Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. International Pegylated Liposomal Doxorubicin Study Group.

PURPOSE: Cytotoxic chemotherapy is frequently required for the more severe manifestations of human immunodeficiency virus (HIV)-related Kaposi's sarcoma. Combinations of bleomycin and vincristine (BV) or BV with the addition of doxorubicin (ABV) are the most commonly used regimens against which new treatments may be compared. We report a multicenter phase III study that compared pegylated liposomal doxorubicin (PLD) to the BV combination. PATIENTS AND METHODS: We conducted a randomized study that compared PLD 20 mg/m2 with a combination of bleomycin 15 IU/m2 and vincristine 2 mg in 241 patients with HIV-related Kaposi's sarcoma. Both regimens were administered by intravenous infusion every 3 weeks for six cycles. RESULTS: A total of 121 patients received PLD and 120 patients the BV combination. The response to PLD was superior to BV: 58.7% versus 23.3% (P < .001). Patients who were randomized to receive BV, however, were more likely to terminate treatment early because of an adverse event (26.7% v 10.7%), and fewer completed the full six cycles of treatment (30.8% v 55.4%). Treatment with BV was associated with a significantly higher incidence of peripheral neuropathy (P < .001), whereas PLD treatment was more commonly associated with neutropenia and delays in receiving treatment (P < or = .001). CONCLUSION: Pegylated liposomal doxorubicin is an effective treatment for HIV-related Kaposi's sarcoma with a higher response rate than the BV combination. It is well tolerated but more myelosuppressive.

A patient with progressive myelopathy and antibodies to human T-cell leukemia virus type I and human immunodeficiency virus type 1 in serum and cerebrospinal fluid.

A 52-year-old human immunodeficiency virus type 1-seropositive bisexual black man was evaluated at UCLA because of the recent onset of progressive lower-extremity weakness. Initial neurologic examination showed that the patient's distal weakness was greater than his proximal weakness, with bilateral foot drop and electrophysiologic evidence of denervation in the distal lower extremities. Magnetic resonance imaging of the brain and spinal cord disclosed no abnormalities. Subsequent neurologic evaluation 8 months later showed a myelopathy, with progression of lower-extremity weakness, spasticity, and flexor spasms, and urinary incontinence, as well as the peripheral neuropathy noted previously. A second magnetic resonance imaging scan of the brain showed patchy foci of increased signal intensity in white matter and cortex, with mild generalized cerebral and cerebellar atrophy and no lesions in the spinal cord. Specimens of the patient's serum and cerebrospinal fluid contained antibodies to human immunodeficiency virus type 1. Additionally, specimens of his serum and cerebrospinal fluid were tested for antibody to human T-cell leukemia virus type I by Western blotting and radioimmunoprecipitation, and found to be positive for human T-cell leukemia virus type I gag, env, and tax antibodies. The primary cause of severe myelopathy in this patient may be infection with human T-cell leukemia virus type I rather than with human immunodeficiency virus type 1. Treatment with prednisolone resulted in improvement of the lower-extremity weakness, reduction in flexor spasms, and slower but significant improvement in urinary symptoms. Patients who are infected with human immunodeficiency virus type 1 and have unusual motor findings should be tested for concomitant human T-cell leukemia virus type I infection.

Intravenous recombinant tumor necrosis factor in the treatment of AIDS-related Kaposi's sarcoma.

