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Background The spectrum of Kaposi's sarcoma (KS) has been expanded to include pre-KS lesions. Case Presentation We report, for the first time, a case providing direct histological evidence of the development of early (in-situ) KS from mediastinal lymphatic vessels in the setting of chronic lymphedema in an HIV-positive patient. Spindle-shaped and endothelial cells in these early KS-appearing lesions were immunoreactive for HHV8, D2-40 and CD34. Conclusion Our findings suggest that HHV8-infected spindle-shaped cells associated with lymphangiogenesis that evolve into KS lesions, acquire from the outset an aberrant mixed vascular and lymphatic endothelial cell phenotype.

Through the mentorship process, Dr. Arthur Pardee emphasized the critical importance of bidirectional translational research—not only advancing drug development from bench to bedside, but also bringing back precious clinical material to the laboratory to assess the biologic effects of therapeutic agents on their targets. This mini-review focuses on the signal transduction pathways of Kaposi's sarcoma (KS) and on how the knowledge of such pathways has led to the rational development of molecularly targeted pathogenesis-driven therapies. Acquired immune deficiency syndrome (AIDS) related-KS results from co-infection with human immunodeficiency virus and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8), which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of KS. KS is driven by KSHV/HHV8-specific pathways, which include viral G protein-coupled receptor (vGPCR), viral interleukin-6 (vIL-6), and viral chemokine homologues. In addition, cellular growth/angiogenic pathways, such as vascular endothelial growth factor (VEGF), insulin-like growth factor, platelet-derived growth factor (PDGF), angiopoietin and matrix metalloproteinases (MMPs) are “pirated” by KSHV/HHV8. As a very tangible example of how translational research has led to a marked improvement in patient outcome, the signal transduction inhibitor imatinib (a tyrosine kinase inhibitor of c-kit and PDGF) was administered to patients with KS whose tumors were serially biopsied. Not only did the patients' tumors regress, but also the regression was correlated with the inhibition of PDGF receptor (PDGFR) in the biopsy samples. Recent and future clinical trials of molecularly targeted therapy for the treatment of KS are a prelude to a shift in the paradigm of how KS is managed. J. Cell. Physiol. 209: 659–662, 2006. © 2006 Wiley-Liss, Inc.

Sickle cell intrahepatic cholestasis (SCIC) is a rare complication of sickle cell anemia, characterized by marked hyperbilirubinemia and acute hepatic failure with an often fatal course. However, the few reported adult cases that were treated with exchange transfusion had a favorable outcome. We herein describe a 48-year-old African-American man with hemoglobin S/B thalassemia and previously treated hepatitis C with compensated cirrhosis, who presented with a total bilirubin of 59.7 mg/dL and direct bilirubin of 43.6 mg/dL in the absence of choledocholithiasis. Despite an exchange transfusion and aggressive packed red blood cell transfusions, which successfully decreased the hemoglobin S levels to

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.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.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.

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 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.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 CD56bright 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 CD56bright 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 μg/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 μg/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.

Background Ovarian cancer is known to metastasize to the thyroid gland. Despite an incidence of ovarian metastasis to the thyroid of 3–15%, clinical hypothyroidism resulting from such metastasis has not yet been reported. We present a case of metastatic ovarian cancer to the thyroid resulting in clinical hypothyroidism. Case A 55-year-old woman with recurrent papillary adenocarcinoma of the ovary presented with fatigue, abdominal distention, lymphedema, and depression. Thyroid stimulating hormone was markedly elevated, and thyroid biopsy demonstrated bilateral metastatic ovarian carcinoma. Conclusion Although uncommon, metastatic disease to the thyroid should be considered when evaluating a patient with advanced ovarian cancer and clinical hypothyroidism.

