides. hookworm, and ascaris whilepossibly serving as reservoirs for transrnission, Parasites: may remain asvmptomatic for years or maypresent with symptoms outside the gastrointestinaltract, Some of the most frequently recognized parasites in recent years include Crsptosporidiumparnornand Blastocvstis hono,u.s; they remain threats becauseof their presence in natural reservoirs and public watersupplies.: The chances of eradicating these organismsare small, Both are thought to he transmitted via afecal-oral route. C. paul’uoi has survived in publicwater supplies due to its small size (passes through<I urn filters) and resistance to chlorination,3Controversy exists as to whether B. hominis is a pathogenicversus commensual organism. However, outbreakswith symptoms have been reported:’

The Center of Disease (.‘ontrol estimated a parasiteburden of 20% in the Lnited States during I 957,3 Withadvances in sanitation and medication, surveillanceand t’eportins actis ities ss crc reduced, such that thereis little record of the incidence of intestinal parasites orchanges that have occurred since. In addition. “new”microorganisms are being recoeniicd that are notvisible ss ith standard os a and parasite diagnostic tests.These require special stains and identification techniques in the lahorator . -

Reports of’ intestinal pai’:isnes in Hass au or otherPacific Islands are scarce. Prior publications in I 901and I M7 5 indicated 12 and I 3( recovers rates.’ The1975 study was primaril of school aged children inOahu svith the majority of positis e samples occurrinein ftweign—born subjects.’ Information about parasiticdiseases in other Pacific Islands has been limited toreports of small outbreaks rather than surve\ results.Old reports do not indicate the distribution ofcrvptosporidia. microsporidia or blastocvstis as theyhave only recently been identified and reported aspathogens.

Because of the presence of endogenous parasites inHawaii and the potential for nuportation from otherislands in the Pacific. we set out to gather informationfrom ts o laboratories in Oahu that perform a lai’genumber of tests for ova and parasites front specimenscollected in Hawaii as well as other islands.

MethodsMedLINE was searched for information about intestinal parasites. Attempts were made to contact theministries ofhealth in Hawaii .Austral ia. New Zealand,Saipan, and Guam plus the London School of Hygieneand Tropical Medicine, the Center thr Disease Control, the World Health OrganIzation, and the SwissTropical Institute through web pages and e-mail.

Laboratory information was gathered from Diagnostic Laboratory Services (DLS). a commercial laboratory based in Honolulu and from the microbiology’department at Tripler Army Medical Center (TAMC).DLS processes samples from all the islands of Hawaiiand from Guam, Saipan. and Rota. it was not possibleto determine whether samples submitted by Hawaiiphysicians were taken ‘from patients residing outsideof Hawaii, TAMC receives samples from militarybases all over the Pacific: hosses em. samples were notidentified by geographic source. Both laboratories arecertified by the College of American Pathologists forova and parasite examinations. DLS screens for giar—dia in all samples. but does does not routine lv look foi’cryptosporidium or cvclospora ss ithout a special request. T.-\NIC routinel ‘crcens for giardia in allsamples, and uses Direct Fluorescence .Antibod DFAstains to screen for giardia and ci’s pto’poridium in allchildren under l’ix e veal’s old. Identification ofblastocvstis. hookss oi’ni. iaeni:i. and Ii,iianu’etw sp,

.- Ian H. Ti ‘e .1.’!!)

216

was part of a routine parasitology work up at bothlaboratories, This included examination of stools withstandard concentration and permanent staining methods. Laboratory records for stool samples collectedfor ova and parasite examinations were accessiblefrom October 1, 2001 until March 1, 2002 throughDLS, and November 2001 through February 20(2 forTAMC. It was not possible to determine the reason forordering tests nor the frequency with which fecal ovaand parasite examinations were done in any specificpopulation.

Information about specimens was collected withoutpatient identifiers. The study was considered exemptfrom the Department of Health and Human ServicesRegulation regarding patient confidentially and informed consent by the Committee of Human Studiesat the University of Hawaii.

ResultsFindings for specimens reported are displayed in table1. Results demonstrate a percentage of parasite recovery in all specimens from Saipan (14.2%), Guam(9.5%), Rota (18.5%) and Hawaii (9.3%). The percentage of positive results was 11.0% in DLS samplescompared to 7.4% in samples from TAMC. Personalcommunication revealed that the majority of TAMCsamples are from active duty, active reserve, retiredmilitary personnel or their families.

The types of parasites identified by the DLS andTAMC labs are also presented in table 1. The parasiterecovered most frequently was B. horninis found in60.9% of positive stool samples in Hawaii and 50-77% in other Pacific islands. Giardia was only recovered in 10.7% of positive Hawaii samples and 0-50%in non-Hawaii Pacific Island samples. Entarnoehahistolvtica was found in samples submitted from physicians in Hawaii. Cryptosporidium was not reportedin any sample from DLS or TAMC. Ascaris, necator,taenia, trichuris and other helminths were infrequentfindings. Strongyloides stercoralis was only identified in one sample from Guam and one from Saipan.

DiscussionThe system used in this study is not able to determinethe true incidence or prevalence of intestinal parasitesin the different populations studied. To do so accurately would require large surveys of the peoples of theregions reported which would not he practical. Furthermore, it was not possible to determine whethersamples submitted from geographic regions represented follow-up samples from individual patients,thus falsely raising or lowering any calculations ofprevalence or incidence. However, the data collecteddoes provide current information about the primarypathogens recovered from various regions in the Pacific, allows for rough comparisons of recent resultswith old surveys, and demonstrates trends which may

appear to be taking place over the last 27 years.Conclusions based on this data are limited in that thecriteria for collecting the reported specimens are notclear and undoubtedly vary from one source to another.

