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Background: The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients (ClinicalTrials.gov identifier: NCT00890747)., Methods: In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed., Results: Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib., Conclusions: Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir., (© 2013 American Cancer Society.)

Purpose: Infusional chemotherapy is efficacious in patients with AIDS-related lymphoma, but it may be difficult to administer. We studied standard agents with rituximab plus pegylated liposomal doxorubicin (DR-COP) in an attempt to provide a more practical approach to therapy while ascertaining rates of response, potential infectious complications, and prognostic role of biologic markers., Patients and Methods: We conducted a prospective, multi-institutional phase II trial, employing (day 1) pegylated liposomal doxorubicin 40 mg/m(2), rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2) (not > 2 mg), and prednisone 100 mg orally on days 1 through 5, with concomitant antiretroviral therapy., Results: In 40 evaluable patients, median CD4 cells was 114/μL (range, 5 to 1,026/μL), and median HIV-1 viral load (VL) was 25,000 copies/mL. High or intermediate/high age-adjusted International Prognostic Index was present in 28%. Overall response was 67.5%, with complete remission in 47.5% (95% CI, 31.5 to 63.9). Of 19 complete responders, 84% had extranodal disease, 47% had CD4 < 100/μL, and 47% had VL > 50,000 copies/mL; one relapsed. With 25.5-month median follow-up, 62% (95% CI, 44 to 75) of patients remain alive. Sixteen patients (40%) experienced 22 infections, with grade 4 in only two (5%). No patient died as a result of infection during treatment; one had opportunistic infection., Conclusion: Profound immunodeficiency and high HIV-1 viral load do not preclude attainment of complete response after DR-COP with highly active antiretroviral therapy. The regimen is tolerable, and use of rituximab was not associated with death as a result of infection during treatment. This approach may be useful in patients in whom the more intensive infusional regimens are impractical.

Salivary gland disease is an important manifestation of HIV-infection. The aim of this study was to evaluate the cytologic findings of salivary gland fine needle aspiration (FNA) in South African human immunodeficiency virus (HIV)-infected patients. A retrospective review was performed on confirmed HIV-positive patients who underwent FNA of various body sites, including salivary glands, over a 5-year period. There were 495 (14.1%) salivary gland FNAs out of a total of 3,501 HIV-positive patients. This included 260 (52.5%) parotid, 226 (45.7%) submandibular, 2 (0.4%) sublingual, and 7 (1.4%) specimens labeled as a salivary gland aspirate, exact site not provided. Patients were of average age 34 years (range 9 months to 63 years) with a female: male ratio of 1:0.6. There were 37 (7.5%) inadequate FNAs and 22 (4.4%) that contained normal gland constituents only. Most diagnoses were benign and comprised 168 (33.9%) reactive lymphadenopathy, 115 (23.2%) benign lymphoepithelial cysts, 62 (12.5%) mycobacterial infections, and 52 (10.5%) abscesses, of which 10 had associated mycobacterial infections. Neoplasms accounted for 31 (6.7%) diagnoses including 11 pleomorphic adenomas, 13 lymphoma, 3 Kaposi sarcoma, 1 squamous cell carcinoma, 1 metastatic carcinoma, and 1 rhabdomyosarcoma. There were four epidermoid inclusion cysts, three non-specific sialadenitis, one mucocele, and one spindle cell lesion not able to be further characterized. FNA is a useful procedure to evaluate salivary gland lesions in an HIV-infected population, allowing prompt management to be undertaken and obviating the need for surgery in many instances, an important consideration in an underfunded public health care system., (Copyright © 2011 Wiley Periodicals, Inc.)

Purpose: The mammalian target of rapamycin is activated in Kaposi sarcoma (KS) and its inhibitor, rapamycin, has induced KS regression in transplant-associated KS. This study aimed to evaluate rapamycin's safety and toxicity in HIV-infected individuals with KS receiving antiretroviral therapy (ART), investigate rapamycin interactions with both protease inhibitor (PI)-containing and nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing ART regimens, and assess clinical and biological endpoints including KS response and mammalian target of rapamycin-dependent signaling., Methods: Seven participants, 4 on PI-based and 3 on NNRTI-based ART, had rapamycin titrated to achieve trough concentrations of 5-10 ng/mL. Patients were monitored for safety and KS response. KS biopsies were evaluated for changes in phosphoribosomal S6 protein, and phospho-Akt expression. Interleukin 6 and vascular endothelial growth factor levels, HIV and KS-associated herpesvirus viral loads, and CD4 counts were monitored., Results: Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses. Three of 4 subjects whose biopsies were studied at ≥day 50 showed decreased phosphoribosomal S6 protein staining., Conclusions: Rapamycin seems safe in HIV-infected individuals with KS and can, in some cases, induce tumor regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations but may be exploited to achieve therapeutic benefit.

Purpose: Paclitaxel, a cytotoxic agent metabolized by cytochrome P450 hepatic enzymes, is active for the treatment of human immunodeficiency (HIV) associated Kaposi's sarcoma. Protease inhibitors are commonly used to treat HIV infection and are known to inhibit cytochrome P450. We sought to determine whether protease inhibitors alter the pharmacokinetics of paclitaxel., Methods: Patients with advanced HIV-associated KS received paclitaxel (100 mg/m(2)) by intravenous infusion over 3 h, and plasma samples were collected to measure paclitaxel concentration. The area under the curve (AUC) was calculated using a combination of the log and linear trapezoidal rule, and clearance was calculated as the dose/AUC. Pharmacokinetics were compared with respect to antiretroviral therapy and toxicity,, Results: Thirty-four patients received paclitaxel, of whom 20 had no prior paclitaxel therapy and were assessable for response. Twenty-seven had pharmacokinetic studies performed. Paclitaxel exposure was higher in patients taking protease inhibitors compared to those who were not taking protease inhibitors. The increased exposure did not correlate with efficacy or toxicity. Of the 20 patients assessable for response, 6 (30%) had an objective response and median progression-free survival was 7.8 months (95% confidence interval, 5.6, 21.0 months)., Conclusion: Despite higher exposure to paclitaxel, patients on protease inhibitors did not experience enhanced toxicity or efficacy.