Background: Treatment of elderly AML patients considered unfit for conventional chemotherapy is inadequate and hypomethylating agents are commonly used alternatives. In the case of azacitidine, responses are typically seen after 3–6 cycles of therapy, and a recent large randomized trial in elderly unfit patients reported a complete response (CR)/CR with incomplete blood count recovery rate of 28% (Dombret et al, EHA 2014). Pevonedistat (MLN4924) is an investigational, first-in-class NEDD8-activating enzyme (NAE) inhibitor. A phase 1 trial previously reported pevonedistat single-agent clinical activity in relapsed/refractory AML patients. Preclinical studies of pevonedistat and azacitidine identified synergistic lethality in AML cell lines and murine xenografts. The current phase 1b dose-escalation study evaluated the safety and tolerability of pevonedistat combined with azacitidine in elderly AML patients considered unfit for conventional chemotherapy. Methods: The primary objective was to assess the safety and tolerability of pevonedistat combined with azacitidine. Secondary objectives included assessment of pevonedistat pharmacokinetics (PK) and clinical activity. Treatment-naive AML patients aged ≥60 years who were considered unfit for standard induction therapy received pevonedistat via 1-hour IV infusion on days 1, 3, and 5 of 28-day cycles. Dose escalation began at 20 mg/m2 and used an adaptive Bayesian continual reassessment method. Azacitidine 75 mg/m2 was administered (IV or SC) on days 1–5 and 8–9. Patients were treated until disease progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses were assessed according to International Working Group response criteria for AML. Serial blood samples were obtained for PK analysis following dosing on days 1 and 5 of cycle 1. Results: As of May 30, 2014, 25 patients (median age 75.0 years [range 63–85]; 16 [64%] male) had received pevonedistat 20 mg/m2 (n=22) and 30 mg/m2 (n=3). Primary diagnoses were 16 (64%) de novo AML and 9 (36%) secondary AML. Fourteen (56%) patients had intermediate- and 6 (24%) had adverse-risk cytogenetics (5 [20%] undetermined). During dose escalation, dose-limiting toxicity (DLT) at the 30 mg/m2 pevonedistat dose level included reversible grade 2 increased bilirubin (n=1) and grade 3/4 increased transaminases (n=1) without clinical sequelae. In 1 of the 22 patients treated at the maximum tolerated dose (20 mg/m2 pevonedistat plus 75 mg/m2 IV/SC azacitidine), 1 additional DLT (grade 4 AST/ALT elevation) was seen in the expansion cohort. This patient was successfully re-challenged with a reduced pevonedistat dose. The most common all-grade AEs are shown in table 1. Twelve (48%) patients experienced drug-related grade ≥3 AEs (table 1). The nature and frequency of the reported toxicities (excluding DLTs) were similar to previous reports for azacitidine alone. Preliminary PK data showed that addition of azacitidine did not alter the known PK profile of single-agent pevonedistat. In the 18 response-evaluable patients, there were 6 (33%) CRs and 4 (22%) PRs (table 2), for an overall response rate of 56%. Nine of the 10 responses occurred within the first two cycles of therapy and included 1 patient with bone marrow blasts >80%. Conclusions: Combination therapy with pevonedistat and azacitidine was generally well-tolerated. The characteristics of the observed responses suggest added benefit from the addition of pevonedistat compared with azacitidine alone. | Common all-grade AEs | n (%) | Most frequent (≥10%) drug-related grade ≥3 AEs | n (%) | | -------------------- | ------ | ---------------------------------------------- | ------ | | Febrile neutropenia | 9 (36) | Febrile neutropenia | 4 (16) | | Constipation | 8 (32) | Thrombocytopenia | 3 (12) | | Decreased appetite | 7 (28) | – | – | | Thrombocytopenia | 7 (28) | – | – | Table 1 | Responders* | Tumor Type | Cytogenetic Risk Group | Current Status | Response | Molecular CR | | ------------ | ------------- | ---------------------- | -------------- | -------- | ------------ | - | | 1st Response | 1st CR | | 1 | De novo AML | Adverse | C12 | C4 | – | – | | 2 | Undetermined | C4† | C1 | C1 | Y | | 3 | Adverse | C9 | C1 | C1 | Y | | 4 | Undetermined | C5‡ | C1 | C2 | Y | | 5 | Intermediate | C5† | C1 | C2 | N | | 6 | Intermediate | C7 | C1 | C4 | Y | | 7 | Intermediate | C2 | C2 | – | – | | 8 | Secondary AML | Undetermined | C4 | C2 | C2 | – | | 9 | Normal | C4 | C1 | – | – | | 10 | De novo AML | – | C1 | C1 | – | – | Table 2 Molecular CR, complete remission confirmed by molecular studies *All received 20 mg/m2 pevonedistat except #4, who started on 30 mg/m2 and had a dose reduction to 20 mg/m2. †Patient off study ‡Patient off treatment and in follow-up Disclosures Swords: Novartis: Consultancy; KaloBios Pharmaceuticals, Inc.: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Savona: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Erba: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding. Foran: Takeda Pharmaceuticals International Co.: Research Funding. Hua: Takeda Pharmaceuticals International Co.: Employment. Faessel: Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Dash: Takeda Pharmaceuticals International Co.: Employment. Sedarati: Takeda Pharmaceuticals International Co.: Employment. Dezube: Takeda Pharmaceuticals International Co.: Employment. Medeiros: Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Takeda Pharmaceuticals International Co.: Research Funding.

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.