Tumor necrosis factor (TNF) has demonstrated antitumor activity against a variety of tumors and is particularly cytotoxic to capillary endothelial cells, which are the presumed cell of origin of Kaposi's sarcoma. We evaluated the toxicity and clinical antitumor and antiretroviral effects of recombinant TNF administered at a once weekly dose of 100 micrograms/m2 intravenously for 8 weeks in five men with AIDS-related Kaposi's sarcoma and without prior opportunistic infection. One patient was removed from study at week 4 due to rapid progression of Kaposi's sarcoma, another patient with stage IV disease and a pretreatment CD4 count of 11 developed fever, hypotension, and pneumonia at week 7 and died 8 days after discontinuing recombinant TNF. No pathogenic organisms were isolated. He had marked eschar formation of his Kaposi's sarcoma lesions, particularly in areas previously exposed to radiation therapy. Uniform toxicities included fevers, rigors, and headaches during drug infusion that were ameliorated by prophylactic meperidine hydrochloride and acetaminophen. All experienced fatigue and three had arthralgias. One patient had transient hypotension which corrected with i.v. fluids. No significant hematologic, hepatic, or renal toxicities were seen. All patients had some progression of their Kaposi's sarcoma on study. There was no change in CD4 or CD8 count or in CD4:CD8 ratios. Serum human immunodeficiency virus (HIV) p24 antigen levels increased greater than 50% in three patients. We conclude that, as a single agent, at a dose of 100 micrograms/m2 recombinant TNF by i.v. infusion has no obvious antitumor or antiretroviral effects in patients with AIDS-related Kaposi's sarcoma.

Detection of human T-cell leukemia/lymphoma virus type I in a transfusion recipient with chronic myelopathy.

A white man with a progressive spastic paraparesis that began 15 months after sustaining severe trauma in a motor vehicle accident was positive for antibodies to human T-lymphotropic virus type I (HTLV-I) by enzyme-linked immunosorbent assay. Serum antibody to HTLV-I was confirmed by Western blot and radioimmunoprecipitation assay. We detected specific proviral DNA in peripheral blood lymphocytes by the polymerase chain reaction. Because the incidence of HTLV-I is generally restricted to Southern Japan and Caribbean black populations, the most likely source of HTLV-I infection in this patient was multiple intraoperative blood transfusions. The relatively short interval between transfusion and development of HTLV-I-associated myelopathy is consistent with the more rapid evolution of this clinical syndrome compared with adult T-cell leukemia.

Human T-cell leukemia virus type-I/II (HTLV-I/II) serologic testing: the importance of assaying for the full complement of viral antigens.

Seventy-one Japanese adult T-cell leukemia (ATL) patients and 411 Japanese asymptomatic patients from HTLV-I endemic regions of southern Japan were found to be seropositive by radioimmunoprecipitation assay (RIPA). Of these 482 positive controls, 62% of ATL patients and 67% of the asymptomatic seropositive patients were found to harbor antibodies to p40x. Additionally, 333 preselected Japanese blood donors who were identified as seropositive by particle agglutination (PA) assay were further tested for antibodies to HTLV-I/II gene encoded envelope (env) or group specific antigens (gag) by means of enzyme-linked immunosorbent assay (ELISA) and RIPA. Concordance between ELISA and RIPA was noted in 318 samples (92.5%). Discordance between ELISA and RIPA was observed in 15 sera (7.5%)--2 were seropositive by ELISA and seronegative by RIPA and 13 were seronegative by ELISA and seropositive by RIPA. Seven of these 13 samples (53.8%) contained antibodies to p40x by RIPA and may represent ELISA false negatives on the basis of both clinical and laboratory data. Current HTLV-I/II ELISA kits may yield false negative results. Additional research into the development of rapid detection cost-efficient assays that test for the full compliment of viral antigens is needed.

Human T-cell leukemia virus infection in non-intravenous drug using HIV seropositive men in Los Angeles.

Sera from 634 homosexual men with Western blot-confirmed human immunodeficiency virus (HIV) infection were subjected to radioimmunoprecipation assay (RIPA) using an HTLV-I-infected human T-cell line (SLB-I). Sera obtained from Japanese adult T-cell leukemia patients, noninfected healthy individuals served as positive and negative controls. HIV-infected groups were comprised of asymptomatic homosexuals (n = 131), AIDS-related complex (n = 115), Kaposi's sarcoma (n = 300), AIDS-defining opportunistic infections (n = 76), and high-grade lymphomas (n = 12). Only two patients were known to be intravenous drug users. No instances of dual retroviral infection were detected. As a corollary, no cross reactivity between HTLV and HIV gene products was noted by RIPA. We conclude that HTLV infection is uncommon among select groups of HIV seropositive homosexuals who do not engage in intravenous drug abuse. Additional studies examining the seroprevalence and consequence of HTLV infection in broader based populations at risk for retroviral infection are required.