Background: Human immunodeficiency virus (HIV)-infected individuals are at increased risk for primary lung cancer (LC). We wished to compare the clinicopathologic features and treatment outcome of HIV-LC patients with HIV-indeterminate LC patients. We also sought to compare behavioral characteristics and immunologic features of HIV-LC patients with HIV-positive patients without LC., Patients and Methods: A database of 75 HIV-positive patients with primary LC in the HAART era was established from an international collaboration. These cases were drawn from the archives of contributing physicians who subspecialize in HIV malignancies. Patient characteristics were compared with registry data from the Surveillance Epidemiology and End Results program (SEER; n = 169,091 participants) and with HIV-positive individuals without LC from the Adult and Adolescent Spectrum of HIV-related Diseases project (ASD; n = 36,569 participants)., Results: The median age at HIV-related LC diagnosis was 50 years compared with 68 years for SEER participants (P < .001). HIV-LC patients, like their SEER counterparts, most frequently presented with stage IIIB/IV cancers (77% vs. 70%), usually with adenocarcinoma (46% vs. 47%) or squamous carcinoma (35% vs. 25%) histologies. HIV-LC patients and ASD participants had comparable median nadir CD4+ cell counts (138 cells/µL vs. 160 cells/µL). At LC diagnosis, their median CD4+ count was 340 cells/µL and 86% were receiving HAART. Sixty-three HIV-LC patients (84%) received cancer-specific treatments, but chemotherapy-associated toxicity was substantial. The median survival for both HIV-LC patients and SEER participants with stage IIIB/IV was 9 months., Conclusion: Most HIV-positive patients were receiving HAART and had substantial improvement in CD4+ cell count at time of LC diagnosis. They were able to receive LC treatments; their tumor types and overall survival were similar to SEER LC participants. However, HIV-LC patients were diagnosed with LC at a younger age than their HIV-indeterminate counterparts. Future research should explore how screening, diagnostic and treatment strategies directed toward the general population may apply to HIV-positive patients at risk for LC.

Background: There are limited studies investigating the cytopathology of HIV-related breast disease. The aim of the current study was to evaluate a large series of fine needle aspirations (FNA) performed on breast lesions in HIV-positive patients., Methods: A retrospective review at the National Health Laboratory Service (NHLS) in Johannesburg, South Africa, was performed on confirmed HIV-positive patients who underwent breast FNA. Cases were evaluated for patient age and sex, presence of a clinical breast lesion, antiretroviral therapy use, specimen adequacy, and cytologic diagnosis., Results: A total of 152 breast FNA procedures were recorded in patients of average age 36 years (range, 10-64 years). Cytologic findings in 100 females patients included 28 inadequate aspirates, 29 cases with a benign diagnosis, 25 abscesses, 3 with reactive intramammary lymphadenopathy, 3 with fat necrosis, 1 galactocele, 1 papillary lesion, 8 breast carcinomas, and 2 non-Hodgkin lymphomas. Fifty-two males underwent breast FNA, of which 6 were inadequate, and 43 (82.7%) showed gynecomastia. In 17 (40%) males with gynecomastia, a history of antiretroviral therapy was recorded. Two males were diagnosed with breast abscess and 1 with Kaposi sarcoma. Microbiology culture revealed 7 Mycobacterium tuberculosis infections in this patient population., Conclusions: FNA is a procedure to evaluate breast lesions and is capable of rendering results useful for a broad range of diagnoses likely to be encountered in an human immunodeficiency virus (HIV)-positive population. Unlike HIV-infected females who may present with a wide range of benign and neoplastic breast entities, HIV-positive males may have breast lesions that will most likely be attributed to gynecomastia associated with antiretroviral therapy., ((c) 2010 American Cancer Society.)

Background: Paclitaxel and pegylated liposomal doxorubicin (PLD) are active cytotoxic agents for the treatment of human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS). A randomized trial comparing the efficacy and toxicity of paclitaxel and PLD was performed, and the effects of therapy on symptom palliation and quality of life were determined., Methods: Patients with advanced HIV-associated KS were randomly assigned to receive paclitaxel at a dose of 100 mg/m2 intravenously (iv) every 2 weeks or PLD at a dose of 20 mg/m2 iv every 3 weeks. The KS Functional Assessment of HIV (FAHI) quality of life instrument was used before and after every other treatment cycle., Results: The study included 73 analyzable patients enrolled between 1998 and 2002, including 36 in the paclitaxel arm and 37 in the PLD arm; 73% of patients received highly active antiretroviral therapy (HAART) and 32% had an undetectable viral load (<400 copies/mL). Treatment was associated with significant improvements in pain (P=.024) and swelling (P<.001). Of the 36 patients who reported that pain interfered with their normal work or activities at baseline, 25 (69%) improved. Of the 41 patients who reported swelling at baseline, 38 (93%) improved. Comparing the paclitaxel and PLD arms revealed comparable response rates (56% vs 46%; P=.49), median progression-free survival (17.5 months vs 12.2 months; P=.66), and 2-year survival rates (79% vs 78%; P=.75), but somewhat more grade 3 to 5 toxicity for paclitaxel (84% vs 66%; P=.077)., Conclusions: Treatment with either paclitaxel or PLD appears to produce significant improvements in pain and swelling in patients with advanced, symptomatic, HIV-associated KS treated in the HAART era., (Copyright (c) 2010 American Cancer Society.)