There has been an apparent decline in the identification of ova and parasites compared to the older studiesof 1974 and l9$7. ‘ This likely reflects improvedsanitation, public health measures, and modern anti-parasitic medications. Giardia was reported to he themost frequently identified intestinal parasite in theUnited States.° It was found in 7.2% of all reportedstool samples in 1992 with the greatest recovery rateoccurring in the Midwest. Desowitz identified giardiain 4. I % of samples taken from Hawaii school agedchildren in l974. A recent overall decrease in recovery may be due to greater public awareness of giardiain outdoor waters and travel safety measures. Childrenages 0-5 years old, as used in Desowitz’s study.demonstrate ahigher incidence than otherage groups.The prevalence of giardia in the United States may heunderrepresented since only 20-50% of patients showsigns of illness and patients may not shed cysts in theirstool on a daily basis.’’ It is unlikely that giardia isunderreported in this study as DLS and TAMC routinely screen for the protozoan during standard ovaand parasite detection procedures.

The recovery of Strongvloides stercoralis in Guamand Saipan reinforces the need to look for parasites inimmigrants from these regions. The nematode is foundworld wide, but primarily in tropical climates. Patientsmay remain asymptomatic carriers for many years.Serious disease may occur in asymptomatic patientswho later become immunocompromised. StrongvIonic’s may also cause a variety of extra-intestinalsymptoms including cough. pruritis. and weight loss.Hyperinfective strongyloidiasis is often fatal inimmunocompromised individuals: frequently leadingto acute respiratory distress syndrome and E. colisepticemia. It may he beneficial to screen forStronvbides in patients who are HIV positive or about tobegin immunosuppressive therapy, particularly if theyoriginate from or traveled to an endemic region.

The discovery of B. horninis as the most frequentlyrecovered parasite is of interest. It was reported in only2.6% of all stool specimens in the 1987 CDC nationalsurve,’° Desowitz did not report B. horninis in 1975,likely due to differences in laboratory staining andreporting requirements. Over the last 25 years, numerous studies have been undertaken to determine whetherB. honnnis is responsible for gastrointestinal disease.Amin recorded B, horninis as the most frequentlyidentified parasite (23%) recovered from 2896 patients in the United States during 2000,k Doyle reported diarrhea. flatulence. and abdominal pain in agroup of 143 patients with B. honunis as the onlyidentified organism on studies for bacterial and para

HAWAH MEDOAL JOURNAL, VOL. VA. 00 LONER 2EO3217

Table 1 —Percent recovery of parasites from positive stool samples submitted for ova and parasites to Tripler Army Medical Center (TAMC)and Diagnostic Laboratory Services (DLS). Samples from DLS were collected between October 1 2001 and March 1, 2002. Samples fromTAMC were collected between November 27, 2001 and February 27, 2002.

Stool Samples from Diagnostic Laboratory Services

Stool Samples fromTAMC, N277

Hawaii, Guam, Saipan, Rota, Tinian,N=2394 N652 N1583 N=27 N=8

Total Number Positive —

Stool Samples20 225 6i 230

Parasite

81 t t’ h 8 of 20 137 of 225 34 of 67 178 of 230 3 of 5 1 of 2as ocys is ominis (400°’l (60.9%) (507%) (77.4%) (60.0%> (50.0%)

E t b2 of 20 19 of 225 4 of 67 8 of 230 0 of 5 0 of 2

namoe a coi (10.0%) (8.4%) (6,0%) (3.5%) (0.0%) (0.0%)

Et b hIlt’Oof2O 13of225 3of67 2of230 Oof5 Oof2

namoe a Isoytca(0.0%) (5.8%) (4.5%) (0.9%) (0.0%) (0.0%)

H 0 of 20 1 of 225 0 of 67 0 of 230 0 of 5 0 of 2ymeno apsis nana

(0.0%) (0.4%) (0.0%) (0.0%) (0.0%) (0.0%)

8’ d’8 of 20 24 of 225 11 of 67 18 of 230 0 of 5 1 of 2

iar ia sp(4u00’ >0 1 >164%> 78 ) 00 >500/1

Ac 1 of 20 2 of 225 1 of 5 0 of 2oars p ‘50 (0° ,2°0 > 00%

TaeniA sp,

sitic pathogens. Otherstudies maintain acommensualrole for the protozoan.5 The mcreased recovery offl.Iioininis sho n in our study is in part due to improvedlahorator methodolocv. DLS also began routinelyreportin B. hominis in I 998. However, it is alsopossible that the organism is be coming more frequentin Hawaii as a result of contamination of public watersupplies and s aning standards for water puritication.

There was a low recovery rate for F. histolvricu inHawaii, Comparisons with prior national studies arelimited by the study methods. Differences in immigrant populations and the protozoan s they often carryalso prevent us from making conclusions about recentnational and local trends.

Crvptosporidium was nut reported in our data setseven though there was a O.2i recos er rate from stoolsamples submitted to diagnostic laboratories in the1987 national survey. ‘ Crvptosporidium has receivedmore attention as a cause of chronic, profuse waterydiarrhea in inmiunocompromised populations. Theorganism has also been the cause of several largewaterborne outbreaks of gastroenteritis. it has a lowinfectious dose. is capable of passing through man\water purification filters, and is resistant to chlorination treatments.iS Detection for cryptosporidiurn isalso still suboptimal in many laboratories. Currently,DLS does not routinely screen for crptosporidium.cyclospora. or microsporidia , .Special requests mustbe made in order to identify these organisms in submitted stool samples. TAMC routinely screens forcrvtosporidium only in children tinder 5 years old.