Human T cell leukemia virus (HTLV-I/II) serodiagnostic testing: disparate results among a cohort of intravenous drug users.

Three hundred and forty-six sera collected over a 2-year period from 154 San Francisco IV drug users were subjected to HTLV-I/II RIPA, Western blot (WB), Du Pont ELISA, and p24 radioimmunoassay (RIA). Tests were performed at separate sites and code not broken until study end. RIPA-positive and -negative controls consisted of Japanese adult T cell leukemia patients, healthy blood donors, and non-IV drug-using HIV-positive men. RIPA identified HTLV-I/II-positive sera not identified by the other tests. Positive RIPAs were noted in 43% of negative ELISAs (n = 279), 34% of negative WBs (n = 243), and 40% of negative RIAs (n = 270). Seventy-two sera were negative by all 3 assays, but were RIPA positive. All sera positive by RIA (n = 76) and WB (n = 67), and 66 of 67 by ELISA, were positive by RIPA. Thirty-five of 36 indeterminate WBs were RIPA positive. Seven samples indeterminate by RIPA were negative by WB and RIA; one of seven was positive by ELISA. In all instances, samples negative by RIPA (n = 154) were ELISA, p24 RIA, and WB negative or indeterminate. We conclude that when studying HTLV-I/II-endemic cohorts, screening ELISA or RIA followed by confirmatory WB or RIPA only of seropositive samples may result in a substantial number of undetected cases. Additional studies focusing on performance characteristics of serodiagnostic tests are needed to ensure accurate inferences are made in assessing HTLV-I/II prevalence rates among high-risk groups. The RIPA may be a uniquely sensitive assay to detect HTLV-I/II gene-encoded products.

Regression of acquired immunodeficiency syndrome-related pulmonary Kaposi's sarcoma after highly active antiretroviral therapy.

Kaposi's sarcoma (KS) is the most common neoplasm affecting people with the human immunodeficiency virus (HIV) infection. The skin is the most common site of disease; however, KS can also involve visceral organs such as the lungs, leading to severe morbidity and contributing to death in almost 30% of patients with the acquired immunodeficiency syndrome (AIDS). New antiretroviral strategies incorporating combination nucleoside analogues with a protease inhibitor lead to increased circulating CD4+ lymphocyte counts, decreased plasma levels of HIV, and decreased mortality from AIDS-defining opportunistic infections. The effects of highly active antiretroviral therapy (HAART) on AIDS-associated KS remain largely unknown. Herein the case of an antiretroviral-naive man with advanced AIDS (CD4+ helper T-lymphocyte count, 35/mm3; HIV viral RNA quantification, more than 800,000 copies/mL), and symptomatic pulmonary KS is described. After HAART was initiated, his CD4+ cell count increased fourfold, his HIV-viral load decreased to nondetectable levels, and the pulmonary KS regressed dramatically. To my knowledge, this report represents the first documented case of pulmonary KS regression after the initiation of HAART. Although this finding is preliminary, if confirmed by other clinicians, the effect of potent antiretrovirals on KS growth and development will have important implications on the manner in which KS is staged and treated.

Etanercept for the treatment of human immunodeficiency virus-associated psoriatic arthritis.

