The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients.

Short DNA sequences have been identified, originally in association with Kaposi's sarcoma (KS) biopsies, that are highly homologous to oncogenic, lymphotropic herpesviruses. Recently a virus, Kaposi sarcoma associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), bearing these sequences has been identified in a cell line derived from a body cavity-based lymphoma. In this report, we show that the same sequences are present in KS biopsies as DNA molecules of a form and size characteristic of latent herpesviruses-large, covalently closed, circular episomes. The genomes migrate with an apparent size larger than the herpesvirus Epstein-Barr virus (172 kb). This form of the viral genome was found in four of four biopsies and three of five peripheral blood samples from KS patients. Linear forms of the viral genome, characteristic of viral replication, were not detected in the biopsies, but were present in the peripheral blood of three out of five patients. The sequences for KSHV/HHV-8 were also detected in the blood of four of five allograft patients and three of five healthy donors without KS suggesting that the virus is widespread throughout the human population.

Immunohistochemistry in Kaposi's sarcoma.

The importance of immunohistochemistry (IHC) to our understanding, ability to confidently diagnose and treat Kaposi's sarcoma (KS) has grown steadily in the past few decades. IHC has been performed on many KS specimen types, with > 100 different primary antibodies. Therefore, it is not surprising that IHC has helped unravel the histogenesis, understand the pathogenesis and facilitate the diagnosis of KS and identify novel therapeutic targets in the disease. This paper reviews the literature on the use of IHC in the study of KS.

Phase I trial of escalating pentoxifylline dose with constant dose thiotepa.

Pentoxifylline, a methylxanthine, is an effective modulator of alkylating agents in tissue culture and in human tumor explants in mice. In this Phase I trial, escalating dose controlled release pentoxifylline was administered p.o. 3 times daily for 5 days (15 doses) with a constant dose of thiotepa, 40 mg/m2 i.v. on day 2. Forty-four courses of escalating doses of pentoxifylline varying from 400 to 2400 mg were administered to 22 patients with refractory malignancies. Gastrointestinal toxicity, consisting mainly of nausea and vomiting, was dose limiting at 2400 mg pentoxifylline and subsided completely within 24 h of cessation of the drug. Nongastrointestinal toxicity of this thiotepa/pentoxifylline combination was infrequent and included bone marrow depression and supraventricular tachycardia. Increasing the dose of pentoxifylline did not increase the frequency of these rare toxic effects. Plasma concentrations of pentoxifylline and its major metabolites were determined by gas chromatography. Drug accumulation was noted within a cycle (i.e., by day 5) in only two patients and between cycles in no patient. The recommended Phase II dose of p.o. pentoxifylline is 1600 mg (four 400-mg tablets) when given 3 times daily for 5 days (15 doses) with 40 mg/m2 i.v. thiotepa. Based on an interspecies comparison, this dose exceeds that predicted from mouse models to enhance chemotherapy. This regimen can be safely administered on an outpatient basis, with adequate control of gastrointestinal symptoms achieved by standard antiemetics and intermittent dosing with meals. Phase II trials are required to determine the activity of alkylator/modulator combinations.

Inhibitors of HIV-1 transcription.

No curative drug against HIV has yet been found, despite enormous efforts aimed at reverse transcriptase and a variety of other targets. The long terminal repeat (LTR) of HIV-1 has recently become a promising site for antiviral action. This article briefly summarizes information on the nature of this target and potential anti-LTR expression drugs.

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.

Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma after failure of standard chemotherapy.

PURPOSE: To determine the efficacy and safety of pegylated-liposomal doxorubicin in patients with AIDS and Kaposi's sarcoma (AIDS-KS) who experienced failure of standard chemotherapy. METHODS: Fifty-three patients with advanced AIDS-KS who experienced disease progression or intolerable toxicities while receiving standard doxorubicin/bleomycin/vincristine (ABV) or bleomycin/vincristine (BV) chemotherapy were identified from a cohort of patients who were then treated with pegylated-liposomal doxorubicin. Patients received 20 mg/m2 pegylated-liposomal doxorubicin (Doxil; Sequus Pharmaceuticals, Inc, Menlo Park, CA) every 3 weeks. RESULTS: Nineteen patients (36%) had a partial response (PR) and one patient had a clinical complete response (CCR). The median duration of response and time (from study entry) to treatment failure were 128 and 134 days, respectively. Of 28 patients who experienced disease progression while receiving combination regimens that contained standard doxorubicin, the PR rate was 32%, which suggests that the pegylated-liposomal encapsulation increases the therapeutic effect of doxorubicin. Patients obtained clinical benefits such as flattening of lesions (48%), improved lesion color (56%), relief of pain (45%), and loss of edema (83%). Forty-nine percent of patients had more than one clinical benefit. The most common adverse effect was leukopenia, which occurred in 40% of patients. Only 15% of patients had nausea and/or vomiting, none of which was severe; 9% experienced alopecia, also generally mild. CONCLUSION: Pegylated-liposomal doxorubicin offers a new alternative for treatment of patients who have experienced failure of standard chemotherapy for AIDS-KS.

Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team.

PURPOSE: Angiogenesis is a major component of Kaposi's sarcoma (KS) and a critical process in tumor growth. The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS. PATIENTS AND METHODS: Patients with AIDS-related KS were required to have cutaneous disease with > or = 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks. RESULTS: The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had > or = 50 cutaneous lesions and 19 (49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability. Elimination half-life values were short (range, 0.01 to 0.61 hours). Seven patients (18%) achieved a partial response. The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 11 weeks (range, 3 to 26+). CONCLUSION: TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested. Tumor responses were observed in a substantial number of cases and occurred at various dose levels. TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy.

Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial.

PURPOSE: Kaposi's sarcoma (KS), the most common neoplasm in patients with AIDS, is a significant clinical problem for which current therapies are frequently unsatisfactory. We conducted a randomized phase III clinical trial to compare the efficacy and toxicities of a new form of therapy, pegylated-liposomal doxorubicin, with standard combination chemotherapy in patients with advanced AIDS-related KS (AIDS-KS). PATIENTS AND METHODS: Two hundred fifty-eight patients with advanced AIDS-KS were randomly assigned to receive either pegylated-liposomal doxorubicin (20 mg/m2) or the combination of doxorubicin (20 mg/m2), bleomycin (10 mg/m2) and vincristine (1 mg) (ABV) every 14 days for six cycles. Standard response criteria, toxicity criteria, and predefined indicators of clinical benefit were examined to evaluate outcomes. RESULTS: Among 133 patients randomized to receive pegylated-liposomal doxorubicin, one achieved a complete clinical response and 60 achieved a partial response for an overall response rate of 45.9% (95% confidence interval [CI], 37% to 54%). Among 125 patients randomized to receive ABV, 31 achieved a partial response (24.8%; 95% confidence interval [CI], 17% to 32%). This difference was statistically significant (P < .001). In addition to objective responses, prospectively defined clinical benefits and toxicity outcomes also favored pegylated-liposomal doxorubicin. CONCLUSION: Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.

AIDS-related Kaposi's sarcoma: a phase II study of liposomal doxorubicin. The TLC D-99 Study Group.

TLC D-99 is a unique liposomal formulation of doxorubicin that consists of phosphatidyl choline/cholesterol. The objectives of the study were to evaluate safety and efficacy of two doses of TLC D-99 in the treatment of patients with AIDS-related Kaposi's Sarcoma (KS). Forty HIV-infected persons with biopsy-proven KS were randomized to receive TLC D-99 at doses of either 10 (low) or 20 (high) mg/m2 every 2 weeks. Patients assigned to the low-dose arm could be escalated to the high-dose arm if their KS progressed after 3 cycles of therapy. Median age was 35 years (range, 26-47) and median CD4 count was 13 (range, 0-440). Nineteen patients were assigned to receive the low dose, and 21 patients were assigned to the high dose. Partial response occurred in 15% (6 of 40) of the patients or in 5% (1 of 19) and 24% (5 of 21) in the low- and high-dose arms, respectively; stable disease was observed in 65% (26 of 40) or in 68% (13 of 19) and 62% (13 of 21) in the low and high doses, respectively. Neutropenia was the major toxicity and was observed in 68 and 81% of patients with the low- and high-dose arms, respectively; grade 4 neutropenia was observed in 16 and 14%, respectively. Mild alopecia was noted in only 8%. Therefore, TLC D-99 is active against AIDS-related KS, and the response is dose-dependent.

Dose escalation of N,N',N"-triethylenethiophosphoramide combined with pentoxifylline for advanced breast cancer.