The discrepancy between the recovery rates inTAMC and DLS samples are best explained by thedifferent populations the laboratories service. Samplessubmitted to TAMC are primarily from military andretired military with dependents who reside in Hawaii. In contrast, the samples fi’oin DLS are likelyfrom native residents or from immigrants from otherislands in the Pacific,We are unable to compare the recovery rates ofintestinal parasites between Hawaii and non-HawaiiPacific Islands. However, limited resources in sanitation and medication, as well as the natural presence ofthese pathortens in developin nations give theseregions a relatis clv high pres alence of intestinal parasites.Intestinal luirasites continue to be a challenge toclinicians in Hawaii. Although the classic pathogen’.are recovered less frequently. thc ma\ continue to heimported b recent or past immigrants. The situationis further complicated by the ability of some parasites

to produce no intestinal symptoms and to mimic otherdiseases for which parasites are not suspected. Patients with acute orchronic intestinal symptoms shouldhe studied flr parasite infections as part of a completework-up. Patients without smptoms who spent significant time in Pacific Islands other than Hawaii alsobenefit from ova and parasite screening.

AcknowledgmentsWe gratefully acknowledge the assistance of Mr Bardwell J.Eberly. Department of Pathology & ALS at Tripler Army Med:colCenter for nis contributions in provioing data for this article.

References5

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The American

DiabetesAssociation

219

Lamivudine Prophylaxis forChemotherapy Induced ReactivationHepatitis B: A Case Report and Review

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AbstractReact.vator? t?COOi/iS B as a resu:t o ccsrnotheracr

a ceo r> j”Q ow, . S IL

tOe rned,ca ‘terature Corn iicaticns range frornanicteric hepattstc fulrnnant hepatic ta/ore aria deathAlthough iamivudine has been successfully used totreat hepatitis B reactivation in cancer oatients its roleas prophy/axis in these patients is less well defined.

We describe successful lamivudine prophylaxis ofa patient with chronic hepatitis B undergoing chemotherapy for acute myelogenous leukemia (A ML). Wesupport the position that lamivudine may playa significant role in the successful prevention of reactivationhepatitis B in cancer patients undergoing chernother.apv.

The views espressedin this manuscript are those ofthe authors and do not reflect the official policy orpositIon of the Department of the Army. Department ofDefense. or the LI S. Government

IntroductionReactivation hepatiti sB in cancer patients undergoingchemotherapy is well documented in the literature. Inthe setting of chemotherapy-induced immunosuppression, reactivation of hepatitis B can lead to a spectrumof adverse outcomes including fulminant hepatic failure and death. Lamivudine, a reverse transcriptaseinhibitor, has been used to treat reacti\ ation hepatitisin this subset of patients. Although prophvlaxis is

otten suggested. reports arc rare. We describe successful lamivudine prophvlaxis of a patient with chronichepatitis B undersoing chemotherapy for acute mvel—ogenous leukemia (

Case ReportThe patient is a 25-year-old female with chronichepatitis B who was diagnosed with AML after evaluation for buccal ecchymosis and extremity hematomas. Initial labs were remarkable for hepatitis Bsurface antigen ([IBsAg) reactivity, hepatitis B virusif-lB V) DNA ol .1)3 pg/mI, aspartate arniuotransferasei .-\ST)of69 [IL. and alanine arninotransferase (ALT)of h2 [/L.

She began prophv lactic treatment ss ith lamivudineprior to induction chemotherapy with daruhicin andcvtarabine. Proph axis was continued throughout the

subsequent consolidation chemotherap . which included fourc clesofhieh dosec tatabinc. \side fromses erul episodes of neutropenic fes er. she toleratedthe chemotheraps well. Althou 11 the patient hidpersistentl\ I ated li\ er associ t d en/\ mes \l Ttingin om 68 to 7 1 IL and AST ran ‘ing 1mmto ISO [IL) HB\ DN \ 1ev 1 r tn in d undetei.. abland th pan nt had no clint all si nih ant h patiequ lae.

Dut im h r ninth month of trcatm nt th pati nt hada Pt olony d p nod of panc top ma v ith hone mat tohiops show in a i elapse of her AvlI . \ftei failedteinduction with mito\antrone and etoposide. the patient was schduled for an al Iogenetc bone mat rowtransplant. At that time, the patient’s li er associateden/i mes included an AST of O [IL and an \1 Tot 6%f-/I . HBV DNA leels were still undetectable. 1 hehighest le els of transaminases occurred during induction and retnduction and were thouuht secondaryto chemotheraps induced hepatoto icit (Figure h

DiscussionA spectrum of liver injury is associated with chemotherapy, ranging, from anicteric hepatitis to fulminanthepatic failure and death. Etiologies include viralhepatttts. drug hepatoto\icitv. malignant hepatic tnftl—trat it ‘n. shock, sepsi. and crvptovenic cause.A growing body of’ literature has concentrated on the ad erscoutcomes of chemothet’apv patients with iral ht.’pati -