Etanercept may play an important role in modulating the inflammatory activity and progression of human immunodeficiency virus (HIV)-associated psoriasis and psoriatic arthritis. We report the case of a 45-year-old homosexual man with a CD4 cell count of less than 0.05 x 10(9)/L and an HIV viral load of 4200 copies/mL (while receiving highly active antiretroviral therapy) who developed extensive psoriatic plaques, 4.5-kg weight loss, onychodystrophy, and psoriatic arthropathy with severe periarticular bone demineralization. The arthritis progressed despite the use of several disease-modifying medications, including corticosteroids, hydroxychloroquine, and minocycline. Because of uncontrolled, progressive, and disabling arthritis and resulting profound disability, he was treated with etanercept. Within 3 weeks, his psoriasis had improved dramatically and his joint inflammation had stabilized. For the next 4 months, immunologic and viral parameters remained stable, but his clinical course was complicated by frequent polymicrobial infections. Etanercept was thus discontinued despite continued improvements in his psoriasis, psoriatic arthritis, and functional status. While both cutaneous and joint manifestations of psoriasis improved dramatically, the experience with this patient dictates that caution and careful follow-up must be exercised when prescribing etanercept in the setting of HIV infection.

The epidemiologic, pathologic, and clinical features of AIDS-associated pulmonary Kaposi's sarcoma.

AIDS-related Kaposi's sarcoma (KS) occurs principally in homosexual or bisexual men infected with the newly identified human herpes virus-8, also called KS-associated herpes virus. Unlike classical forms of the disease, AIDS-associated KS is a multicentric entity that frequently involves lymph nodes and the GI tract. KS may also occur in the lung, commonly in the setting of extensive mucocutaneous disease and very rarely as an isolated event. The exact incidence of intrathoracic KS in patients with AIDS is unknown. Before the advent of highly active antiretroviral therapy (HAART), pulmonary KS had been reported in approximately 10% of patients with AIDS, 25% of patients with cutaneous KS, and in roughly 50% of postmortem examinations of patients with AIDS, KS, and respiratory infections. In the HAART era, the incidence of KS has declined precipitously in North America and Europe but not in third world countries where HAART is largely unavailable. Pulmonary KS may cause radiographic infiltrates and respiratory symptoms that mimic a variety of other infectious and neoplastic processes. An aggressive diagnostic evaluation of patients who have this condition is essential because chemotherapy and radiation therapy may provide significant palliation, particularly if used in conjunction with HAART. This review briefly explores the changing epidemiology of KS. The pathology and pathogenesis of KS is also reviewed, along with the clinical and radiographic presentation, diagnosis, and management of pulmonary KS.

Dextran syndrome. Acute hypotension, noncardiogenic pulmonary edema, anemia, and coagulopathy following hysteroscopic surgery using 32% dextran 70.

Dextran solutions are favored distending media for many hysteroscopic procedures because they are easy to administer, distribute uniformly within the uterine cavity, and are relatively nontoxic. We present the case of a 26-year-old woman who developed hypotension, noncardiogenic pulmonary edema, and hemorrhagic diathesis following hysteroscopic surgery with 32% dextran 70. A medical literature review indicates that following hysteroscopic surgery in which dextran solution has been used, "dextran syndrome" has been diagnosed in some patients. This syndrome is characterized by acute hypotension, hypoxia, coagulopathy, and anemia. We speculate on the pathogenesis of this condition and offer recommendations on how to evaluate and treat this rare dextran-related complication.

Cardiac tamponade due to primary pericardial lymphoma in a patient with AIDS.

Cardiac tamponade due to lymphomatous involvement of the heart is a dramatic and unusual complication. Because of their nonspecific clinical presentation, these tumors are seldom diagnosed antemortem. We report the case of a patient with AIDS who presented with signs and symptoms of cardiac tamponade. Emergency pericardiocentesis followed by staging studies revealed large cell B-lymphocyte lymphoma confined to the pericardial space. With combination chemotherapy, a durable complete response was obtained. This case illustrates the potential benefit of aggressive treatment of extranodal non-Hodgkin's lymphoma in a patient with AIDS. The case is of particular interest because of the unusual development of isolated pericardial involvement as the sentinel sign of lymphoma.

