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`arguments begin to split physicians from patients and from
`each other.
`Recognizing and correcting homophobia may be difficult
`for many, but insisting on actual data regarding transmission
`risk should be easier. Here, with respect to the risk of physi-
`cians acquiring HIV from patients, the data have been in-
`creasingly reassuring. Even orthopedic surgeons, argued by
`some to be at a theoretically high occupational risk, have
`been shown to be free of HIV unless they have had nonoccu-
`pational transmission-prone behaviors. The documented de-
`gree of risk, as opposed to the speculated risk, is insufficient
`as the basis for compromises in patient confidentiality or
`limitations in access to optimal medical or surgical care.
`Similarly, evidence of any benefit to physicians from routine
`nonvoluntary testing and reporting of patients for HIV is also
`lacking.
`Now that data show the limited risk of transmitting HIV
`from patients to professionals, the number of calls for invol-
`untary HIV testing and reporting of patients has decreased.
`Our current situation with HIV-infected physicians appears
`at first to be very different. The transmission of HIV to
`patients in the office of an infected dentist is recognized to
`have occurred. Instead of physicians being afraid, patients
`are now afraid. Instead of patients putting physicians at risk
`because oftheir socially disapproved behaviors, medical pro-
`fessionals are portrayed as irresponsible and selfish and will-
`ing to put their patients in jeopardy to protect their own
`privacy and careers. If opinion polls are to be believed, 90%
`of all adult Americans believe that something needs to be
`done to protect them from their physicians. In a rapid re-
`sponse, especially following the publication of these opinion
`polls, draconian (Helmsian) bills criminalizing the practice
`of medicine have passed the US Senate, and even the most
`moderate positions taken by the Centers for Disease Control,
`the American Medical Association, and the Senate "leader-
`ship" bill would probably eventuate in mandatory physician
`HIV testing, at least in some states, and an essentially forced
`termination of practice. How confident are we that when left
`to local specialty boards, "exposure-prone procedures" will
`not include essentially all surgery? Recall the Chicago physi-
`cian with HIV for whom "invasive" procedures included
`routine oral examination with an instrument no sharper than
`a tongue depressor.
`Is all of this necessary? Will we look back at these mea-
`sures as appropriate and useful in instilling public confidence
`in the medical profession? Or will we see it as an overreaction
`that perpetuates the fractures ofthe medical communities and
`abdicates responsibility for the profession and for public
`health in favor of momentarily popular and political forces?
`Certainly our past experience with physicians' fears of pa-
`tients might have taught that data can be reassuring, not just
`alarming, and that initial reactions in the absence of data
`might be based more on fear and discrimination.
`Given that, what is the strength of the current data on the
`risk physicians might pose to patients? Five patients were
`infected in one dentist's office, but not one of the hundreds of
`other patients of HIV-infected surgeons who have been "re-
`called" for testing are reported to have acquired HIV. Many
`physicians, on receiving an HIV-positive report, immedi-
`ately ask themselves whether they should alter their practice.
`Some have done so, whereas others-again after careful con-
`sideration and consultation with AIDS experts-decide to
`continue their careers, believing that the care they provide
`
`outweighs the remote risk of transmission. Some of these
`conscientious physicians nevertheless live in mortal fear that
`they will be publicly exposed, humiliated, and ruined.
`Most American adults may be afraid, but perhaps they are
`also wrong. Knowing how little data are now available, we
`can at least assume that public opinion is not fully informed.
`We might also believe that it recognizes neither the potential
`harm in taking the wrong steps at this time nor that other
`approaches are possible. The media will forget about HIV-
`infected physicians, as they have forgotten about other
`health-related issues after an amazingly short period. With
`more time and data, public opinion will also change rapidly.
`Most physicians will continue to act in their patients' and
`their own best interests. Physicians will be voluntarily tested
`for HIV in confidential settings, and they will use this infor-
`mation to adjust their practices if they think they pose any
`risk to their patients.
