Kaposi sarcoma (KS) gained public attention as an AIDS-defining malignancy; its appearance on the skin was a highly stigmatizing sign of HIV infection during the height of the AIDS epidemic. The widespread introduction of effective antiretrovirals to control HIV by restoring immunocompetence reduced the prevalence of AIDS-related KS, although KS does occur in individuals with well-controlled HIV infection. KS also presents in individuals without HIV infection in older men (classic KS), in sub-Saharan Africa (endemic KS) and in transplant recipients (iatrogenic KS). The aetiologic agent of KS is KS herpesvirus (KSHV; also known as human herpesvirus-8), and viral proteins can induce KS-associated cellular changes that enable the virus to evade the host immune system and allow the infected cell to survive and proliferate despite viral infection. Currently, most cases of KS occur in sub-Saharan Africa, where KSHV infection is prevalent owing to transmission by saliva in childhood compounded by the ongoing AIDS epidemic. Treatment for early AIDS-related KS in previously untreated patients should start with the control of HIV with antiretrovirals, which frequently results in KS regression. In advanced-stage KS, chemotherapy with pegylated liposomal doxorubicin or paclitaxel is the most common treatment, although it is seldom curative. In sub-Saharan Africa, KS continues to have a poor prognosis. Newer treatments for KS based on the mechanisms of its pathogenesis are being explored.

The availability of uniform and precise criteria for disease evaluation, response to treatment, and clinical staging of Kaposi's sarcoma (KS) in individuals with the acquired immune deficiency syndrome (AIDS) would facilitate therapeutic trials in patients with this neoplasm. Recently, a group of oncologists conducting clinical trials in patients with AIDS-associated KS as part of a cooperative group established by the National Institute of Allergy and Infectious Diseases (NIAID) drafted such criteria. The criteria take into account the unique problems associated with the evaluation of patients with a disseminated cutaneous neoplasm in the setting of a systemic virus infection associated with immune deficiency. The recommendations include a standardized format for documenting the extent of KS on initial and subsequent evaluations, response definitions that include assessments of lesion nodularity and tumor-associated edema in addition to more traditional methods for evaluating tumor response, and a new staging system that includes extent of tumor, immune status, and other AIDS-related disease manifestations, akin to the tumor-node-metastasis (TNM) system used to stage other tumors. The adoption of standardized criteria for the evaluation of KS should prove useful for group trials and for other investigators involved in the treatment of this disease.

TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ.

The ACTG TIS classification predicts survival in patients with AIDS-associated KS; CD4 count and tumor stage provide the most predictive information. However, a lower CD4 count than the one originally proposed provides better discrimination between prognostic groups.

Purpose: Activation of the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase/AKT pathway seems to be critical for melanoma proliferation. Components of these pathways are client proteins of heat-shock protein 90 (hsp90), suggesting that inhibition of hsp90 could have significant antimelanoma effects. We conducted a phase II trial using the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in melanoma patients. The primary end points were clinical responses and whether treatment inhibited MAPK pathway activity. Experimental Design: Melanoma patients with measurable disease were stratified on the basis of whether or not their tumor harbored a V600E BRAF mutation. The hsp90 inhibitor 17-AAG was administered i.v. once weekly Â6 weeks at 450 mg/m 2 . Tumor biopsies were obtained pretreatment and 18 to 50 hours after the first dose of 17-AAG, and were snap-frozen. Results: Fifteen evaluable patients were treated; nine had BRAF mutations and six were wild-type. No objective responses were observed. Western blot analysis of tumor biopsies showed an increase in hsp70 and a decrease in cyclin D1expression in the posttreatment biopsies but no significant effect on RAF kinases or phospho^extracellular signal-regulated kinase expression. Plasma analyzed by mutant-specific PCR for V600E BRAF showed 86% sensitivity and 67% specificity in predicting tumor DNA sequencing results. Conclusions: At this dose and schedule of 17-AAG, the effects of 17-AAG on RAF kinase expression were short-lived, and no objective antimelanoma responses were seen. Future trials in melanoma should focus on a more potent hsp90 inhibitor or a formulation that can be administered chronically for a more prolonged suppression of the MAPK pathway.Most melanomas are driven by activating mutations within the mitogen-activated protein kinase (MAPK) pathway, specifically in NRAS and BRAF (1 -3). Because melanomas harboring BRAF mutations often have concurrent mutations in the phosphatidylinositol 3-kinase/AKT pathway (2, 4), effective antimelanoma strategies will likely require blockade of both the MAPK and phosphatidylinositol 3-kinase/AKT pathways.17-allylamino-17-demethoxygeldanamycin (17-AAG) is a derivative of the natural product geldanamycin. Both 17-AAG and geldanamycin bind to a conserved pocket in the heat-shock protein 90 (hsp90) family of chaperone proteins and inhibit (5) hsp90 function. This leads to the degradation of hsp90 client proteins, such as Raf-1 (6, 7), mutated BRAF (8), AKT (9), and cdk4 (10). This results in an Rb-dependent G 1 growth arrest and, in some systems, differentiation and/or apoptosis (11). Thus, 17-AAG is an attractive agent for the treatment of melanoma because it can block both the MAPK and AKT pathways.In phase I trials, 17-AAG has been evaluated using dosing schedules of 1, 2, 3 and 5 doses within a week, although these studies included relatively few melanoma patients. Using daily dosing of 5 days every 3 weeks, the maximum tolerated dose was only 40-56 mg/m 2 (...