Hematologic abnormalities in AIDS.

The hematologic manifestations of HIV infection include morphologic abnormalities of peripheral blood and bone marrow changes. Laboratory abnormalities, including measures of coagulation, serum vitamin B12 levels, and positive Coombs's test, are seen with HIV infection and may not carry the same clinical consequence as when noted in non-HIV infected populations. Antibodies to circulating red blood cells, platelets, and granulocytes may represent alterations in autoimmunity or nonspecific HIV-induced B-cell stimulation, but they do not necessarily correlate with development of peripheral blood cytopenias. The advent of commercially available hematopoietic growth factors has allowed greater insight into specific host-virus-drug interactions that may be important in regulating viral growth and expression. Novel clinical approaches using hematopoietins alone or in combination with antimicrobial, antiviral, and antitumor drugs represent exciting developments in the treatment of HIV infection.

Fatal bone marrow necrosis following fludarabine administration in a patient with indolent lymphoma.

We report the first known case of fulminant bone marrow necrosis (BMN) occurring after infusion of fludarabine monophosphate in a patient with recurrent low-grade non-Hodgkin's lymphoma (NHL). Extensive BMN is characterized by the development of fever, bony pain, a leukoerythroblastic peripheral blood film, variable degrees of pancytopenia and elevations in lactate dehydrogenase and alkaline phosphatase. The diagnosis of BMN is rarely entertained ante-mortem. Although the precise role chemotherapy may have played in triggering fatal BMN remains speculative, we alert clinicians to be aware of this entity as more patients with indolent lymphomas and leukemias are treated with this and other potent nucleoside analogs.

Epidemiology and pathogenesis of AIDS-related lymphomas.

Among patients with congenital and acquired immunodeficiencies, non-Hodgkin's lymphoma (NHLs ) are the most common tumors of the immune system. In the setting of human immunodeficiency virus (HIV) infection, as many as 10% to 20% of people ultimately developed NHLs. These tumors are clinically aggressive, frequently involve extranodal sites, and often exhibit unique features that distinguish them from NHL arising in individuals with other forms of immunosuppression. Important in the development of HIV-associated NHL are cytokines and other factors that induce B-cell proliferation and increase the likelihood of mutations of c-myc, bcl-6, and other tumor-suppressor genes with carcinogenic potential. Specific forms of HIV-associated NHL are linked to expression of Epstein-Barr virus (EBV)-latent proteins; the newly described DNA virus, Karposi's sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV-8); and perhaps HIV. Elucidation of the factors that contribute to the high incidence of NHL among patients infected with HIV provides insights into important elements of lymphomagenesis.

Use of hematopoietic hormones for bone marrow defects in AIDS.

Bone marrow suppression is a substantial problem in patients infected with HIV. Contributing factors include the underlying HIV infection, alterations in the marrow microenvironment (resulting in abnormal cytokine regulation of hematopoiesis), and opportunistic infections and their associated medical treatments. Hematopoietic stimulants offer the promise of correcting peripheral blood cytopenias, augmenting host immune function, and permitting the continued use of potentially beneficial myelosuppressive therapies, which would otherwise result in dose-limiting side effects. The bone marrow abnormalities and mechanisms that contribute to alterations in hematopoiesis in HIV infection are briefly reviewed. Attention is then focused on the expanding clinical role of myeloid colony-stimulating factors (CSFs) and recombinant human erythropoietin (rHuEPO [Epogen, Procrit]) in the treatment of patients with AIDS.

Primary cutaneous large B-cell lymphoma of the legs: a distinct clinical pathologic entity treated with CD20 monoclonal antibody (rituximab).