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Reacti ation hepatitis B in cancer patients receivingcvtotoxic chemotherapy is vell reported. Althoughmost cases have involved hematological rnalignan—cies (ie. lvmphomaL occasional cases involving solidtumors ha e been reported as well. In a I 991 retrospective study of Chinese lvmphoma patients. 27%were found to he HBsAg seropositive. Of these patients, 47% developed reactivation hepatitis duringchemotherapy. which resulted in a 5% mortality.2 Ina similar Japanese study. 3.3% of lymphoma patientswere found to have chronic HBV infection .Seerehepatitis occurred in 53% of these patients and mortal—tv rates were as high as 24%. In 2000. Yeo et al.

conducted the first prospective assessment of HBVreactivation rates in Chinese cancer patients recei ingc\totoxic chemotherap. In this study. 12% of 626consecutive cancerpatients were HBsAg positive, andreactivation occurred in nearly 20% of these patients.This data clearly supports the need for in depth assessment of this adverse process. Of note, hepatitis Cinjection has also been documented in associationwith chemotherap —induced hepatitis. and mortalit\rates appear to he similar to that seen in patients withHBV reactivation.

There are two proposed mechanisms ofreactivationhepatitis B in cancer patients undergoing c totoxicchemotherapy. The first involves immunosuppres—sion, enhanced KBV replication, and direct hepatotoxicity from infection. The second mechanism involves a rebound immune response upon withdrawalofchernotherapv. resulting in hepatocyte destruction.

Attempts to identify risk factors for reactivationhepatitis B ha e produced conflicting results. A 190study of 105 lvmphoma patients b Liang et al. con—eluded that age, sex, stage. symptoms. lvmphomasubtype. presence of hepatic lvinphoma. treatment.presence of HBcAg and anti-H13e serologies. andunderlying liver pathology \ere not predictive ofhepatic complications.5However, a prospective studyby Yeo et al. identified several significant associatedfactors. These included male sex, younger age. presence of lymphoma. chernotherapeutic agent (mostcommon being corticosteroids. anthracvclincs. cvclo—phosphamide. and ‘ inca alkaloids), and HBeAg posi—ti\ itv (although %ome virulent precore mutant strainsare unable to produce the eAg and are still highlyassociated v ith fulminant hepatic failure

Perhaps the most promising treatment for reactivation hepatitis in cancerpatients is the use of lami udine(3-thiacytidine), areverse transcriptase inhibitor, Thisnucleoside analog, originally used for HJV infection,was found to reduce KBV DNA to undetectable les elsin 86% of I-IlV infected HBV carriers ithin t omonths. Several successful pilot studies and fourlarge multicenter randomized control led trials sho’ edthat lamivudine therapy va’ associated with an in—creased tate of HBeAc serocon\ erion. impro ed

serunt ALT levels and liver histology, and a decreasein the development of eiThosis.’ - In addition to itsefficacy. lamivudine was associated with few if anyside etfects.r The drug was approved as therapy forHBeAg positi e chronic hepatitis B patients in 1998.Lamivudine’s role has subsequently been broadened

to treat chemotherapy-induced reactivation hepatitisB. There are at least 13 documented case reports ofsuccessful lamivudine treatment of reactivation hepatitis. including those patients with fulminant disease.4

Lamivudine may also play an important role asproph laxis for chronic HBV cancer patients prior tochemotherap . B’ suppressing HBV DNA replication(as evidenced by histology and HBV DNA levels).lami vudine prevents hepatocvte infection, the reboundimmune response. and subsequent reacti\ ation hepatitis. Several case reports (including our own) and tworecent studies, give direct support to this proposal.8In our patient, HBV DNA levels remained undetectable throughout chemotherapy, and transient elevations in her liver enzymes were secondary to chemotherap —induced hepatotoxieitv. In a retrospective Israeli study. 13 FIBV infected cancer patients wereprophylactically treated with lamivudine prior to andfollo ing immunosuppressive therapy, with a meanfollow—up of 2 1 months. None of the patients hadclinical or serological evidence of HBV reactivationduring or after prophvlaxis. Likewise, in a prospectiveItalian study, 20 consecutive patients with HBV andhematologic malignancies were prophylacticallytreated with 100 mg of lamivudine from the start ofchemotherapy until one month after the end of treatment. Only one patient developed reactivation hepatitis during a median follow—up of six months.

Several unresolved issues regarding lamivudineprophvlaxis need to he addressed. Specificaii. optimal dose, duration of therapy, and resistance havebeen investigated in chronic HBV patients, but not inthose patients undergoing chemotherapy. In a oneyear trial of lamivudine. Lai et al. showed that 100mgdaily was more effective than 25 mg in the extent ofhistologic improvement, degree of HBV DNA suppression. and prevention of fihrosi. - Duration oftherapy and resistance have also been studied extensivel . as prolonged lamivudine therap allows forgenot pie mutations in the YMDD locus of HBV thatconfers a reduced sensitivity to lamivudine, Resistance rates at one, two. three, and four years are 17%.40%, 55%, and 67%. respectively. These patientstypically have higher ALT and HBV DNA levels thanthose ithout resistance. but levels on average are stilllower in affected indi iduals than their pretreatment

alues. Continued histologic improvement is alsoseen ith extended therap regardless of YMDDresistance, as evidenced by liver biopsies from patients treated with t o or more years of lamivudine inthe .\%ian 1uiticenter trial. - In addition. a large co—

HAWAS MEENCAL. JOURNAL. VOL 62, OCTOBER 200322

hon study showed no increased incidence of hepaticinsufficiency or change in adverse events noted with

the YMDD mutant I-IBV. Therefore, while prophy

laxis nn ith 100mg of larnivudine for extended periods

of time seems safe and effective in chronic HBVpatients despite YMDD resistance. randomized double-blinded trials will be needed to better assess theseissues in cancer patients undergoing cvtotoxicchemotherapy

ConclusionThere are 400 million cases of hepatitis B worlcks idewith prevalence rates in chemotherapy patients re

ported at 12%. Reactivation hepatitis occurs in 20-

50% of these patients and is a potentially lethal com

plication, with mortality rates documented as high as

25% in affected individuals. Lamivudine therapy,

originally used in HIV patients and then approved for

HBeAg chronic HBV, has now been used to success

fully treat reactivation hepatitis B in chemotherapypatients. We support the position that lamivudine

should also be used as prophylaxis to prevent reactivation hepatitis in cancer patients, and we provide a case

report of successful lamivudine prophylaxis.