Human immunodeficiency virus (HIV)-infected individuals are at high risk of malignancies. However, it is not currently the standard of care to routinely test cancer patients for HIV. In 2006, the Centers for Disease Control and Prevention recommended HIV testing in all health care settings, calling for standard nontargeted "opt-out" HIV screening. For a variety of reasons, routine opt-out HIV testing is still not widely used in the United States. Although many barriers to routine opt-out HIV testing have been addressed, such opt-out HIV testing continues to be conducted primarily in venues that target specific patient populations such as pregnant women. Although opt-out testing has been piloted in emergency departments, less emphasis has been placed on opt-out HIV testing in other clinical settings. In this article, the background, rationale, and evidence for supporting opt-out HIV testing as routine care for cancer patients are presented. In addition, evidence is discussed for the potential of opt-out HIV testing to improve clinical outcomes by facilitating appropriate HIV management during cancer treatment for individuals who are found to be HIV positive.

Anaplastic large cell lymphoma (ALCL) is a distinct subtype of peripheral T-cell lymphoma (PTCL) characterized by the expression of CD30 in lymphoma cells. Like aggressive B-cell non-Hodgkin lymphoma, the risk of developing PTCL is also increased in the setting of HIV infection. To date, the occurrence of ALCL in HIV-positive individuals is limited to a few case reports and small case series. A total of 37 cases of HIV-associated ALCL were identified after reviewing the available published literature. Analysis of these cases showed that this group of HIV-infected patients was on average 38 years of age with a male-to-female ratio of 4:1, and a reported median CD4 cell count of 83 cells/mm(3). HIV-associated ALCL cells rarely expressed anaplastic lymphoma kinase. Epstein-Barr virus infection was associated with one-third of the cases. These lymphomas manifested almost exclusively with extranodal involvement and exhibited a very aggressive clinical course. The median overall survival was 5 months. The administration of chemotherapy and early stages at presentation were identified as good prognostic factors, while the use of HAART showed a statistical trend toward improved survival in HIV-associated ALCL.

Background: As human immunodeficiency virus (HIV)-infected individuals are living longer, non-AIDS-defining cancers are becoming increasingly recognized. Primary esophageal tumors in people living with HIV have seldom been reported. We sought to document patient, virologic, and tumor characteristics and clinical outcomes in this patient group., Methods: International physicians involved in the care of AIDS-defining and non-AIDS-defining cancers accrued cases of primary esophageal malignant neoplasms in HIV-infected individuals. Patient demographics, HIV status, cancer risk factors, esophageal tumor characteristics, treatment, and outcomes were analyzed., Results: A total of 19 patients with primary adenocarcinoma and/or squamous cell carcinoma of the esophagus were identified. The median age was 48 years (range, 35-69 years) and the median CD4 lymphocyte count measured 376 cells/microL (range, 42 to >1000 cells/microL) (to convert to x10(9)/L, multiply by 0.001). The majority of patients were men with a history of smoking or considerable alcohol consumption. Prior esophageal disease (reflux, peptic ulcers, and achalasia) was reported in almost half of all patients. Seven patients (37%) underwent surgical resection, 11 (58%) received fluorouracil-based chemotherapy, and 7 (37%) underwent radiotherapy; survival correlated with stage at cancer presentation. While the majority of patients died, only 5 deaths (26%) were attributed to progression of esophageal carcinoma., Conclusions: Primary esophageal carcinoma is another non-AIDS-defining cancer associated with moderate immunosuppression and lifestyle habits including tobacco and alcohol use. The biological behavior, treatment, and outcome of HIV-related esophageal cancer appear similar to the general population with this disease; the same screening and risk moderation strategies are likely to apply.

Background: Patients infected with Human immunodeficiency virus (HIV) living longer with antiretroviral therapy (ART) are more likely to develop non-AIDS-defining cancers such as adenocarcinoma of the colon. There have been limited case reports regarding HIV-associated colon adenocarcinoma. The aim of this study was to characterize the clinicopathologic findings and outcome in a series of HIV-infected patients diagnosed and treated for colon adenocarcinoma., Patients and Methods: A retrospective study involving HIV-related colon adenocarcinoma was performed. Cases were accrued from the personal archives and published case reports. Data regarding demographics, HIV acquisition, ART use, immunosuppression, cancer location, pathology, and outcome were extracted and analyzed., Results: A total of 17 patients were identified, including 7 personal cases. Patients were of average age 43 years (range, 25-67 years) and predominantly male (male:female ratio, 14:3). Most carcinomas (57%) involved the right colon, were largely TNM stage 4 cancers (47%), and, when present, metastases were mainly to the liver. Many (47%) individuals died within 1-26 months after their cancer diagnosis. Immunosuppression (AIDS diagnosis and/or CD4+ < 500 cells/mm3) did not appear to correlate with tumor grade, stage, or an adverse outcome., Conclusion: These data show that HIV-infected patients with adenocarcinoma of the colon tend to be young men with a high incidence of right-sided involvement. Additional research is needed to determine if screening HIV-infected individuals for colon cancer should include younger patients and involve the entire colon.

