Alleviating the shortage of physicians.

A curriculum is described whereby qualified Ph.D's can become M.D.'s within a period of 18 to 24 months. It is feasible and logical not only for us, but for other schools of medicine. It is our belief that adequate safeguards have been included to preserve high quality in education while responding to the need not only for more physicians, but also for improved utilization of some of our best-trained manpower.

Azidothymidine and interferon-alpha induce apoptosis in herpesvirus-associated lymphomas.

Lymphoproliferative diseases that occur in immunocompromised patients are frequently associated with herpesviruses. These patients often fare poorly after treatment with conventional chemotherapy. We reported previously that patients with AIDS-related Burkitt's lymphoma (BL) responded to parenteral azidothymidine (AZT) and IFN-alpha. We found that EBV-positive lymphoma cells derived from these patients cultured with AZT express CD95 and undergo apoptosis. AZT-mediated apoptosis was caspase dependent and occurred despite Fas receptor blockade. In contrast, EBV-negative lymphomas were resistant to AZT-induced apoptosis, as were EBV-positive lymphomas that expressed high levels of bcl-2. Primary effusion lymphoma (PEL) cell lines infected with human herpesvirus type 8 required IFN-alpha to potentiate AZT-induced apoptosis. IFN-alpha did not up-regulate CD95 in BL or PEL but did induce expression of the death receptor ligand, CD95 ligand. AZT-sensitive lymphomas also accumulated significantly higher intracellular AZT monophosphate than did resistant lymphomas. Our data demonstrated distinct apoptotic responses to AZT and IFN-alpha in herpesvirus-associated lymphomas. EBV-positive BL cells that expressed low BCL-2 levels were sensitive to AZT alone; PEL cells required the addition of IFN-alpha to enhance apoptosis, and EBV-negative lymphomas were insensitive to both agents. AZT-sensitive BL cells transfected with BCL-2 became resistant. Susceptibility to antivirus-mediated apoptosis may be exploited to improve the therapy of certain herpesvirus-associated lymphomas.

HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators.

Human herpes virus 8 (HHV-8) has developed unique mechanisms for altering cellular proliferative and apoptotic control pathways by incorporating viral homologs to several cellular regulatory genes into its genome. One of the important pirated genes encoded by the ORF K9 reading frame is a viral homolog of the interferon regulatory factors (IRF), a family of cellular transcription proteins that regulates expression of genes involved in pathogen response, immune modulation and cell proliferation. vIRF-1 has been shown to downregulate the interferon- and IRF-mediated transcriptional activation of ISG and murine IFNA4 gene promoters. In this study we demonstrate that vIRF-1 efficiently inhibited virus-induced expression of endogenous interferon B, CC chemokine RANTES and CXC chemokine IP-10 genes. Co-expression analysis revealed that vIRF-1 selectively blocked IRF-3 but not IRF-7-mediated transactivation. vIRF-1 was able to bind to both IRF-3 and IRF-7 in vivo as detected by coimmunoprecipitation analysis, but did not affect IRF-3 dimerization, nuclear translocation and DNA binding activity. Rather, vIRF-1 interacted with the CBP/p300 coactivators and efficiently inhibited the formation of transcriptionally competent IRF-3-CBP/p300 complexes. These results illustrate that vIRF-1 is able to block the early stages of the IFN response to virus infection by interfering with the activation of IRF-3 responsive, immediate early IFN genes.

Induction of a TRAIL-mediated suicide program by interferon alpha in primary effusion lymphoma.