`Meanwhile, the medical profession must stop reacting to
`uninformed political pressure and insist that it can and must
`deal with this issue itself. As voluntary guidelines are estab-
`lished, physicians can vigorously and quickly collect addi-
`tional information. They can develop a consensus about the
`degree of risk that can be tolerated, as is done for other
`common conditions that might impair a physician's perform-
`ance and hence patients' safety. In a sense, the difficulties of
`charting a course on the current debate and the scrutiny phy-
`sicians are under offer unique opportunities. If the medical
`profession succeeds in creating an informed public and polit-
`ical opinion and if rational policies result from this, at least
`some pride in its leadership could be restored. Also, if it is
`insisted that standards of safe physician behavior be devel-
`oped beyond those that simply address HIV, the overall qual-
`ity of medical care can benefit from these efforts.
`PAUL A. VOLBERDING, MD
`Professor of Medicine
`University of California, San Francisco,
`School of Medicine
`Director, AIDS Program
`San Francisco General Hospital
`Medical Center
`San Francisco, California
`
`Liver Transplantation-Challenges for the Future
`ORTHOTOPIC LIVER transplantation (OLT) is the accepted
`treatment of a variety of irreversible acute and chronic liver
`diseases for which no other form of therapy is available.`3
`Liver transplantation was initiated nearly 30 years ago when
`the first human OLT was performed by Starzl in 1963; sur-
`vival for more than a year was not achieved until 1967, how-
`ever. The one-year survival rate following OLT was
`approximately 30% before 1980 but increased to 65% in the
`early 1980s at the University of Pittsburgh (Pennsylvania).'
`These improved results led a consensus development confer-
`ence of the National Institutes of Health to conclude in June
`1983 that liver transplantation was no longer experimental.4
`This conference was instrumental in broadening funding for
`the procedure by health insurance carriers and government
`agencies and in stimulating the development of more trans-
`plant centers, resulting in the increased availability and per-
`formance of liver transplantation.5 In 1989, a total of 2,162
`liver transplantations were done at 69 transplant centers in
`the United States; in 1990, there were 2,656 liver transplants
`performed, a 23% increase over the previous year. In 1989,
`about 60% of liver transplant procedures in the United States
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`were performed at 10 centers doing 5i) or more per year, and
`40% were carried out in the remaining 59 smaller, and often
`newer, programs. Liver transplant programs are now situ-
`ated in most major metropolitan areas in the US, and OLT is
`considered in virtually every patient with irreversible acute
`and chronic liver disease. As demonstrated by Szpakowski
`and co-workers elsewhere in this issue of the journal, new
`liver transplant centers can achieve excellent results-that is,
`an 85% two-year survival.6
`Currently more than 80% of private insurance carriers
`provide liver transplant coverage. Medicare limits coverage
`for the procedure to federally designated medical centers and
`restricts the underlying causes of liver diseases that qualify
`postnecrotic cirrhosis associated with the presence of hepati-
`tis B surface antigen and primary hepatic malignancy are
`excluded. Organ transplantation is an optional benefit under
`the Medicaid program; most states, however, provide cover-
`age for OLT, although about 20% of states limit it to children
`only. Finally, a substantial number of Americans are unin-
`sured, and insurance does not fully cover the total costs of
`OLT. Thus, significant gaps remain in coverage for the pro-
`cedure; the challenge of the 1990s is to close this gap. The
`current 75% to 80% survival rate three to five years following
`the operation and the results of quality-of-life studies show-
`ing that more than 85% of patients are able to return to work7
`should be an impetus to broaden coverage for the procedure.
`Another important challenge, as organ donation rates sta-
`bilize and waiting lists continue to grow, is to increase the
`number of donors. For too many potential liver transplant
`recipients, particularly children, the wait for a donor liver
`proves fatal. It is estimated that between 20,000 and 25,000
`of the 2.2 million Americans who die each year meet age and
`medical criteria that would allow organ donation, but the
`number of organ donors in 1989 to 1990 was only about
`6,000.5 In recent years, several measures have been adopted
`to increase organ donation: incorporating donor cards onto
`drivers' licenses, distributing donor cards by hospitals and
`other groups, and enacting required request laws. More in-
`novative approaches are needed to further promote donation
`and relieve the increasing shortage of organs.