Purpose of Review: Highly active antiretroviral therapy has led to a dramatic improvement in the prognosis of patients diagnosed with HIV and AIDS. This includes a significant decline in the rates of AIDS-related cancers, including Kaposi's sarcoma and non-Hodgkin's lymphoma. Unfortunately, rates of non-AIDS-defining cancers are on the rise, and now exceed the rates of AIDS-related cancers in patients with HIV. Treating non-AIDS-defining cancers in patients who are on highly active antiretroviral therapy is an open and complicated clinical question., Recent Findings: Newer targeted therapies are now available to treat cancers which were historically refractory to traditional cytotoxic chemotherapy. Highly active antiretroviral therapy agents are notorious for causing drug-drug interactions. The co-administration of targeted chemotherapies with highly active antiretroviral therapy could well impede the efficacy or increase the toxicity of these targeted therapies. Unfortunately little is known about possible drug-drug interactions because HIV patients are typically excluded from clinical trials., Summary: We highlight what is known about how and why highly active antiretroviral therapy agents can affect drug metabolism. We then present the clinical and pharmacological data for nine recently approved targeted therapies - imatinib, dasatinib, nilotinib, erlotinib, sunitinib, lapatinib, bortezomib, sorafenib, and temsirolimus. We conclude with considerations on how to use these new agents to treat non-AIDS-defining cancers, and discuss a future research agenda to better understand and predict potential highly active antiretroviral therapy-targeted therapy interactions.

Background: Chronic human immunodeficiency virus (HIV) infection is associated with an increased incidence of Non-Acquired Immunodeficiency Syndrome (non-AIDS) defining cancers. To date, only a limited number of cases of bladder cancer have been linked with HIV infection. We sought to describe the clinical characteristics of HIV-associated bladder cancer., Methods: A retrospective study was performed involving HIV-positive patients with bladder cancer, combining cases from multiple institutions with published case reports. Data regarding patient demographics, HIV status, clinical presentation, pathology, cancer treatment, and outcome were analyzed using descriptive statistics., Results: Eleven patients were identified with a median age of 55 years (range, 33-67). The median CD4+ count at cancer diagnosis was 280 cells/mm3 (range, 106-572 cells/mm3). Six patients (55%) had a known risk factor for bladder cancer, and nine (82%) presented with hematuria. Ten patients had transitional cell carcinoma, and most had superficial disease at presentation. Treatment included mainly transurethral resection of bladder tumor followed by a combination of local and systemic therapies. One patient received intravesical bacillus Calmette-Guèrin (BCG) without complication. Several patients (55%) were alive following therapy, although many (64%) suffered from local relapse and metastatic disease., Conclusion: Bladder cancer is part of the growing list of cancers that may be encountered in patients living longer with chronic HIV-infection. Our patients presented at a younger age and with only mild immunosuppression, however, they experienced an expected course for their bladder cancer. Hematuria in an HIV-infected patient warrants a complete evaluation.

Background: Case series of patients with a diagnosis of thrombotic thrombocytopenic purpura (TTP) have reported different frequencies of human immunodeficiency virus (HIV) infection; some series suggest that HIV infection may cause TTP., Methods: We systematically reviewed all reports of HIV infection in case series of patients with TTP. We analyzed data from the Oklahoma TTP-HUS (hemolytic uremic syndrome) Registry, an inception cohort of 362 consecutive patients, for 1989-2007., Results: Nineteen case series reported the occurrence of HIV infection at the time of diagnosis of TTP in 0%-83% of patients; individual patient data were rarely described. The Oklahoma TTP-HUS Registry determined the HIV status at the time of diagnosis of TTP in 351 (97%) of 362 patients. HIV infection was documented in 6 (1.84%; 95% CI, 0.68%-4.01%) of 326 adult patients (age, 26-51 years); follow-up data were complete for all 6 patients. The period prevalence of HIV infection among all adults in the Oklahoma TTP-HUS Registry region for 1989-2007 was 0.30%. One patient had typical features of TTP with 5 relapses. Five patients had single episodes; in 4, the clinical features that had initially suggested the diagnosis of TTP were subsequently attributed to malignant hypertension (in 3 patients) and disseminated Kaposi sarcoma (in 1 patient)., Conclusions: HIV infection, similar to other inflammatory conditions, may trigger acute episodes of TTP in susceptible patients. More commonly, acquired immunodeficiency syndrome-related disorders may mimic the clinical features of TTP. If the diagnosis of TTP is suggested in a patient with HIV infection, there should be careful evaluation for alternative diagnoses and cautious consideration of plasma exchange, the required treatment for TTP.

Kaposi sarcoma (KS) occurs as a result of Kaposi sarcoma-associated herpesvirus (KSHV) infection, typically in the context of one of several immunodeficient states. In the US, patients with KS may either be co-infected with HIV or receiving immunosuppressant therapy following solid-organ transplantation. Systemic treatment of KS has traditionally involved one of several chemotherapeutic agents administered either in combination or as single agents, which typically provide reasonable response rates and short-term control. However, recurrence of KS is common, and progression-free intervals are under 1 year. For these reasons, new therapies have been sought and with the elucidation of novel pathogenic mechanisms of KS infection, rational therapeutic targets have been identified. These include KSHV replication, restoration of immune competence, and signal transduction pathways utilized by KSHV in the propagation of KS. This review focuses on these emerging targets in the treatment of patients with KS and also highlights important clinicopathologic characteristics.

Background: Non-AIDS-defining cancers are an important problem in HIV-infected patients. The occurrence of neuroendocrine (NE) tumors in sites other than the lung and skin has not been well characterized in the setting of concurrent HIV infection., Methods: HIV-positive patients with biopsy-confirmed NE tumors localized to the gastrointestinal tract were identified based on the personal archives of the authors. A retrospective chart review was performed, and data regarding demographics, HIV status, presenting symptoms and signs, diagnostic work-up, therapeutic interventions, and outcome were extracted., Results: We identified 4 adult patients, mean age 42 years (range: 37-47) infected with HIV, who developed NE tumors originating in their gastrointestinal tact. They had only moderate immunosuppression with a median CD4 count of 497 cells/mm (range: 182-1100) and chronic HIV infection (2-15 years duration). Symptoms at presentation were nonspecific, including abdominal pain, diarrhea, weight loss, and rectal bleeding. A specialized diagnostic work-up was required, including serum chromogranin and urinary 5-hydroxyindoleacetic acid levels, colonoscopy, radioactive isotope scans, and the demonstration of NE differentiation in procured pathologic material. The spectrum of tumors ranged from benign (typical carcinoid) to highly aggressive neoplasms (NE carcinoma). Treatment with octreotide, surgical resection, or systemic chemotherapy provided effective symptomatic relief and was associated with a favorable outcome, despite metastases in 2 patients., Conclusions: These cases serve to broaden the spectrum of neoplasms that may be encountered in the current HIV era, and illustrate the difficulty in establishing the diagnosis of NE tumors in the context of HIV infection.