Gammaherpes viruses are often detected in lymphomas arising in immunocompromised patients. We have found that Azidothymidine (AZT) alone induces apoptosis in Epstein Barr Virus (EBV) positive Burkitt's lymphoma (BL) cells but requires interferon alpha (IFN-alpha) to induce apoptosis in Human Herpes Virus Type 8 (HHV-8) positive Primary Effusion Lymphomas (PEL). Our analysis of a series of AIDS lymphomas revealed that IFN-alpha selectively induced very high levels of the Death Receptor (DR) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in HHV-8 positive PEL lines and primary tumor cells whereas little or no induction was observed in primary EBV+ AIDS lymphomas and EBV-Burkitt's lines. AZT and IFN-alpha mediated apoptosis in PEL was blocked by stable overexpression of dominant negative Fas Associated Death Domain (FADD), decoy receptor 2 (DcR2), soluble TRAIL receptor fusion proteins (DR-4 and DR-5) and thymidine. Trimeric TRAIL (in place of IFN-alpha) similarly synergized with AZT to induce apoptosis in HHV-8 positive PEL cells. This is the first demonstration that IFN-alpha induces functional TRAIL in a malignancy that can be exploited to effect a suicide program. This novel antiviral approach to Primary Effusion lymphomas is targeted and may represent a highly effective and relatively non-toxic therapy.

Splenomegaly as a cause of fecal incontinence. A new problem in an old disease.

Eight patients with fecal incontinence were seen. All eight patients had massive splenomegaly secondary to myelofibrosis and myeloid metaplasia. Six of the eight patients underwent splenectomy for hypersplenism. Five of the six had total improvement of the fecal incontinence. One died two weeks postoperatively and could not be evaluated. In our opinion, the fecal incontinence was related to the splenomegaly. The possible mechanism is discussed. If absolutely necessary for control of fecal incontinence in this situation, splenectomy should be considered.

Strategies to overcome myelotoxic therapy for the treatment of Burkitt's and AIDS-related non-Hodgkin's lymphoma.

BACKGROUND: Strategies to circumvent or lessen the myelotoxicity associated with combination chemotherapy may improve the overall outcome of the management of patients particularly in resource poor settings. OBJECTIVES: To develop effective non-myelotoxic therapies for Burkitt's Lymphoma (BL) and AIDS-related non-Hodgkin's lymphoma. DATA SOURCES: Publications, original and review articles, conference abstracts searched mainly on Pubmed indexed for medline. DATA EXTRACTION: A systematic review of the clinical problem of combination chemotherapy. Identification of clinical strategies that circumvent or lessen the myelotoxicity of combination cytotoxic chemotherapy. Length of survival, lack of clinically significant (> grade 3) myelosuppression and weight loss were used as markers of myelotoxicity. DATA SYNTHESIS: Review of published experience with some of these strategies including dose-modification of multi-agent chemotherapy; rationale for targeted therapies, and the preclinical development of a mouse model exploring the role of metronomic scheduling substantiate pragmatism and feasibility of these approaches. CONCLUSION: Myelotoxic death rates using multi-agent induction chemotherapy approach 25% for endemic Burkitt's lymphoma and range between 20% to 60% for AIDS-related malignancy. This is mostly explained by the paucity of supportive care compounded by wasting and inanition attributable to advanced cancer and HIV infection making patients more susceptible to myelosuppressive side effects of cytotoxic chemotherapy. Investigations and alternative approaches that lessen or circumvent myelotoxicity of traditional cytotoxic chemotherapy for the management of Burkitt's lymphoma and AIDS-related non-Hodgkin's lymphoma in the resource-constrained setting are warranted. Pertinent pre-clinical and clinical data are emerging to support the need for abrograting the myelosuppressive effects of traditional cytotoxic chemotherapy. This can be achieved by developing targeted anti-viral and other strategies, such as the use of bryostatin 1 and vincristine, and by developing a preclinical mouse model to frame the clinical rationale for a pilot trial of metronomic therapy for the treatment of Burkitt's and AIDS-related lymphoma. Implementation of these investigational approaches must be encouraged as viable anti-cancer therapeutic strategies particularly in the resource-constrained settings.

Human T lymphotropic virus type I-associated myelopathy. A report of 10 patients born in the United States.