`New operative procedures have been developed in the
`past few years to alleviate the shortage of size-matched organ
`donors for children.8"9 Reduced-size OLT is a procedure in
`which part of the liver graft is reduced by dissecting appro-
`priate right or left lobe anatomic segments and then implant-
`ing in the orthotopic position after total recipient
`hepatectomy. It is also possible to obtain two grafts from a
`single donor, known as the "split-liver" procedure.8 Another
`approach to the scarcity of infant and child donors is trans-
`plantation of a liver graft from a living related donor.9 The
`donor undergoes a resection of the left lateral segment of the
`liver, which is then transplanted into the recipient. Experi-
`ence with this approach is increasing in the United States at
`the University of Chicago Hospitals, and the ethical issues
`are being addressed.
`Introduction of the University of Wisconsin (UW) solu-
`tion is another new development that has revolutionized liver
`transplantation.10 In an experience with liver homografts
`preserved for 4 to 24 hours with UW solution compared with
`grafts preserved for 3 to 9 hours with conventional Euro-
`Collins solution, the UW-preserved grafts had a lower rate of
`primary nonfunction with a reduced need for retransplanta-
`tion.'0 In addition, the UW solution has improved donor
`
`operation logistics, reduced the costs of transplantation, and
`allowed a semielective approach to liver transplantation. In
`the 1990s, we may witness the discovery of even better
`organ-preserving solutions.
`The overall goals of OLT are to prolong life and improve
`the quality of life. The selection of appropriate patients to
`achieve these goals is difficult and inexact, with no uniformly
`agreed-on national criteria. Even more troublesome is deter-
`mining the appropriate timing of liver transplantation during
`the course of advanced chronic liver disease. General indica-
`tions for liver transplantation in adults are as follows'-3: irre-
`versible advanced chronic liver disease, fulminant hepatic
`failure, unresectable hepatic cancer confined to the liver, and
`metabolic liver disease. In addition, there should be no con-
`traindications to the procedure and the patient should be able
`to provide for its costs. The absolute and relative contraindi-
`cations to OLT have evolved over the past ten years of cumu-
`lative experience. The usual absolute contraindications
`include the following" 3: the acquired immunodeficiency
`syndrome or human immunodeficiency virus positivity, ma-
`lignancy outside the liver, uncontrollable infection outside
`the hepatobiliary system, active alcoholism or intravenous
`drug abuse, and advanced cardiopulmonary disease. Relative
`contraindications or conditions that complicate and increase
`the risk of transplantation include advanced age, stage III to
`IV hepatic coma, advanced chronic renal failure, hypoxemia
`from intrapulmonary shunts, portal vein thrombosis, pre-
`vious portosystemic shunt operation, previous biliary tract
`operation, severe malnutrition, and massive ascites.
`Guidelines are needed for referring patients with fulmi-
`nant or chronic end-stage liver disease for OLT. " The opti-
`mal timing of the procedure requires a knowledge of
`prognostic indices and the natural history of each specific
`liver disease suitable for transplantation. The best applica-
`tion of prognostic survival models to the timing and outcome
`of OLT in chronic liver disease has been applied to primary
`biliary cirrhosis, a disease with the most predictable natural
`history.1'213 The application ofthe Mayo Clinic model, which
`includes five independent prognostic variables (serum levels
`of bilirubin and albumin, prothrombin time, age, and the
`presence of peripheral edema), has demonstrated that the
`procedure improves survival compared with supportive ther-
`apy in patients with primary biliary cirrhosis.'2",3 Primary
`sclerosing cholangitis has a less predictable natural history
`because of a fluctuating course and the possibility of cholan-
`giocarcinoma developing, but similar independent predictors
`of prognosis can be identified.'4 Investigators at King's Col-
`lege Hospital in London have proposed specific demographic
`and laboratory criteria for liver transplantation in patients
`with fulminant hepatic failure based on a large and longitudi-
`nal experience. II Separate criteria have been established for
`patients with fulminant hepatic failure due to acetaminophen
`overdose and those with failure caused by viral or drug-
`induced hepatitis. Clinical judgment and assessment of the
`patient's quality of life, important factors not found in any of
`the current models, will likely remain critical in deciding the
`timing of OLT, but they require standardization.