References1 Yeo W, Chan P. Zhong S, et al, Frequency of Hepatitis B Virus Reactivation in

Cancer Patients Undergoing Cytotoxic Chemotherapy: A Prospective Study of626 Patients With ldentificaton of Risk Factors, J Med Virol 2000: 62(3): 299-307.

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<AADzi.xux

AMERICAN ACADEMY OF DERMATOLOGY

Medical School Hotline

Student Profile: Class of 2007John A. Burns School of Medicine

(JABSOM)

Satoru Izutsu PhDSenior Associate Dean

Chair, Admissions Committee

ii August 1 . 2003. sixtv-t\vo ne’ h admitted lirst yearmLdiL il students m lrLhed to the ch tnt of Di K ii mi Biad‘82 JABSOM eraduate into the auditorium at the Hawaii

State Convention Center. The occasion s as the ‘‘White CoatCeremony” that welcomed the students into the medical commu—nit. Present were family, friends and facult. Each student waspresented a white coat. also called “cloaks ot compassion. bymembers of the Class of’82 on the occasion ot their 25h anniversaryof graduation from JABSOM . in addition, each student received aStethoscope from the Hawaii Medical Association and PacificCardiology, and books. “On Doctoring” from the Robert WoodJohnson Foundation and “Bates’ Guide to Physical Examinationand Histor\ Taking” from the Friends of the Medical School. Theceremony concluded with the administration of the HippocraticOath

The sixty-two outstanding candidates selected were from 1 .284applicants. Of this number, 256 qualified tohe interviewed, 156 instate and 100 out-of-state applicants. The final roster is made up of56 in-state and 6 non-residents. Sixty percent are women, theaverage age is 25, and 24% are reapplicants.

The entering class is ethnically diverse (self-declared) withMixed/Other Asian 13, White 11, Filipino 9, Japanese 9, Chinese 7,Native Hawaiian/Other 3, Native Hawaiian! American indian!Filipino/Other 1, Native Hawaiian/Samoan!Other I, Korean 2,Taiwanese 2, Filipino/Japanese I, Other Pacific Islander/Asian I.Samoan!White 1.. and no response 1.

Twenty-three attended colleges in Hawaii and 39 are from mainland colleges. The colleges include: University of Hawaii at Manoaand Hilo, University of Washington. University of California—LosAngeles and San Diego, University ofSouthern Califtirnia. ClaremontMcKenna College, Cornell University. Occidental College. Universitv of Notre Dame. University of Puget Sound, i3randeis. Brighamoung University—Hawaii and Utah, Chaminade. Christian Brothers. Emory University, Franklin and Marshall College. Gonzaga.Hass au Pacific University, Loyola Marymount Unis ersitv. Montana State University, Mount Holvoke College. North estern liii—versitv. Pomona College. Rutgers Universit . Tulane Lni\ ersit.Lni crslt of Massachusetts, Universit\ of \lichigan. [ni\ ersit\ ofPcnns Ix ania. Lniversit of Portland. tniversit of Southern California. \ a’.sar CoIlev’e and Welleclev College.

Over forts—live percent of the cla”s maorcd in Biology ss oh acomhmncd or minor emphasis in cell and molecular. icuroscience.psvcholov. chemi.trv. phvsioloes . public health, and folklore and

folk life. Other majors represented are psychology, economics.microbiology. anthropology and human hiolog . bacteriology, biomedical eneineering. chemistr . computer engineering, dietetics.epidemiolog. medical technolog\. Mandarin, nutrition, physics.psychobiology, public health. Sociology, and speech patholocu andaudiology . Allstudents completed their pre-med science requirements. One student with no Baccalaureate degree was accepted.Eleven students have their masters’ degree and one has a masters anda doctorate.

The median scores for the entering class are: cumulative GPA.3.63: Science GPA 3.54: MCAT total 28: Verbal Reasoning. 9:Physical Sciences. 9: Writing Sample. 0: and. Biological Sciences.1(1.

The 11-member Admissions Committee rated all of the 256interviewed applicants. The Committee was composed of 6 womenand 5 men: 8 clinicians, 2 basic scientists and one social scientistwho represented the major ethnic groups in Hawaii. This group met21 times to examine the records of each applicants that consisted ofthe academic transcript, MCAT scores, essays and the interviewersreports. The applicants were discussed. after which each committeemember submitted a secret ballot by rating the applicants from 1-10.The ratings were given to the Registrar who averaged the ratings andset them aside. At the end of April. when all of the applicants hadbeen rated, the applicants were ranked. Fifty-two applicants wereoffered acceptances. The alternate list was determined by theDean’s Office. Joining the 52 selected candidates were 9 graduatesfrom the Post-Baccalaureate Program, Imi F1o’Ola. These 9 students completed successfully a year of intensive review of materialuseful in medical school and prepared to matriculate into the firstyear.