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) (tropical spastic paraparesis/HAM) has rarely been reported in the United States. We present 10 well-documented cases with positive Western immunoblot test results and polymerase chain reactions for HTLV-I. The clinical and laboratory features of these American-born patients resemble those previously reported series of tropical spastic paraparesis and HAM from the Caribbean and Japan, but important differences were observed. In our study there were equal numbers of whites and blacks and of men and women. Age at onset was younger than that reported from the Caribbean and Japan. Rate of progression to paraparesis varied but was more rapid than previously reported. Half were transfusion recipients but six had multiple sexual partners, with one regularly interacting with prostitutes and reporting a history of drug abuse. Although more rapid progression was seen in the transfusion recipients, this did not explain the earlier age of onset in this group of patients. The HTLV-I, and the associated myelopathy, are endemic in Florida, suggesting that immigration from, and proximity, to the Caribbean basin are contributing risk factors.

HTLV-I-associated leukemia/lymphoma in south Florida.

We report here 10 cases of adult T-cell leukemia/lymphoma (ATL) seen in South Florida between February 1988 and July 1989. All were seropositive for human T-lymphotropic virus type I (HTLV-I) and seronegative for human immunodeficiency virus type 1 (HIV-1). DNA extracted from tumor biopsies/peripheral blood lymphocytes of nine patients was shown by the polymerase chain reaction (PCR) to contain HTLV-I proviral DNA. Blot hybridization of DNA extracted from seven patients with an HTLV-I cDNA probe revealed a monoclonal pattern of proviral integration consistent with a diagnosis of ATL. Eight of the 10 patients were women. Six patients were from Haiti, three from Jamaica, and one from the Bahamas. All patients had very aggressive non-Hodgkin's lymphoma. Two patients presented with sinus and retro-orbital involvement; another had gastric lymphoma that perforated. Nine patients developed hypercalcemia. Eight patients died within 1 year of diagnosis. Two were lost to follow-up. During the course of this study, 66 new cases of non-Hodgkin's lymphoma were diagnosed at this hospital. Ten of these cases were ATL. The prevalence of HTLV-I-related lymphoma in this sample was 15%. Since tissue from all patients was not available for HTLV-I screening, however, it is possible that other cases of ATL went undetected. We conclude from this initial survey that a retroviral etiology should be considered in patients from populations known to be at risk for HTLV-I infection who present with non-Hodgkin's lymphoma.

Association of '(tropical) ataxic neuropathy' with HTLV-II.

Jamaican Neuropathy of the ataxic type (tropical ataxic neuropathy [TAN] and spastic type (tropical spastic paraparesis [TSP]) have been recognized for over a century in Jamaica. The recent association of TSP with HTLV-I (TSP/HAM) is now well established. We now present evidence for a possible association between a TAN-like illness with HTLV-II in four females aged 34-49. All presented with ataxic gait and all four have prominent mental changes. Three of the four also have minor motor deficits with urinary frequency and two have nocturnal leg cramps. All have serum antibody and all had PCR evidence of HTLV-II infection. Antibody to HTLV-II is present in CSF from two subjects. The distinctive picture of prominent ataxia and altered mental status in these subjects contrasts with a predominantly myelopathic picture seen in TSP/HAM.

Tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM): treatment with an anabolic steroid danazol.

Tropical spastic paraparesis or HTLV-I-associated myelopathy is a progressive spastic disorder associated with the human T-lymphotropic virus type I. Some cases have responded to prednisone. Danazol is an attenuated androgen with minimal virilizing effects. It is used in the treatment of endometriosis and various autoimmune hematologic diseases shown to be responsive to prednisone. Because danazol is anabolic, useful in prednisone-responsive diseases, and less toxic than prednisone, we gave danazol to 6 patients with TSP and 1 with HIV, HTLV-I-associated myelopathy. Five patients had a favorable response. Two became ambulatory after having been confined to a wheelchair. Three were able to ambulate greater distances (in walkers) than prior to danazol. Three had noticeable decreases in spasticity. Urinary incontinence resolved in two. Physical therapy was variably employed in all except one patient. Two patients who had not responded to physical therapy responded to physical therapy and danazol. One patient did not tolerate danazol and one patient did not improve. Toxicities noted were mild elevations in liver enzymes in 4 patients; these responded to a decrease in dose of danazol; amenorrhea in one and mild fluid retention in one. We conclude that danazol is a useful agent in the management of TSP.