Primary cutaneous large B-cell lymphoma of the legs (PCLBLL) is most commonly diagnosed in the elderly, and is generally confined to the lower parts of one or sometimes both legs. Despite treatment with radiotherapy, relapses and extracutaneous involvement can occur, and unlike other low-grade cutaneous-B-cell non-Hodgkin's lymphomas (NHLs), the prognosis is variable, with an estimated 5-year survival rate of 58%. This report describes the case of an 81-year-old man who was diagnosed with PCLBLL. Staging evaluation did not reveal NHL elsewhere. The patient declined recommendations to receive cytotoxic chemotherapy. Instead, he was treated with anti-CD20 monoclonal therapy (rituximab) and his cutaneous lesions completely regressed during a 16-week period. This report suggests that rituximab is a therapeutic option for those patients with PCLBLL who may not be good candidates to receive radiation therapy or chemotherapy. Long-term follow-up and greater experience with rituximab in a variety of clinical settings will ultimately determine the appropriate role of this costly, but relatively safe, antibody-based therapy for CD20+ expressing NHLs.

Retinoid-induced hypercalcemia in a patient with kaposi sarcoma associated with acquired immunodeficiency syndrome.

Retinoids are commonly used for the treatment of nonmalignant skin disorders and occasionally for the treatment of various neoplasms including epidemic Kaposi sarcoma (KS). Dry skin and mucus membranes, muscle and joint aches, alopecia, headaches, and liver and lipid abnormalities are the most frequent medication-related side effects. Very rarely, this class of drugs is associated with the development of hypercalcemia. The authors report the case of a man with acquired immunodeficiency syndrome (AIDS)-associated KS who, while participating in a phase II clinical trial of LGD 1057 (9-cis-retinoic acid) for treatment of epidemic KS, developed hypercalcemia, mental status changes, and renal insufficiency. The etiologic factors of retinoid-induced hypercalcemia are imperfectly understood, but with drug withdrawal his serum calcium, mental acuity, and renal function quickly normalized. Hypercalcemia occurs infrequently in the setting of AIDS and when present, is usually mediated by opportunistic infections. Clinicians should be alert to this potentially life-threatening iatrogenic complication that responds favorably to drug withdrawal.

Extramedullary facial plasmacytomas with anaplastic features: a diagnostic dilemma with implications for treatment.

Extramedullary plasmacytomas (EMPs) are rare plasma-cell tumors of the soft tissue that occur predominantly in the nasal sinuses and oropharynx. Subcutaneous and cutaneous plasmacytomas of the face are distinctly unusual. The authors report a case of rapidly expanding EMP involving the lip and contralateral nasolabial fold of a native Alaskan man with a 25-year history of recurring solitary bone plasmacytomas (SBP). An incisional biopsy revealed sheets of monotypic plasmablasts with anaplastic features. The pathologic and clinical findings were most consistent with a Richter transformation from a low-grade to a high-grade malignancy, or anaplastic myeloma (AM). With combined chemotherapy and radiation therapy, he achieved a complete response. The clinical and laboratory features of this most unusual plasma-cell dyscrasia are reviewed with an emphasis placed on diagnosis and treatment.

Aggressive Kaposi's sarcoma and campylobacter bacteremia in a female with transfusion associated AIDS.

The vast majority of patients with Kaposi's sarcoma (KS) of the epidemic, endemic or sporadic variety are men. Although 35 percent of men with AIDS will develop KS, only three percent of women will develop this malignancy. To date, a single case report of transfusion associated KS in an HIV-infected female has been described in the medical literature. We report a second case. A 54-year-old HIV-infected female without other identifiable risk factors for AIDS developed disseminated KS six years after a blood transfusion. Her illness was marked by rapidly proliferating tumors not responsive to a single course of chemotherapy. Another unusual aspect of this case is that, in conjunction with weight loss and diarrhea, Campylobactercinaedi was recovered from her blood. This enteric pathogen has previously been described exclusively in homosexual men. Autopsy studies showed KS tumors involving all major visceral organs. This case report demonstrates that in HIV-infected females KS may follow an aggressive course similar to that seen occasionally in male KS patients with profound immunosuppression.