Pentoxifylline potentiates the cytotoxicity of alkylating agents in preclinical models. In this study we sought to define the maximum tolerated dose (MTD) of N,N',N"-triethylenethiophosphoramide (thioTEPA) with pentoxifylline, and to estimate the antitumor response to this combination in previously treated breast cancer patients. Thirty-five previously treated advanced breast cancer patients received 70 cycles (median, 2 cycles/patient; range, 1-6) of 1600 mg of oral sustained release pentoxifylline every 8 h for 4 doses in combination with escalating doses of i.v. bolus thioTEPA 40-65 mg/m2 administered 3 h after the second dose of pentoxifylline. Thrombocytopenia was dose limiting at 65 mg/m2 of thioTEPA, and the MTD was defined as 60 mg/m2. Among 25 patients treated at the MTD, leukopenia was grade 2 in 9 patients (36%), grade 3 in 4 patients (16%), and grade 4 in 2 patients (8%); thrombocytopenia was grade 2 in 3 patients (12%), grade 3 in 4 patients (16%), and grade 4 in 3 patients (12%). No other thioTEPA-related toxicity was observed. Plasma concentrations of thioTEPA, TEPA, and pentoxifylline were measured in 6 patients. The median (range) area under the plasma concentration versus time curve for thioTEPA was 29.4 microM/h (26. 2-40.5) and for TEPA was 16.3 microM/h (9.2-21.7 microM-h). The median (range) maximal plasma concentration of pentoxifylline and major metabolites I, IV, and V were 1.2 microgram/ml (0.2-7.8), 4.0 microgram/ml (0.5-16.4), 0.4 (range 0.1-0.8), and 2.9 (1.1-5.5), respectively. No objective responses were observed among 21 evaluable patients treated at the MTD (95% confidence interval, 0-15%). The combination of pentoxifylline and thioTEPA is well tolerated but not active in previously treated advanced breast cancer patients. Further clinical trials using commercially available oral sustained release pentoxifylline as a modulator of alkylating agents are not warranted.

Vascular endothelial growth factor-C (VEGF-C) and its receptors KDR and flt-4 are expressed in AIDS-associated Kaposi's sarcoma.

Kaposi's sarcoma is characterized by clusters of spindle-shaped cells that are considered to be tumor cells and by prominent vasculature. Whereas spindle cells are most likely endothelial in origin, it remains controversial whether they are of lymphatic or blood vascular derivation. To test the hypothesis that the lymphangiogenesis factor vascular endothelial growth factor-C and its receptors, KDR and flt-4, are involved in the pathogenesis of Kaposi's sarcoma, we performed in situ hybridizations and immunofluorescent stainings on human immunodeficiency virus-associated Kaposi's sarcoma. Spindle-shaped tumor cells strongly expressed KDR and flt-4 mRNA. Immunofluorescent staining confirmed expression of the flt-4 receptor in Kaposi's sarcoma cells, and double labeling revealed its colocalization with the endothelial cell marker CD31. Vascular endothelial growth factor-C was strongly expressed in blood vessels associated with Kaposi's sarcoma. In vitro, human dermal microvascular endothelial cells also expressed vascular endothelial growth factor-C mRNA that was further upregulated by vascular permeability factor/vascular endothelial growth factor. Vascular endothelial growth factor-C potently stimulated the proliferation of Kaposi's sarcoma tumor cells in vitro. These results demonstrate important paracrine functions of vascular endothelial growth factor-C, produced by blood vessels, in the pathogenesis of cutaneous Kaposi's sarcoma, and suggest a lymphatic origin and/or differentiation of Kaposi's sarcoma tumor cells.

Pentoxifylline inhibits HIV-1 LTR-driven gene expression by blocking NF-kappa B action.

The drug pentoxifylline (PTX) (1-(5'-oxohexyl) 3,7-dimethylxanthine) down-regulates human immunodeficiency virus (HIV-1) long terminal repeat (LTR)-directed gene expression in the human monocytic cell line U38. This effect of PTX has been tested in clinical trials. In this investigation, a similar inhibitory effect of PTX on HIV-1 LTR-driven gene expression was observed (a) in a stable transfectant of the human embryo kidney cell line 293-27-2 carrying an expression plasmid construct with the HIV-1 LTR fused to the bacterial lac Z gene, and also (b) by transient transfection of human embryo kidney cells 293 S with fusion plasmid constructs with wild-type [pHIV-LTR-chloramphenicol acetyltransferase (CAT)] or mutated (pHIV-LTR-mut-CAT) nuclear factor kappa B (NF-kappa B) motifs. In both stable and transient transfection studies, 4-beta-phorbol-12-beta-myristate-acetate (PMA)-induced or tumor necrosis factor-alpha (TNF-alpha)-induced activation of the HIV-1 LTR was correlated with a concomitant elevated level of NF-kappa B interaction with its motifs. The inducibility of HIV-1 LTR-driven gene expression by PMA or TNF-alpha in transiently transfected cells was completely eliminated by point mutations in the NF-kappa B motifs, suggesting that NF-kappa B plays a major role in the activation of the HIV-1 LTR by these agents in this cell system.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokine dysregulation in AIDS: in vivo overexpression of mRNA of tumor necrosis factor-alpha and its correlation with that of the inflammatory cytokine GRO.