Identification of human T cell lymphotropic virus type IIa infection in the Kayapo, an indigenous population of Brazil.

Human T cell lymphotropic virus type II (HTLV-II) infection is endemic in a number of indigenous populations in North, Central, and South America. In the present study we have employed serological and molecular methods to identify HTLV-II infection in Indian communities in the Amazon region of Brazil. Sera (1324) from 25 different Indian communities were analyzed by ELISA and Western blot. One hundred and four samples (7.8%) from a number of culturally distinct and geographically unrelated populations were found to have reactivities consistent with HTLV-II infection. Of these, 67 were from the Kayapo Indian communities, which had an overall seroprevalence rate of greater than 30%. In addition, high seroprevalence rates were observed in three other communities, the Munduruku, Arara do Laranjal and the Tyrio, suggesting that there are additional foci of endemic infection in the Amazon region. In the Kayapo, seroprevalence rates tended to increase with age, supporting the importance of sexual transmission of the virus, and family studies demonstrated that vertical transmission is also an important route of infection. Restriction fragment length polymorphism (RFLP) and nucleotide sequence analysis of a region of the env gene demonstrated that the Kayapo are infected with the HTLV-IIa subtype. Moreover, nucleotide sequence analysis of the LTR demonstrated that this belonged to a distinct HTLV-IIa phylogenetic group. The identification of HTLV-IIa in the Kayapo is, as far as we are aware, the first identified endemic focus of infection by this subtype of HTLV-II in the Americas.

Treatment of AIDS-related primary central nervous system lymphoma with zidovudine, ganciclovir, and interleukin 2.

AIDS-related primary central nervous system lymphoma (AIDS PCNSL) is a rapidly fatal disease. Conventional therapeutic modalities offer little and new approaches are needed. Previous work has shown that zidovudine (AZT) in combination with other agents is active in retroviral lymphomas. Epstein-Barr virus (EBV) is detected in tumor tissue and cerebrospinal fluid of AIDS PCNSL patients. In a preliminary in vitro study we found that an Epstein-Barr virus-positive B cell line underwent apoptosis on coculture with AZT. This effect was accentuated by the addition of ganciclovir (GCV). We treated five patients with AIDS PCNSL with a regimen consisting of parenteral zidovudine (1.6 g twice daily), ganciclovir (5 mg/kg twice daily), and interleukin 2 (2 million units twice daily). Four of five had an excellent response. Two patients are alive and free of disease 22 and 13 months later; another responded on two separate occasions, 5 months apart, and the last patient responded with a 70-80% regression of tumor but could not be maintained on therapy owing to myelosuppression. We conclude that parenteral zidovudine, ganciclovir, and interleukin 2 is an active combination for AIDS-related central nervous system lymphoma.

Increased platelet calcium in thrombosis and related disorders and its correction by nifedipine.

Using chlorotetracycline (CTC) as a probe we studied calcium homeostasis of platelets in various disorders. Studied were healthy subjects and patients with disorders where platelets play an important role. These included thromboses, hypertension, diabetes mellitus, vasculitis, immune thrombocytopenia, thrombotic thrombocytopenic purpura, myelofibrosis, hemolytic anemias and uremia. Significant elevation of calcium levels were observed in all of these disorders except uremia. Nifedipine reduced or normalized the increased levels in most patients and its discontinuation resulted in a return of the abnormality. We propose that platelets in thromboses and related disorders are exposed to subcritical concentrations of activating factors, leading to enhanced calcium influx and elevated free cytoplasmic calcium followed by elevated resting dense tubular calcium. Nifedipine appears to protect platelets from these stimuli and coupled with their known action on vessel walls, calcium channel blockers show promise as antiatherogenic as well as antithrombotic agents.

Estimating impacts on developing countries of the decrease in U.S. training opportunities for foreign medical graduates.