Objective: The spectrum of diseases associated with human immunodeficiency virus (HIV) infection has changed dramatically following the introduction of highly active antiretroviral therapy (HAART). Non-AIDS-defining cancers, including renal cell carcinoma (RCC), are being recognized increasingly in this population. Our aim was to describe the risk factors, clinical findings, pathology, and response to therapy of RCC in patients infected with HIV., Patients and Methods: We identified 9 men with HIV infection who developed RCC. Data regarding their HIV status, RCC risk factors, clinical presentation, and pathology were collected. A detailed retrospective chart review focusing on the course of their malignancy, response to therapy, and outcome was performed., Results: Renal cell carcinoma was diagnosed in patients with a median age of 48 years, and most had a history of tobacco use. No association between HIV-related immunosuppression (mean CD4 count, 301 cells/mm3) and the development, clinical presentation, pathology, or behavior of RCC was identified. Long-term survival correlated with early nephrectomy, and the use of interleukin-2 therapy for advanced RCC was not additive. A total of 5 patients died, 1 from a pulmonary embolism and 4 from disseminated RCC., Conclusion: Renal cell carcinoma should be included in the expanding array of non-AIDS-defining malignancies that develop during the course of HIV infection. Acknowledging the inherent limitations of our small study, these data show that the clinical presentation and behavior of RCC in patients with HIV appear similar to that of the HIV-negative population and that chronic immunosuppression plays a lesser role than age and exposure to risk factors in this setting.

Objective: To characterize the clinicopathological findings and the outcome of human immunodeficiency virus (HIV)-infected patients diagnosed and treated for prostate carcinoma, as HIV-positive men being treated with highly active antiretroviral therapy (HAART) are living longer and thus are more likely to develop cancers such as prostate cancer., Patients and Methods: We performed a retrospective, multi-institutional study involving HIV-positive men with concomitant prostate carcinoma. We collected data regarding patient demographics (age, race), HIV status (CD4(+) cell count, HIV viral load, HAART), PSA level (at cancer diagnosis), symptoms and signs, radiological findings, pathology (Gleason score, stage), cancer treatment (type, side-effects), and outcome (response, survival). Accrued data was analysed using descriptive statistics., Results: We identified 17 patients (mean age 59 years) with HIV-associated prostate adenocarcinoma. The mean CD4(+) count was 336 cells/mm(3) and the mean HIV viral load was 17 319 copies/mL. In all, 14 (82%) of these men were receiving HAART. Most patients were diagnosed with carcinoma after an abnormal screening PSA level. The mean PSA level was 30 ng/mL. Only six (35%) men had an abnormal prostate on examination. The mean Gleason score was 6.8, and in most cases, cancer was confined to the prostate gland. Most patients were amenable to curative treatment with hormonal therapy, radiation, and/or prostatectomy. There were no serious treatment related side-effects. One patient remained untreated. All treated patients had a complete response (undetectable PSA level). Most patients were long-term survivors. Documented death in five cases was unrelated to prostate cancer., Conclusion: The management of HIV-positive men with prostate carcinoma in the HAART era is becoming increasingly important. Our data shows that in men receiving HAART, their age, PSA levels, clinical presentation, management, and outcome from treated prostate carcinoma does not appear to be significantly altered by HIV status. Therefore, we recommend that patients with prostate cancer and well-controlled HIV viraemia be managed similarly to their HIV-negative counterparts.

Multicentric Castleman's disease (MCD), a relatively rare lymphoproliferative disorder that presents with heterogenous symptoms including fevers, anemia, and multifocal lymphadenopathy, is today most commonly observed in individuals infected with human immunodeficiency virus type-1 (HIV). In such individuals, a lymph node biopsy typically identifies cells that stain for Kaposi's sarcoma-associated herpesvirus proteins, and most HIV-associated MCD features can be attributed to the presence of this gamma-herpesvirus. Surgery and antiviral therapies including highly active antiretroviral therapy, interferon-alpha, foscarnet, ganciclovir, and antibodies to interleukin-6 have proved largely ineffective, and chemotherapy in HIV positive individuals is complicated by limited efficacy and pronounced toxicity. While no randomized trials have been performed, more recently the use of the anti-CD20 monoclonal antibody rituximab in large single center cohorts has been associated with prolonged remissions, radiologic responses, as well as hematologic and serum chemistry normalization of the inflammatory picture observed, at the expense of B cell depletion and flare of Kaposi's sarcoma. MCD represents a model of disease at the interplay between tumor biology, infection, and immunology., (Copyright 2008 Wiley-Liss, Inc.)