Sixty-two students with their white coats and stethoscope in handhave begun an exciting journey toward becoming physicians. Theyare sure to recall the Oath of Hippocrates that they repeated duringthe “White Coat Ceremony”, “I will remember that caring for thepatient will be my primary concern and while doing so I will honorthe autonomy of the sick. I will recogniie that such caring requiresmy being available, giving my time generously, communicatinghonestl .and comforting as well as treating. Such care also ins ols esotlering my support to m patients’ lox ed ones.’’

References

223

LIb Cancer Research Center Hotline

Targeting Oncogene Expressionin a Childhood Cancer

Matthew C. Tuthill, PhDJunior Researcher

Cancer Research Center of Hawaii

Randal K. Wada, MDAssociate Researcher

Cancer Research Center of Hawaii

Neuroblastoma is a common solid tumor ofyoung childrenNeuroblastoma is a childhood cancer originating in pluripotentnerve cells from the neural crest that normally give rise to thepostganglionic sympathetic nervous system. It is the most commonextra-cranial tumor in infants, with 600 new cases diagnosed in theUnited States annually. In children neuroblastoma represents I 0of all tumors, hut is responsible for more than 15% of pediatriccancer deaths.

One reason for this discrepancy is that in the majority of cases. thetumor has already metastasized by the time of diagnosis. Unlikeother forms of childhood cancer, advances in theraps. have onlyrecently begun to yield an increase in survivorship for neurohiastoma patients with the more aggressive forms of disease. Since mostneuroblastoma patients are infants and oung children, the need forless toxic vet more effective therapy is especially important. Someof the major challenges that are being addressed are how to balancethe effectiveness of treatment and side effects from radiation!chemotherapy with long-term patient health. Nev approaches capitalize on the emerging insights we have gained into the biolog\ of

tins tumor.

Neuroblastoma can regress, or mature to abenign formOne of the most remarkable and unique features of neuroblastomais the occurrence of complete spontaneous regression, or differentiation. In fact, despite its aggressive behavior in the majority ofpatients. neuroblastoma exhibits the highest rate of spontaneousregression of any human malignancy. Tumor regression is most

comrnonl observed in infants. while tumors in older patients call

differentiate into benign ganglionenroblastoma or ganglioneurorna.Neuroblastoma thus provides an interest ini model system for thede elopment of differentiation therap that could he less debilitating than conentional ehernotherap . et increase un ivorship.

Retinoic acid turns off the N-myc oncogene, akey step in inducing differentiationExperinwntail\ . cultured neuroblastoma cells can be induced to

differentiate by a number of agents. including retinoie acid.

phenylacetate, gamma interferon, and vitamin D An early. key

event in the differentiation process. both in tumor cells exposed to

retinoic acid and in normal fetal neuroblasts during neuronal des ciopment, is a decrease in N-myc oncogene expression. In turn, N

rnvc downregulation immediately precedes growth arrest, and is

followed by morphologic and biochemical maturation (neurite

extension, neurotransmitter biosynthesis, nerve impulse conduc

non). In patient tumors. actis ation of the N-myc oncogcne is

associated with aggressive disease, including tumor metastasis.resistance to chemotherapy, and rapid tumor progression. In the

laborator . if N—nivc dosvnregulation is prevented by the introduction of exogenous N-myc genes. retinoic acid-induced differentia

non can he blocked. Conversely, decreasing N-rnsc expression by

specific anti—sense oligonucleotides induces tumor cell differentia—

tion even in the absence of any drugs. Thus, regulation of N—myc byagents such as retinoic acid appears to he an important factor in

determining the biological behavior of this tumor.

Retinoic acid improves patient survivalClinically, differentiation therapy with retinoic acid has been 5110w nto have its greatest benefit in tile setting of mmimal residual disease.

following gross tumordebulking by chemotherapy. surgery, autolo

gous stem cell transplant, and radiation therapy. Patients treated

with retinoic acid have a significantly higher survival rate than those

receiving the same therapy without retinoic acid. With multi—modalconventional therapy, stem cell transplant, and retinoic acid, thecuiTent 5-year disease-free survival rate has increased to approximately double that of historical controls,

Retinoic acid resistance is associated withpersistent N-myc expression\\ hile new tindngs on the cluitcal usefulness of retinoie acid

represent encouracing prouress. a cigniticant number of childrennonetheless suffer from tuntor relapse, and sursival in patients w ohdisease prcgrecston is dismal. Based on cell culture and anitrtal

ifiOdds, a potential cause 01’ failure may he the development ofreti note acid resistance. involv itIC loss of tile ability to dovitregulate‘s-tllve expresston.

COfltifllft i UT

HAWAS MED WAL JD.LH.!. A.. WA CATDEEH 20)3.

224

Understanding the molecular regulation ofN-myc transcriptionPart of our work at the Cancer Research Center of Hawaii has focused on gaining anunderstanding ofthe molecular switch that turns the N-mvc gene off in response to treatmentwith retinoic acid. A decrease in N-mvc expression appears to he necessar\ for differentianon to proceed. Our data cuagest that mutation in the control region, or promoter. of theN—rn c c’ene result in the recruitment of alternative transcription factors. \—mvc mRNAproduction is thusdri en by aditierent set of regulatory proteins than in the normal promoterwith wild type sequence. Unlike the usual proteins, those associating with mutant promotersmay he unaffected by retinoic acid, so that treated cells bearing these mutations can nolonger shut the N—ms c gene off and continue on ith the ditferentiation proerain. PersistentN-mc expression. even in the face of retinoic acid, would confer a gross th advantage onthese cells, and contribute to their chentotherap\ resistance. Clinically, such factors maunderlie the process ot tumor relapse and disease progression.