`Immunosuppressive drug regimens vary from center to
`center but generally include corticosteroids, cyclosporine,
`and azathioprine. Corticosteroids are used initially in high
`doses, which are progressively reduced to maintenance lev-
`els of 10 to 20 mg daily during the initial several months after
`the operation and then to 5 to 10 mg daily long term. Cyclo-
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`sporine is administered at a dose to maintain therapeutic
`trough levels, and its use is often begun postoperatively only
`after adequate urinary output is established. Several centers
`use so-called triple therapy with azathioprine, which allows
`the use of lower doses of all three drugs, thus avoiding toxic-
`ity of individual agents. A recent immunosuppressive varia-
`tion is the use of prophylactic OKT3 for 7 to 12 days
`following the operation, with the later introduction of cyclo-
`sporine. In general, however, OKT3 is reserved for episodes
`of rejection. In this decade, three new candidate immunosup-
`pressive drugs have been developed: FK 506,16 rapamycin,
`and 15-deoxyspergualin. FK 506 appears to be the most
`promising, both as an agent to reverse rejection unresponsive
`to conventional drugs and as primary immunosuppressive
`therapy to achieve better patient survival and fewer episodes
`of rejection. Multicenter studies are under way in Europe and
`the United States to determine the efficacy of FK 506 com-
`pared with cyclosporine and to better define toxicity. The
`treatment of rejection episodes following OLT typically in-
`cludes giving a bolus of corticosteroids, sometimes followed
`by an oral recycle of high doses with rapid tapering back to a
`maintenance level, the use of OKT3, and retransplantation.
`These treatments are usually applied in a stepwise fashion.
`With refinements in the indications, timing, and technical
`aspects of the procedure, the scarcity of organs and the pre-
`cise diagnosis and optimal management of rejection loom as
`the major challenges of transplantation.
`There are several controversial areas in liver transplanta-
`tion today. Alcoholic cirrhosis is the leading cause of hepatic
`morbidity and mortality in the US. The major deterrents to
`liver transplantation in patients with alcoholism are concerns
`regarding abstinence after transplantation and the possible
`presence of medical problems associated with chronic alco-
`holism, such as pancreatitis, cardiomyopathy, neuromuscu-
`lar syndromes, or severe malnutrition. In a recent report by
`Starzl and colleagues, of4l patients with alcoholic cirrhosis
`treated with liver transplantation, 73% were alive at one year
`and 68% between one -and three years.17 These results were
`no different from those obtained in 625 adult patients who
`received liver transplants for other reasons. Moreover, of 35
`patients who survived longer than six months, only 2 re-
`turned to active alcoholism. These preliminary results,
`which require verification in other centers and longer periods
`of follow-up, have led to the consensus that patients with end-
`stage alcoholic liver disease should not be excluded from
`consideration for liver transplantation. The current policy of
`many transplant centers is to require some period of alcohol
`abstinence, typically six months, to mandate involvement in
`a structured alcohol rehabilitation program and to verify
`that the patient has a stable and supportive psychosocial
`structure.
`Hepatitis B typically recurs after liver transplantation,
`and the long-term survival of patients (45% to 50%) is sub-
`stantially less than for patients receiving transplants for other
`causes of end-stage liver disease (75% to 80%). 18 Efforts to
`treat hepatitis B infection perioperatively or postoperatively
`with hepatitis B immune globulin or interferon alfa have
`generally failed. Not all centers continue to do OLT in pa-
`tients with hepatitis B, and newer experimental modalities to
`prevent or treat recurrent hepatitis B are desperately needed.