Between 1973 and 1983, the number of foreign nationals from developing nations who entered the United States for graduate medical education decreased by approximately 90%. Many of those who would have studied in the United States if this decrease had not occurred would have returned home to serve their countries. To estimate the impact of this loss, a survey was conducted in six major cities in Latin America between 1983 and 1989. Selected local medical students interviewed 554 physicians who had returned home after U.S. training and 60 of their classmates who had not trained there. The findings indicate that the returned physicians had given approximately twice as much time to teaching, research, and medical administration as did those who had not left home. The authors maintain that this and related findings show how the curtailment of opportunities for training foreign nationals in the United States is detrimental to both the aspirations of developing nations and the influence of the United States in world affairs.

Very low dose danazol in idiopathic thrombocytopenic purpura and its role as an immune modulator.

Danazol, an attenuated androgen, has been used successfully at its conventional dose (400-800 mg/day) in the treatment of idiopathic thrombocytopenic purpura (ITP). To minimize side effects, the authors tried a very low dose (50 mg/day) regimen which has not been used in any other disease and observed its efficacy in ITP. Fifteen patients were given this dosage of danazol. Its effects on T-cell subsets, B cells, and blastogenic response to pokeweed mitogen (PWM) and staphylococcus aureus (Staph A) were studied before and during therapy. The percentage of CD3 and the percentage and numbers of CD4 were significantly increased during therapy. Responses to PWM, a T-cell dependent B cell mitogen, were also significantly elevated during therapy. However, no change in the percentage of B (CD19) lymphocytes and response to Staph A, a polyclonal B cell mitogen, were noted. There were seven excellent-good and eight fair-poor responses in platelet counts. The excellent-good responders were found to have a more stable CD4 subset between before and during therapy compared to the fair-poor responders (p less than 0.05, Fisher's exact test). Very low dose danazol regimen, therefore, produced a significant increase in the CD4 without affecting the B cells. However, the excellent-good responder patients showed no significant increase in the CD4 lymphocytes.

Iatrogenic disorders from cancer treatment.

All cancer therapies have potential and often serious side effects. With judicious selection of therapies, the risks are acceptable as are the contributions to better care, including that of iatrogenic disorders from therapy. It should, again, be stressed that new drugs and new modalities in combinations of treatments increase iatrogenic disorders from cancer therapy; as this increase is more and more appreciated, adjustments in schedules are resulting in decreased incidences of such disorders. Truly long-term effects over decades or generations are, of course, not yet known for most of the modern cancer therapies.

Treatment of idiopathic thrombocytopenic purpura (ITP).

In summary, idiopathic thrombocytopenic purpura (as defined here) should be treated initially with glucocorticoids unless there is life-threatening hemorrhage (such as intracranial bleeding), in which case emergency splenectomy is indicated, since it generally gives the most prompt improvement in platelet count of all modes of the disease and to better define the cause of the thrombocytopenia. A complete, sustained remission following treatment with steroids may occasionally be obtained. In most cases the steroid response is transient, and splenectomy is the most definitive measure with respect to a lifelong cure. Complete clinical cure is obtained in 70-80% of instances following splenectomy, with a very low operative risk. The remainder either fail to respond or experience relapse. In this group of patients steroids should again be tried; if a good response is obtained, steroids should be given every second or third day to lessen long-term side effects. If these measures fail, the use of immunosuppressive agents is justified. Both vinca alkaloids and cyclophosphamide are especially useful. Vinca alkaloids act more promptly, but cyclophosphamide may have a more lasting effect. Azathioprine may also be used; however, it appears to yield a lower remission rate. Nonsteroidal immunosuppressive agents should not be used as the primary modality of therapy. And, due to their carcinogenic and teratogenic potential, they should be avoided, if possible, especially in children and in women during their childbearing years.

The relapse of hairy cell leukemia after a 32-year remission.

The optimum therapy for hairy cell leukemia (HCL) is controversial. Dramatic responses to interferon-alpha and 2'-deoxycoformycin overshadow the established role of splenectomy in HCL, and patients currently can avoid surgery altogether. A case is presented of clinical remission lasting 32 years after splenectomy--a prolonged normal life, without medication or medical intervention. When relapse occurred, the patient's response to interferon-alpha was prompt and predictable. Prognostic variables are an important consideration at the time of diagnosis in predicting the response to splenectomy.