We studied the prevalence and nature of immunoglobulin abnormalities in HIV-1-infected patients in the era of highly active antiretroviral therapy. Protein electrophoreses (PEP) were performed on and quantitative immunoglobulin levels obtained in samples from 320 consecutive HIV-1-infected patients. Samples with possible PEP abnormalities underwent immunofixation. The PEP pattern was normal in 83.8% of samples, 8.1% had subtle oligoclonal banding, and 4.4% had a low-concentration (<5% of total protein) monoclonal band. Hypogammaglobulinemia and polyclonal hypergammaglobulinemia accounted for 1.9% each. In multivariate analysis, younger age (odds ratio [OR], 1.06 with each decreasing year of life; 95% confidence interval [CI], 1.02-1.11; P = .016), female sex (OR, 2.4; 95% CI, 1.13-5.11; P = .02), viral load (OR, 1.50 with each increasing logarithmic viral load of 1.0; 95% CI, 1.14-1.98; P = .004), and CD4 cell count (> or =350 vs <350/microL [0.35 x 10(9)/L]) (OR, 2.71; 95% CI, 1.09-6.75; P = .032) were associated with monoclonal or oligoclonal banding. These results suggest that younger HIV-1-infected patients with a more robust immune system (higher CD4 cell count), which is stimulated by uncontrolled viremia, are most likely to have an augmented B-cell response to HIV infection. One manifestation of this B-cell response is low-concentration monoclonal banding in 4.4% of the patients studied.

The differential diagnosis of a breast mass in an HIV-infected patient is broad. We report a case of HIV-associated intramammary lymphadenopathy that manifested itself as a painful solitary breast mass best demonstrated by ultrasound imaging. Fine-needle aspiration (FNA), ultrasound-guided core needle biopsy, and subsequent excisional biopsy demonstrated an intramammary lymph node with reactive changes typical of acute HIV-associated lymphadenopathy. Intramammary lymphadenopathy, an otherwise under-reported entity, should be included in the differential diagnosis of a breast mass in an HIV-positive patient. FNA sampling alone can be adequate in such low suspicion breast lesions that appear benign on clinical and imaging evaluations, provided that sufficient cellular material is procured for ancillary studies to exclude infection and malignancy.

Background: Monoclonal gammopathy of undetermined significance (MGUS) is unusual in the general population aged <60 years. Various reports indicate a much higher incidence of monoclonal gammopathy among human immunodeficiency virus (HIV)-infected patients and a significantly younger age at diagnosis. We sought to describe the laboratory findings and clinical course of MGUS, including association with plasma cell disorders, other malignancies, and infections, in 25 HIV-infected patients with a detectable serum monoclonal protein., Methods: We reviewed the patients' demographic characteristics, stage of HIV infection, and clinical course. Laboratory studies included determination of CD4(+) T lymphocyte cell counts, HIV type 1 loads, and quantitative immunoglobulin levels; serum and urine protein immunoelectrophoresis; and determination of serum viscosity indices. Skeletal surveys and bone marrow biopsies were performed in selected cases., Results: Twenty-four of 25 patients were male, and the median age of patients was 50 years (range, 21-69 years). The median CD4(+) T lymphocyte count was 350 cells/ microL (range, 40-1029 cells/ microL; mean, 355 cells/ microL), and the median HIV load was <75 copies/mL (range, <50 to 100,000 copies/mL; mean, 20,800 copies/mL). Thirteen of 25 patients had HIV viremia, despite receiving highly active antiretroviral therapy (HAART). After a mean follow-up duration of 21 months, 7 patients (28%) received a diagnosis of a malignancy (multiple myeloma, in 1 patient; non-Hodgkin lymphoma, in 1; Hodgkin lymphoma, in 1; Kaposi sarcoma, in 2; and plasmacytoma, in 2). Ten patients were coinfected with hepatitis B virus and/or hepatitis C virus; 6 were anemic. No patients developed renal failure or hypercalcemia. Nine (56%) of 19 evaluable patients had a decrease of serum monoclonal protein (mean, 0.5 g/dL) while receiving HAART., Conclusions: Patients in our study were characterized by the detection of a monoclonal protein at a younger age and the increased presence of other viral infections (infection with hepatitis B or C virus or Kaposi sarcoma herpesvirus) than is typically seen in an HIV-uninfected cohort. CD4(+) T lymphocyte counts were relatively robust. HAART appeared to have a favorable impact on the serum monoclonal protein level in 9 patients. Long-term follow-up is needed to better define the natural history of MGUS and the link to other possible contributing factors.

Purpose of Review: AIDS-related Kaposi's sarcoma results from co-infection with HIV and Kaposi's sarcoma herpesvirus/human herpesvirus-8, which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of the condition. Recent discoveries regarding Kaposi's sarcoma herpesvirus/human herpesvirus-8 infection and its activation of signal transduction have led to a greater understanding into Kaposi's sarcoma pathogenesis and have identified potential targets for therapy., Recent Findings: Kaposi's sarcoma is driven by Kaposi's sarcoma herpesvirus/human herpesvirus-8-specific pathways, which include viral G protein-coupled receptor, viral IL-6, and viral chemokine homologues. In addition, cellular growth/angiogenic pathways such as vascular endothelial growth factor, insulin growth factor, platelet-derived growth factor, angiopoietin and matrix metalloproteinases are 'pirated' by Kaposi's sarcoma herpesvirus/human herpesvirus-8. Recent findings show Kaposi's sarcoma herpesvirus/human herpesvirus-8 specific signaling pathways and pirated pathways to be important therapeutic targets., Summary: Numerous advances have been made recently that expand the understanding of Kaposi's sarcoma pathogenesis. These findings and recent clinical trials of targeted therapy for treatment are a prelude to a shift in the paradigm of how AIDS-related Kaposi's sarcoma is managed.