`Although data are preliminary, the hepatitis C status of the
`donor and recipient appear to have little bearing on the subse-
`quent course following the operation. One large retrospec-
`
`tive study found that the loss of antibody to the hepatitis C
`virus (anti-HCV) was frequent and acquisition of anti-HCV
`rare following the procedure. The development of hepatitis
`after transplantation was unrelated to the anti-HCV status.19
`There are no data that suggest a lower survival rate following
`OLT for postnecrotic cirrhosis due to hepatitis C, but longer
`follow-up with surveillance using more sensitive serologic
`assays is needed.
`Although transplantation for hepatocellular malignancy
`has a long-term survival that is inferior to all other indica-
`tions for liver transplantation, selected patients may obtain
`meaningful palliation and even long-term survival. Survival
`is distinctly better in those patients receiving transplants for
`hepatocellular carcinoma compared with that for cholan-
`giocarcinoma.20 Certain tumor types have a favorable prog-
`nosis-hemangioendothelioma, fibrolamellar hepatocellular
`carcinoma, and incidental hepatocellular carcinoma-and
`remain excellent indications for liver transplantation. In the
`1990s, it is desirable that all patients with hepatocellular
`carcinoma be placed on experimental adjuvant therapy proto-
`cols to accumulate data regarding the possible benefits of
`such therapy. Orthotopic liver transplantation for cholan-
`giocarcinoma or for primary diseases metastatic to the liver
`should be considered investigational.
`As demonstrated in the report of Szpakowski and associ-
`ates, transplantation can be carried out with excellent results
`in a new liver transplant center at a private medical center.6
`The two critical factors that determine the success of a new
`program are the training and experience of the transplant
`surgeons and a full institutional commitment. These good
`results may have been influenced in part by selection
`factors-a third of the patients were children, and only one
`patient underwent OLT for primary hepatic malignancy. On
`the other hand, seven patients had hepatitis B; six were rein-
`fected, and three died. It should be pointed out to skeptics
`that all 11 patients with alcoholic cirrhosis survived, and
`only 1 returned to drinking. Finally, the immunosuppressive
`regimen using prophylactic antilymphocyte globulin, cyclo-
`sporine, and low-dose corticosteroids was associated with a
`low rate of fungal and viral infections and likely contributed
`to the excellent outcome of these first 100 liver transplant
`operations.
`
`EMMET B. KEEFFE, MD
`Professor ofMedicine
`Division of Gastroenterology
`Oregon Health Sciences University
`Portland, Oregon
`
`REFERENCES
`1. Starzl TE, Demetris AJ, Van Thiel D: Liver transplantation (parts I and 2). N
`Engl J Med 1989; 321:1014-1022; 1092-1099
`2. Dindzans VJ, Schade RR, Gavaler JS, Tarter RE, Van Thiel DH: Liver trans-
`plantation: A primer for practicing gastroenterologists, parts I and II. Dig Dis Sci 1989;
`34:2-8; 161-166
`3. Maddrey WC (Ed): Transplantation of the Liver. New York, NY, Elsevier, 1988
`4. National Institutes of Health Consensus Development Conference Statement:
`Liver transplantation. JAMA 1983; 250:2961-2964
`5. US Department of Health and Human Services, Public Health Service, Health
`Resources and Services Administration, Bureau of Health Resources Development,
`Division of Organ Tranplantation: Annual report on the US Scientific Registry for
`Organ Transplantation and the Organ Procurement and Transplantation Network, 1988
`and 1989
`6. Szpakowski JL, Cox K, Nakazato P, Concepcion W, Levin B, Esquivel CO:
`Liver transplantation-Experience with 100 cases. West J Med 1991 Nov; 155:494-