Clinical applications of mechanism-basedresearchThrough determininc the mechanism of \—mve doss nregulation h retinoie acid we hope toderive a set of moleculardiagnostics that will allow us to examine tumor DNA lorsignificant

promoter mutations, and use this information to gauge patients’ prognoses with respect totheir potential responsiveness to retinoic acid. Rather than using retinoic acid as the defaultdrug to deal v ith minimal residual disease, patients at risk for treatment failure could betriaged to receive new nivestigatis e therapies. Identification of the alternate proteins thatmediate N—ms c transcription in retinoic acid—resistant cells may suggest agents that wouldbe effective even on N-myc genes with mutant promoters. Ultimately these drugs could beused in conjunction with retinoic acid, much like we currently combine different conventional chemotherapeutic agents. However, an important distinction would be that the goalofthiscomhinationdifferentiationtherap would he toeffectcurebv “rehahilitating”cancercells, rather than killing them.

Therapy rooted in tumor cell biology, not tumor cell toxicity\llr’r’tilar. iiis’rIi,Iiti’fli liusetl il).icl1s’s silL h i’ hi .iie part ol a ness l\ enieinmgtreiitiiteltl piiidiuiit muted in a basic understiindni’ at Innini biulos . ml ‘hunld tncreaetieitnieni ellieaL\ ss hile rednemg otu\ieiI\ . Vi hile tIn’. isespeciall\ s aluable mtlietheiapat unnv Juldren. I ‘.‘.uns learned in nnrobla’.iunia ifli\ one Ll,l\ bend it adult piliL’i1t5 s ithR iiIfiicIilt’. and ‘.niaii ccii lung caiLnloiuas. sake these iunioi ‘ are iilsuclrl\ en h\ aneugenesal Iheii1\ Iaiutl\. iitJtidine \-iu laritiore ni rinati n.pkasest’.iithe( anerReseatLh(enter’s \s ebsile at 55 iv hare.

References

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225

The Weathervane Russell T. Stodd MD

She Is A Vision At Night, But A Sight In The Morning!The Transportation Security Ar/rn in 1stration of the government is considering the use of techno1og called “hackscatter” at airport security. whichproduces a black and vs lute image that reveals all there is to know All the

clothi ic disappears on the monitor. and univ dense materials such as netal

or plastic produce a darker image than those deflected off the skin. The

agency is vs orking to modify the machines with an electronic “hg leaf’ to

luiz out sensi Liv e body parts. A tria prolect at Orlandt in Florida got in ixed

results frorti volunteers. Some were uncomfortable and reluctant to be so

revealed. but others stated it was a lot nicer than ha ntg someone pat themdown, Randal Null, the agency’s chief technology officer, hopes to conductsome pilot programs this year. Would the hackscatter also reveal if Null

needs to void?

Perhaps His Purpose In Life Is To Serve As A Warning ToOthers.The doctor, a pain management specialist, was called by a patient vsanting

an injection before leasing for a vacation in Greece the following da

Already hooked with a full schedule, the doctor said lie would try to svot’k

him in. The doctor’s morning surger\ vs as prolonged, he had a 25 minutedrive to the surgery center where the patient was waiting, and it all added up

to a three hour wait for the patient. He sued the doctor for $5,000 tocompensate for his waiting time. ‘They (doctors) have to respect people.It was unprofessional” and ‘not nice.” Moreover, he claimed the doctornever said he svas sorry . I.1timatel. a iudize awarded the plaintiff $250 insmall claims court.

The Fee Will Be Cut In Half, And You Lose Control. SignHere To Enroll.It should be no surprise to aitsone viewing the Medicaid system that fewer

and fewer physicians are vvilling tocare for these patients. In Oklahoma. twodoctors and the hospital are being sued because of the death of a five yearold girl. Her pediatrician found that she had polyps in her airway, andpromptly referred her fcr surgery But svait. the pre-op evaluation at thehospital revealed that she had been assigned to a new priinar\ carepediatrician, so the referral vs as challenged. and the surger\ was canceled.In the ensuing delay in seeing her ness physician and 00mg referred for

surger\. the polyps enlarged. obstructed the airway and the child died. Who

gets sued? The doctors and the medical facility are the targets. of course.even though the court records and documents indicate their actions did not

cause the breakdown in care. The state Child Death Review Board l’oundthat the Medicaijggulaiion.s were at fault, and not the doctors. Perhaps theInstitute of Medicine, which found so many allegedly preventable medicalerrors, should look under some Medicaid and Medicare rocks.

Is Doctor Mengele On The Staff, Too?The question to be anssvered is hoss could a physician svho had been suedseven times for malpractice. whose license had been suspended in Okla

homa. his application denied in Kansas. and was underrev iew in Hasv an. getany dud of surgical privilege’.? At oinc point, one cannot help wonderingabout the credcntialiog process at the hospital. In January 2001. this surgeonwas performing hack surgery and required a titanium rod for a spinal

support. Unfortunately, the rod was absent from the surgical tray. and the

nurse informed the doctor that one could he l’lown in from Honolulu.delaying the procedure h Q0 minutes. l3ut, the surgeon. being a man ofaction. could not wait. lie picked up a stainless steel screw driver. sass ed off

a portior and inserted it in place at’ the titanium rod. The operatinc roomstaff was aghast. A fess days later the steel blade snapped. and additional

ureerv svas necessary, The patient became quadriplecic and eventuallydied from complications of his ‘.urgery Tin’, will likely cost 1—1mb Hospital

and the state a bundle.