The human immunodeficiency virus establishes an intimate interaction with the immune system. The virus can use cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (Il-1), to regulate its own expression by modifying the normal immunoregulatory network. We demonstrate that mRNA of the cytokine TNF-alpha from peripheral blood mononuclear cells is overexpressed in virtually all patients with AIDS who do not have active opportunistic infections compared with uninfected volunteers (p < 0.0001). This overexpression correlates with elevated mRNA levels of the recently discovered GRO (p < 0.05), a cytokine involved in the inflammatory response.

Pentoxifylline decreases tumor necrosis factor expression and serum triglycerides in people with AIDS. NIAID AIDS Clinical Trials Group.

Tumor necrosis factor-alpha (TNF)-cachectin increases the expression of the human immunodeficiency virus (HIV), reverses the therapeutic efficacy of zidovudine (ZDV), and may contribute to the wasting syndrome. Pentoxifylline (Trental) decreases TNF activity; in cell culture, it decreases HIV replication and down-regulates expression of the HIV long terminal repeat (LTR). Therefore, pentoxifylline was administered to 25 patients with advanced AIDS in this AIDS Clinical Trial Group study (ACTG #160), the goal of which was to investigate the ability of the drug to decrease TNF expression and HIV replication in this patient population. One patient discontinued drug treatment because of toxicity. Data were analyzed on the 17 patients who completed the 8-week study treatment with pentoxifylline, 400 mg, thrice daily. The median pretreatment CD4+ lymphocyte count was 32 cells/mm3. Fasting serum triglycerides, which have previously been shown to correlate with levels of interferon-alpha and/or TNF, fell on average by 66 mg/dl (p = 0.06). TNF mRNA levels in peripheral blood mononuclear cells fell in 10 of 16 patients (p = 0.02). HIV load decreased and increased significantly in four and one patients, respectively, but did not change in the group as a whole. This study demonstrates the safety of pentoxifylline in AIDS patients and its ability to decrease triglycerides and TNF mRNA levels.

The role of human immunodeficiency virus-I in the pathogenesis of acquired immunodeficiency syndrome-related Kaposi's sarcoma: the importance of an inflammatory and angiogenic milieu.

People infected with human immunodeficiency virus type-I (HIV-I) have an increased incidence of Kaposi's sarcoma (KS) and HIV-I infection alters the natural history of KS. The potent trans-activator HIV-I protein Tat plays a major role in the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related KS. Among many of its KS-promoting activities, the Tat protein augments the angiogenic activities of basic fibroblast growth factor (bFGF), interferon gamma, and vascular endothelial growth factor (VEGF); it also mimics the effects of the extramedullary matrix proteins fibronectin and vitronectin, and increases the expression of matrix metalloproteinases. Inflammatory cytokines induce endothelial cells to acquire the phenotype and functional features of AIDS-related KS spindle cells. These cytokines act by both autocrine and paracrine mechanisms. The synergy between cytokines and the HIV-I Tat protein provides possible insight into why AIDS-related KS is more aggressive than the classic Mediterranean form, in which the HIV-I Tat protein does not play a role.

Acquired immunodeficiency syndrome-related Kaposi's sarcoma: clinical features, staging, and treatment.