`499
`7. Tarter RE, Erb S, Biller PA, Switala J, Van Thiel DH: The quality of life
`following liver transplantation: A preliminary report. Gastroenterol Clin North Am
`1988; 17:207-217
`8. Broelsch CE, Emond JC, Thistlethwaite JR, et al: Liver transplantation with
`reduced-size donor organs. Transplantation 1988; 45:519-523
`9. Strong RW, Lynch SV, Ong TH, Matsunami H, Koido Y, Balderson GA: Suc-
`
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`cessful liver transplantation from a living donor to her son. N EngIJ
`Med 1990;
`322:1505-1507
`Starzl TE: Extended
`10. TodoS, Nery J, Yanaga K, Podesta L, Gordon RD,
`preservation of human liver grafts with UW solution. JAMA 1989; 261:711-714
`11. DonovanJP, Zetterman RK, Burnett DA, Sorrell MF: Preoperative evaluation,
`preparation, and timing of orthotopic liver transplantation in the adult. Semin Liv Dis
`1989; 9:168-175
`12. Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A: Progno-
`sis in primary biliary cirrhosis: Model for decision making. Hepatology 1989; 10:1-7
`13. Markus BH, Dickson ER, Grambsch PM: Efficacy of liver transplantation in
`patients with primary biliary cirrhosis. N Engl J Med 1989; 320:1709-1713
`14. Wiesner RH, Grambsch PM, Dickson ER, et al: Primarysclerosing cholangi-
`tis: Natural history, prognostic factors, and survival analysis. Hepatology 1989;
`10:430-436
`15.O'GradyJG, Alexander GJM, Hayllar KM, Williams R: Early indicators of
`prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439-445
`16. Macleod AM, Thomson AW: FK 506: An immunosuppressant for the 1990s?
`Lancet 1991; 337:25-27
`17. Starzl TE, Van Thiel D, Tzakis AG, et al: Orthotopic liver transplantation for
`alcoholic cirrhosis. JAMA 1988; 260:2542-2544
`18. Demetris AJ, Todo S, Van Thiel DH, et al: Evaluation of hepatitis B virus liver
`disease after hepatic replacement: Practical and theoretical considerations. AmJ
`Pathol 1990; 137:667-676
`19. Read AE, Donegan E, LakeJ, et al: Hepatitis C in patients undergoing liver
`transplantation. Ann Intem Med 1991; 114:282-284
`20. O'Grady JG, Polson RJ, Rolles K, et al: Liver transplantation for malignant
`disease: Results in 93 consecutive patients. Ann Surg 1988; 207:373-379
`
`Molecular Genetics in the Cancer Clinic
`THE INCORPORATION OF modern molecular approaches into
`research on clinical problems is now extensive. Indeed, one
`can hardly read a medical journal these days without at least a
`general understanding of the various techniques in molecular
`biology. This is arguably as true for investigations of the
`neoplastic diseases as it is anywhere, perhaps reflecting a
`relatively early appreciation that malignant neoplasms are, in
`essence, genetic disorders. Many results of "basic" research
`on the molecular mechanisms of oncogenesis are rapidly
`approaching the point of clinical application in the diagnosis
`and management of human cancer. This work is thus of more
`than passing concern to physicians who care for patients in
`their practice with cancer. The literature in this discipline is
`vast and often minutely focused, however, and so is not al-
`ways readily accessible to interested clinicians. In this issue
`of the journal, Koeffler and colleagues have distilled from
`this mass of information a usefully concise and current sum-
`mary of the genetic lesions that have been identified in human
`tumors.' They also touch on many of the ideas that these
`findings have prompted regarding molecular mechanisms in
`the pathogenesis of cancer. Several of the models that the
`authors discuss are particularly useful in their generality. I
`wish to illustrate this point by reviewing some important
`related findings published too recently for inclusion in their
`article.