Purpose of Review: The incidence and spectrum of non-AIDS-defining cancers has continued to grow. As HIV-infected individuals live longer due to highly active antiretroviral therapy, their risk of dying from one of these cancers is increased. The recent literature pertaining to non-AIDS-defining cancers is reviewed., Recent Findings: Recent epidemiological studies have identified higher rates of carcinoma of the anus, lung, breast, skin, conjunctiva, liver and prostate; hematopoietic malignancies such as Hodgkin's lymphoma, plasma-cell neoplasia and leukemia; and other neoplasms like melanoma and leiomyosarcoma in HIV-positive patients. The role of HIV-induced immunosuppression in the development of these non-AIDS-defining cancers appears less important than lifestyle habits like smoking and sun exposure, as well as coinfection with human papilloma, hepatitis B, hepatitis C and Epstein-Barr viruses., Summary: It is unclear whether the growing number of reports on non-AIDS-defining cancers reflects a true increased incidence or merely the product of increased surveillance, detection and reporting. Highly active antiretroviral therapy not only promotes longevity in the HIV-positive population, but may increase their risk of developing cancer like Hodgkin's lymphoma. Assertive prevention strategies are needed to adequately deal with non-AIDS-defining cancers in an aging and growing HIV-positive population.

Purpose: Ultra low doses of interleukin-2 (IL-2) can activate the high-affinity IL-2 receptor constitutively expressed on CD56(bright) natural killer (NK) cells, the CD34+ NK cell precursor, and CD4+ CD25+ regulatory T cells (Tregs) in vivo. We have previously shown synergy between IL-2 and stem cell factor (SCF) in the generation of CD56(bright) NK cells from CD34+ hemopoietic progenitor cells in vitro and showed synergistic NK cell expansion in an in vivo preclinical model. To determine the safety, toxicity, and immune modulation of this combination of cytokines in vivo, we conducted a first-in-man phase I study., Experimental Design: A phase I dose escalation study was conducted using IL-2 at 900,000 or 650,000 IU/m2/d for 8 weeks with 5 or 10 microg/kg/d of SCF given thrice a week for 8 weeks in patients with HIV infection and/or cancer., Results: Ten of 13 patients completed therapy; four experienced the dose-limiting toxicities of grade 3 fatigue or urticaria. The maximum tolerated doses of IL-2 and SCF in combination is 650,000 IU/m2/d of IL-2 and 5 microg/kg/d thrice a week of SCF. NK cells were expanded over 2-fold on therapy; Tregs were expanded nearly 6-fold from baseline., Conclusions: Administration of IL-2 with SCF is safe and well tolerated and leads to expansion of lymphocyte subsets in patients with HIV or HIV and cancer; however, the changes in NK cell and Treg expansion seen with this cytokine combination were no different than those seen with a similar dose of IL-2 alone.

We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10-15 d, with a mean reduction of >or=1.6 log(10) copies/ml at all twice daily doses >or=100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.

We report a case of an extracavitary primary effusion lymphoma occurring in the anorectum of a patient with advanced acquired immune deficiency syndrome. The morphology, null cell immunophenotype, and acquisition of plasma cell markers in this case are typical of the so-called solid variant of primary effusion lymphoma. Lymphoma cells in this case were shown to be co-infected with human herpesvirus-8 and Epstein-Barr virus. Following combination chemotherapy and highly active antiretroviral therapy, this patient has remained in clinical remission for > 3.5 years. The purpose of this report is to add another case to the emerging literature regarding the heterogeneous category of extraserous human herpesvirus-8-associated lymphomas.

HIV infection and antiretroviral therapy may alter the spectrum and frequency of diseases that affect the breast. The differential diagnosis of conditions of the breast that a practitioner may encounter in HIV-infected persons includes infection, morphologic alterations, and malignancy. Atypical infections may involve the breast as CD4+ T-cell counts wane. More commonly, HIV-infected persons present with gynecomastia, which may be caused by a variety of conditions, including exposure to HAART. True gynecomastia, resulting from proliferation of male breast ducts and periductal stroma, might be differentiated from lipomastia--a manifestation of lipodystrophy, characterized by the deposition of adipose tissue in the breast. In the era of HAART, HIV-infected patients with malignancy--particularly those who have robust CD4+ T-cell counts and well-controlled HIV viral loads--should be treated similarly to their HIV-negative counterparts.

Kaposi sarcoma (KS) is a multicentric vascular neoplasm characterized histologically by the progressive proliferation of spindle-shaped tumor cells in all epidemiologic (AIDS-related, classic, endemic, and iatrogenic) forms. Human herpesvirus 8 (HHV8) is associated with all epidemiologic forms of KS and has been shown in vitro to induce the tyrosine receptor kinase c-kit in HHV8-infected cells. To date, c-kit immunoreactivity has not been systematically studied in KS lesions. Therefore, the aim of this study was to evaluate c-kit expression by immunohistochemistry in different proliferative stages and epidemiologic forms of KS. Archival cases of formalin-fixed, paraffin-embedded KS lesions, including 9 classic, 11 AIDS-related, and 15 African (endemic) forms at various histologic stages (5 patch, 8 plaque, 22 nodular), biopsied from different sites, were stained using immunohistochemistry with antibodies to HHV8 (LNA-1) and c-kit (CD117). C-kit immunoreactivity of lesional cells was demonstrated in 15 (43%) cases overall. A total of five (56%) classic, five (45%) AIDS-related, and five (33%) endemic KS cases were positive for c-kit. There was no difference in the intensity of c-kit staining between the different epidemiologic groups and histologic stages of KS. HHV8 (LNA-1) immunoreactivity was present in all (100%) classic, 10 (91%) AIDS-related, and 9 (60%) endemic cases. LNA-1 staining was demonstrated in 13 (93%) of the c-kit-positive and 15 (75%) of the c-kit-negative KS lesions. These findings indicate that c-kit expression in lesional cells can be detected by immunohistochemistry in different epidemiologic forms and histologic stages of KS. Furthermore, the expression of c-kit does not correspond with the presence of HHV8 (LNA-1) immunoreactivity in KS lesions.