The clinical course of acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS) is highly variable, ranging from minimal stable disease to explosive growth. Although KS is primarily a cutaneous disease, extracutaneous spread is common; the oral cavity, gastrointestinal (GI) tract, lungs, and lymph nodes are often involved. The psychosocial burden associated with KS may be profound. The initial evaluation of a patient with KS consists mainly of a thorough physical examination with special attention paid to those areas typically affected by the disease, the testing of stool for occult blood, and a chest x-ray. Treatment options depend greatly on the tumor (extent of tumor and rate of growth), human immunodeficiency virus type I (HIV-I) viral load, and host factors (CD4+ T-lymphocyte count and overall medical condition). Limited cutaneous disease may be treated with topical alitretinoin gel, intralesional vinblastine, radiation therapy, laser therapy, or cryotherapy. The high benefit-to-risk ratio of liposomal anthracyclines (daunorubicin and doxorubicin) and paclitaxel have tremendously simplified the management of patients in whom systemic therapy is warranted. Additionally, epidemiologic evidence of a marked decline in new KS since the widespread use of highly active antiretroviral therapy (HAART) advocates its use. KS herpes virus/human herpes virus 8 (KSHV/HHV-8), sex hormones, and the processes of angiogenesis and cellular differentiation all serve as targets for pathogenesis-based clinical trials. Virtually all patients with KS can benefit from the many approved and investigational agents developed through years of collaborative translational and clinical research.

Meningioma in four patients with human immunodeficiency virus infection.

We describe four patients infected with the human immunodeficiency virus (HIV) who had development of meningiomas. In contrast to those in the general population who have meningiomas, all our patients were young men; the mean age was 40 years (range, 32 to 50). Their risk behavior for HIV was homosexuality (three patients) and intravenous drug use (one patient). The CD4+ cell count in each of the three homosexual men was less than 50/microL and was 280/microL in the drug user. Imaging studies showed enhancing lesions in three of the patients. Although each of these meningiomas could have occurred in otherwise normal young to middle-aged men, we speculate that the meningiomas may have grown in these HIV-infected hosts because of either loss of immune function or dysregulation of cytokines.

Phase I dose escalation pharmacokinetics of O-(chloroacetylcarbamoyl) fumagillol (TNP-470) and its metabolites in AIDS patients with Kaposi's sarcoma.

The pharmacokinetics of TNP-470 and its major metabolites were investigated in AIDS patients enrolled in a phase I dose escalation trial for the treatment of Kaposi's sarcoma. The patients received TNP-470 by 1-h intravenous infusion in dose cohorts of 10, 20, 30, 40, 50 and 70 mg/m2. The parent drug and metabolites, MII and MIV, were measured by high-performance liquid chromatography/mass spectrometry (HPLC/MS) in plasma samples collected during and out to 168 h after the beginning of the infusion. Both metabolites were detected in all patients' plasma, while the parent drug was undetectable at time-points as early as 5 min after the end of infusion for some patients. A large interpatient variability of pharmacokinetic parameters among the dosing cohorts was observed for TNP-470, with a mean (+/- SD) plasma elimination half-life (t1/2) of 0.06 +/- 0.04 h, plasma clearance (CL) of 1487 +/- 1216 l/h and an area under the concentration versus time curve (AUC) of 49.9 +/- 35.8 ng/ml x h. Time to maximum plasma concentration (Tmax) typically occurred before the end of the infusion. The predominant plasma metabolite was MII with a t1/2 of 1.21 +/- 0.43 h, AUC of 1226 +/- 2303 l/h and a Tmax occurring between 5 and 15 min after infusion. The reported active metabolite MIV had a t1/2 of 0.24 +/- 0.13 h, AUC of 24.9 +/- 32.6 ng/ml x h and a Tmax occurring between the midpoint of the infusion and 15 min after infusion. The parent drug was undetectable by HPLC/MS/MS in urine samples collected and pooled between 0-6 and 6-24 h from the beginning of drug administration. Metabolite MIV was present in the 0-6-h urine pool of two patients enrolled in the highest dosing cohorts, equivalent to 0.4% of the administered dose. Metabolite MII was present in all 0-6-h samples analyzed and represented 1.12 +/- 0.9% of the administered dose. Renal clearance (CLR) for MII was 140 +/- 70 ml/h.

Clinical presentation and natural history of AIDS--related Kaposi's sarcoma.

The clinical course of KS is highly variable, ranging from minimal disease to explosive growth. Extracutaneous spread is common, involving most frequently the oral cavity, GI tract, lungs, and lymph nodes. Both corticosteroid therapy and opportunistic infections are associated with the development of KS and with exacerbation of pre-existing KS in HIV-infected patients. A typical initial evaluation includes a thorough physical examination, fecal occult blood test, chest roentgenogram, and CD4+ T-lymphocyte count. The staging system most commonly used groups patients according to extent of tumor, immune status, and severity of systemic illness. After adjusting for prognostic factors, the most important of which is the median CD4+ T-lymphocyte count at presentation the survival of patients with KS is improving as the AIDS epidemic matures.