`Chromosomal Translocations in Oncogenesis
`The finding of a given chromosomal translocation (at the
`cytogenetic level) in multiple independent specimens of the
`same tumor type is strong circumstantial evidence for partici-
`pation of the associated genes in the origin or progression
`phase of tumorigenesis. Molecular analysis of such recurrent
`translocations is a venerable, and still fruitful, approach to
`the isolation of novel genes involved in oncogenesis. This has
`been particularly true for the lymphoid neoplasms, where
`one partner in the translocation is frequently an immunoglo-
`bulin or T-cell receptor (TCR) gene. These can serve as a
`toehold from which it is possible to "walk" across a cloned
`translocation break point to the candidate proto-oncogene.
`Translocations with gene deregulation. As noted by Koef-
`
`fler and associates, juxtaposition of the c-myc locus with the
`immunoglobulin heavy chain(IGH) gene (as in Burkitt's
`lymphoma) may be regarded as the prototype of situations in
`which proto-oncogenes suffer deregulation as a consequence
`of translocation.' In instances such as these, the cognate
`oncoprotein gene products are inappropriately expressed,
`but they are not physically altered. Several recently described
`cases of this pathogenic mechanism have made for interesting
`additions to the list of cellular functions that are apparently
`oncogenic when corrupted in this context. For example,
`BCL2-a gene "activated" by translocation to the IGH locus
`in most follicular malignant lymphomas-encodes a mito-
`chondrial protein somehow involved in governing B-
`lymphocyte lifespan2'3; overexpression of BCL2 protein in
`association with the translocation seems to block pro-
`grammed cell death in this lineage. This leads in turn to a
`pathologically expanded B-cell population by decreased at-
`trition rather than increased proliferation.23
`The BCLI gene, yet another gene sometimes juxtaposed
`with the IGH locus in lymphoid malignant diseases, codes
`for a member of the cyclin protein family.4
`Several of the
`cyclins are known to be intimately connected with the regula-
`tion of cell-cycle progression in eukaryotes. The BCLI locus
`is also amplified (without known translocation) in a number
`of nonlymphoid tumor types.4 The exact role ofBCLI dereg-
`ulation in tumorigenesis is by no means clear at present. It is
`an intuitively appealing notion, however, that cyclin function
`could sustain derangement in neoplastic cells, leading to the
`loss of a normal control of proliferation.
`A recurrent translocation of T-cell acute leukemia situ-
`ates a 7CR locus adjacent to a so-called homeobox (HOX)
`protein gene.5 The many HOX family proteins appear to fig-
`ure prominently in regulating cell type-specific differentia-
`tion during development. Here, too, nothing is certain
`regarding detailed pathogenic mechanisms of tumorigenesis
`supported by the translocation. It is interesting to suggest,
`though, that this is a case where the abrogation of normal
`differentiation (perhaps an interfering effect of the inappro-
`priately expressed HOX protein), rather than a loss of prolif-
`eration control per se, is the root cause of neoplasia.36
`Translocation with protein alteration. Chromosomal
`translocation can also lead to the synthesis of a functionally
`abnormal and pathogenic fusion protein; the BCR/ABL prod-
`ucts in acute lymphocytic and chronic myelogenous leuke-
`mias'are discussed by Koeffler and co-workers as models for
`this mechanism of neoplastic change.' As another example,
`the breakpoint of the t(15; 17) translocation of acute pro-
`myelocytic leukemia occurs in the retinoic acid-receptor-a
`locus (RAR).3 8 This is intriguing because retinoic acid and
`its analogues are known to be potent inducers of differentia-
`tion in primitive myeloid cells.38 The translocation event
`leads to the formation of a protein in which aminoterminal
`sequences of RAR are replaced with those of a previously
`undescribed gene designated MYL.8 While the MYL/RAR
`fusion protein, like the parent RAR protein, can mediate the
`regulation of gene expression by retinoic acid, its function in
`this respect is clearly abnormal.8 It is possible that the MYLI
`RAR fusion protein acts in an inhibitory way in promyelocytic
`leukemia cells by outcompeting normal RAR molecules. The
`latter would otherwise affect progress along the myeloid
`differentiation pathway.38 It has recently been found that
`administering all-trans-retinoic acid induces complete re-
`mission in a large proportion of patients with acute pro-
`
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