The incidence of human papillomavirus (HPV)-related anal squamous cell carcinoma is increasing. It is likely that long-standing HIV-related immunosuppression plays a significant role in the pathogenesis of anal carcinoma; however, a direct HIV-HPV interaction has also been implicated. Using cervical cancer prevention as a paradigm, anal Pap smear screening as part of routine HIV preventive care has been proposed to detect and treat precancerous anal lesions in the hope of decreasing anal cancer rates. All HIV-positive patients with invasive cancer of the anal canal, particularly those with CD4+ cell counts greater than 200/microL and those receiving HAART, should be managed in the same manner as their HIV-negative counterparts.

Capravirine is a nonnucleoside reverse-transcriptase inhibitor (NNRTI) with a unique resistance profile. Although single mutations allow resistance to established NNRTIs, human immunodeficiency virus (HIV)-1 must undergo multiple mutations to achieve resistance to capravirine. In the present phase 1 study, capravirine was administered orally for up to 28 days to 55 HIV-1-infected individuals with CD4+ T lymphocyte counts of 50-500 cells/microL. The most frequent adverse events were diarrhea (5%) and nausea (4%), with no drug-related rashes observed. The day 15 median (mean) HIV-1 load decreased by 1.34 (1.45) log(10) copies/mL in the patients receiving 25 mg/kg/day. Capravirine demonstrated potent antiviral activity, even in antiretroviral-experienced patients.

Background: hNM01 is a humanized monoclonal antibody that binds to the V(3) region of the HIV-1 envelope protein gp120. This binding leads to the activation of complement and the disruption of the viral envelope., Objectives and Study Design: The aim of this study was to investigate the clinical responses of the individuals when treated with the humanized antibody NMO1. In this phase I study, four HIV-1 infected patients with CD4 counts between 50 and 500 cells/mul received a total of four doses of hNM01 in an intrapatient dose escalation fashion: day 1-0.2 mg/kg, day 15-1 mg/kg, day 29-5 mg/kg, and day 43-5mg/kg. Patients were required to have virus that reacted to hNM01 by a virion capture assay and to have a viral load > or =15,000 copies/mL., Results and Conclusion: The antibody was well-tolerated; no significant adverse events were observed even at the highest dose tolerated. None of the patient developed either human anti-hNM01 (anti-idiotype) or human anti-rat antibodies. The mean elimination half-life was 153 h (6.4 days). During hNMO1 therapy effects were observed on CD4 cell counts and plasma viral loads and further dose finding trials are necessary to better determine the therapeutic activity of hNM01 in HIV-infected individuals.

Background: Recent reports suggest that patients infected with human immunodeficiency virus (HIV) may have an increased risk of developing thrombosis, but the etiology, risk factors, and clinical course remain largely undefined, with few descriptive case series., Methods: We identified 30 patients from an HIV outpatient clinic (treatment population, 650 persons) who had had a total of 43 venous or arterial thromboses during 1996-2002. Data pertaining to demographic characteristics, medical history, thrombosis presentation, and clinical outcomes were abstracted from patient medical records., Results: The median patient age at the time of thrombosis was 43 years. Although the presence of persistent antibody to phospholipids was the most common abnormal finding in the laboratory, evaluation of thrombophilia, cases of low levels of proteins C and S and antithrombin III, and elevated levels of factor VIII and homocysteine were also identified. Seventy-seven percent of the patients smoked cigarettes, 57% had dyslipidemia, and 43% had a malignancy (most commonly Kaposi sarcoma). Although the Centers for Disease Control and Prevention (CDC) classification for 16 patients (53%) was C3, most showed evidence of immune reconstitution (median CD4 cell count, 290 cells/ mu L) and control of the virus (median HIV load, 2290 copies/mL). Lower extremity, deep vein thrombosis and pulmonary emboli accounted for 66% of all thrombotic events. The median time to diagnosis of thrombosis was 1 day (range, 3 h to 3 weeks)., Conclusions: Patients in this series were characterized by a relatively young age at the time of thrombosis, a predominance of elevated levels of lipids, a history of malignancy, and an advanced CDC HIV classification but not by a low CD4 cell count or an elevated HIV load.

Plasma cell disorders are not uncommonly reported in young patients with HIV infection. These disorders range from benign polyclonal hypergammaglobulinemia to indeterminate monoclonal gammopathy of unknown significance (MGUS) to malignant dyscrasias, including multiple myeloma and plasma cell leukemia. Hypergammaglobulinemia and oligoclonal banding had been the most frequently reported disorders in the pre-HAART era. In HIV-infected persons, the incidence of MGUS is reported to be around 2.5%, with an approximate 4.5-fold increased risk of multiple myeloma. Many of these HIV-infected patients had been treated with alkylator-based regimens, and these reports predate the current widespread use of thalidomide-dexamethasone combination treatment in multiple myeloma. Although the optimal therapy for an HIV-infected person might with plasma cell dyscrasia is yet to be defined, in the current era of HAART the otherwise healthy HIV-infected patient might be tested like an HIV-negative person. Consequently, treatment with immunomodulatory agents (eg, thalidomide) and proteasome inhibitors (eg, bortezomib) may also be worth considering. High-dose chemotherapy with an autologous peripheral blood stem cell transplant is increasingly being considered as consolidation therapy in the younger non-HIV-infected myeloma patient. In the next few years, it is anticipated that these approaches will be applied more frequently to HIV-infected persons with myeloma.

We present a case of hemophagocytic syndrome in a human immunodeficiency virus-positive man with iron-deficiency anemia that did not respond to highly active antiretroviral therapy. Clinical resolution occurred only after a splenectomy was performed.