Astrology Was Invented To Provide Accurate Science ForActuaries.You could lose what’s left of your patience with Medicare reimbursement,

if you tried to understand the accountants and actuaries who decide vs hat

doctors should he paid tortakingcare oh .‘\incrica’s seniorciti/ens. Sourcesvs ithmn the CN IS once cal led HCF.-\ I are prrectin a ranee from 0.b’iiinrrea to 5’ irdnstiomt tom 2rt)4 Rsdurtion — ‘t h’. iu C \lScalculates that it the Grass l.)omestic Product GI)Pi got’s down. as has been

projected, then doctors will need less money to take care of Medicarepatients. This relationship only exists in the minds of lame—brained govern

ment actuaries. Congress’ Medicare Payment Advisory Commission(MedPAC) favcrs a logical system based on providers’ costs and inflationindex, and is ads ocati rig a 2,5’ increase I or the comning year. Fat chance

Bush & Co. are busy tring to defend the tax at and the cost ot making war

in I rag. vs ith no indication to see thai doctors are treated fairly . When etioughph sieianc opt out oh’ caring for N ledicare patmeilts. perhaps the po hlem vs ill

he understood.

Airlines, Yes! Doctors, No!Right here in our island state, the local airlmes. Aloha and Hawaiian.received a sweet exetpfjsyn from the Federal Trade Commission (FTC) in

i’egard topriee—fixing andrestraint of trade And that iswhy the airlines soon

Ibllossed vvith limited andcooperative schedules, and iackedupmheairfares.I low nice for the airlines. Doctors are treated ditferently , In Ariiona. the

FTC’ losvered the boom on the C’arlsbad Physiciaii Association “because the

group includes niost of the doctors in the area. health plans had no choice

but to contract with them.” The group will dissolve. the CEO will he barred

front other health plan contracting matters ,and financial penalties will

ensue. This is the sixth time in the last 18 months the FTC has charged a

group of doctors vvith illegal collective bargaining.

Ah, Alcohol! The Cause Of, And Solution To, Life’s ManyProblems.I,ast year Congm’ess directed the National Academy of Sciences to come up

vs ith regulatory and polic strategies to curb underage drinking. The 12

member panel is expected to reveal its findings soon ss’hich should has e

significant influence, since the academy is s iesved as representative oh

scientific consensus on issues oh’ public health. People close to the scene

think the panel is likely to call for a comprehensive fl.deral strateg\’

including higher excise taxes, limits on advertising, tougher enforcement.restm’ictions on youth access to alcohol in retail stores, and perhaps a media

campaign directed at parents. Lobbyists for the beer and liquor industries

argue that the numbers aredeclining. andthat the seopeof the study’ has gone

ss’ell beyond hat Coneress intended. They claim the industry is very

concerned about underage drinking amid spend millions of dollars a year to

discourage consumption by youth. They are vehemently opposed to ness

taxes. advertising restrictions and efforts to linmit access in retail stores,

Osama Could Not Begin To Accomplish What We Have DoneTo Ourselves!While us taxpayers are seeing billions of our tax dollars each month spread

over the middle east to bring democracy to people who don’t seem to want

it. and also imperiling our youth. Congress has designated $2 billion for

public health “hio—ierrorisni asvareness.” This questionable and foolish.

panicky approach allocates l’unds to stockpile drugs and immnuni,mng

vaccnies.Meansv hile, state and local agencies are forced to cut funds. for

xi’ hools and local medical clinics At the same time .Ashcrott and compan

are tappinc telephones. scannm ng library cards and s’mdeo rentals. arrest i rig

pot smokers .and turning our airports into arnmed corrals vs here the

“livestock’ are probed. unshod and forced into a labyrinth of alleys.

sometimes ending inside an aii’craft. The “war” (in terrorism is over - we

lost. Whatever happened to those people we sent to Congress to represent

ADDENDA+ ,\ccot’dmne to Road andirack. oddsthat an American driver ui a crash will

but a tree are I in 05: odds the driver will he a male 9 in 10.

+ In nullions. the number ot cell phones in Japan: 78, in the 1-S.: t46, am

(‘himia: 175.+ Mixing castor oil with holy vs ater will produce a religious movement.

Si, i’.ntists el urn to has ‘.lonr d a mulo thi Is newst I h ive otten mad’.

an ass of myself...

Aloha and keep the faith —— rts

S.’,:;, i;;;’t ;Irt , -‘lonn, ,I,’ ml ii,’. ,-,cri1y ml!,’, I I/ta 1if’i/li0’’’” /‘iO1l!1/1 01 1/,,

Ito’. iii L/tth,l,,,,1’imaI S’o,’u-ti us/rIo’ Ilaoa,’i ‘iI,’,jti at —i V50,’I,iIl’ii. Izthioro,I

to/rh that .1 rii’ o’ru,

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ABOVE &BEYOND

In uncertain times,seek the high groui’icl

TIMES ARE TOUGH IN PROFESSIONAL LIABILITY INSURANCE—again. Insurers are

restricting coverage, leaving the market and some have disappeared. MIEC was

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MIEC is financially secure, with 27 years experience insuring doctors. We dont chase

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