Learning ObjectivesAfter completing this course, the reader will be able to: Describe the pathogenesis and clinical presentation of Kaposi's sarcoma, with a special emphasis on Kaposi's sarcoma herpesvirus/human herpesvirus-8, and outline treatment approaches.Discuss the pathogenesis, epidemiology, and treatment of AIDS-related lymphomas.Discuss the increasing incidence of non-AIDS-defining malignancies such as Hodgkin's lymphoma and plasma cell disorders in patients with HIV infection.Explain how, in the era of highly active antiretroviral therapy, both AIDS-related lymphoma and Hodgkin's lymphoma patients may be treated with therapies previously reserved for their immunocompetent counterparts.Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.comHuman immunodeficiency virus (HIV)-infected patients are at increased risk of developing cancer, particularly in the later stages of acquired immune deficiency syndrome (AIDS). Despite the advent of highly active anti-retroviral therapy (HAART), malignancy in this population is a leading cause of morbidity and mortality. Kaposi's sarcoma (KS) and AIDS-related non-Hodgkin's lymphoma (ARL) are the most common AIDS-defining malignancies. AIDS-related KS varies from minimal to fulminant disease. Treatment decisions for AIDS-related KS are guided largely by the presence and extent of symptomatic disease. In addition to HAART, excellent treatments exist for both localized disease (topical gel, radiotherapy, and intralesional therapy) and advanced disease (liposomal anthracyclines, paclitaxel). Novel therapies that have become available to treat AIDS-related KS include angiogenesis inhibitors and antiviral agents. ARL comprises a heterogeneous group of malignancies. With the immune restoration afforded by HAART, standard-dose chemotherapies now can be safely administered to treat ARL with curative intent. The role of analogous treatments used in HIV-negative patients, including monoclonal antibodies and autologous stem cell transplantation, requires further clarification in HIV-positive patients. HIV-infected patients also appear to be at increased risk for developing certain non-AIDS-defining cancers, such as Hodgkin's lymphoma and multiple myeloma. Although the optimal treatment of these neoplasms is at present uncertain, recent advances in chemotherapy, antiretroviral drugs, and supportive care protocols are allowing for more aggressive management of many of the AIDS-related cancers. This article provides an up-to-date review of the epidemiology, pathogenesis, clinical features, and treatment of various AIDS-related malignancies that are likely to be encountered by an oncologist practicing in the current HAART era.

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.

Objectives. The aim of this study was to define the toxicity, maximum feasible dose (MFD), and pharmacokinetics (PK) of A6, a peptide derived from human urokinase plasminogen activator (uPA), in patients with advanced gynecologic cancers, and to explore anti-tumor activity and the effects of A6 on biomarkers of the urokinase system. Methods. A6 was administered subcutaneously daily, and doses were escalated in cohorts of three to six subjects. Serial blood specimens were obtained for pharmacokinetics and levels of urokinase plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1). Results. Sixteen patients were enrolled and eligible for evaluation. No serious drug-related adverse events or dose-limiting toxicity occurred. A6-related toxicities were limited to grades 1 and 2 adverse effects including local injection site reactions. Five patients had stable tumor measurements for at least 4 cycles, one of whom stayed on study for 12 months. One patient had a confirmed cancer antigen (CA)-125 response (decrease in CA-125 of >50%) with stable disease on CT scan after 14 cycles and continues on study. Time to peak plasma level of A6 was 1–2 h. C max is proportional to dose. The half-life of A6 was approximately 2 h. Baseline biomarker levels did not predict response and trends over time did not correlate with outcome. Conclusions. A6 given daily continuously is well tolerated at all dose levels, without any dose-limiting toxicity. Based on the preliminary activity of A6, a phase II trial is underway in ovarian cancer.

Purpose IM862 is a synthetic dipeptide (l-glutamine l-tryptophan) with in vitro and in vivo antiangiogenic properties. Phase I/II studies showed minimal toxicity and a response rate of 36% in AIDS-Kaposi's sarcoma. We report a 24-week, randomized, double-blinded, placebo-controlled phase III trial with the phase II dose, 5 mg intranasally every other day. Patients and Methods Two hundred two HIV-positive patients were enrolled, 104 on IM862 and 98 on placebo. Results Baseline characteristics were comparable except current antiretroviral therapy: 88% versus 96% (IM862 v placebo group; P = .042). The median treatment durations were 19.5 versus 24 weeks (IM862 v placebo). No significant difference was detected in response rate (IM862, 23%; 95% CI, 15% to 32% v placebo, 21%; 95% CI, 14% to 31%; P = .46), time to response (8.5 weeks v 14 weeks; P = .024), or duration of response. However, IM862 was associated with both a shorter time to response (8.5 weeks v 14 weeks; P = .024) and shorter median time to progression (16 weeks, 95% CI, 13 to 27 weeks v 35 weeks, 95% CI, 26 to 114 weeks; P = .012). Conclusion Despite promising phase I and phase II studies, IM862 5 mg every other day was not superior to placebo and may accelerate time to progression. Highly active antiretroviral therapy alone was associated with a substantial rate of sustained tumor response and may have contributed to prior estimates of IM862 response. Therapeutic trials for AIDS-Kaposi's sarcoma must account for ongoing immune reconstitution in the setting of concurrent highly active antiretroviral therapy that may confound estimates of therapeutic activity.

Despite advances in HAART, patients with HIV infection remain at significantly increased risk for intermediate- and high-grade B-cell non-Hodgkin lymphoma. The reasons for this persistent risk and the clinical and molecular correlates that predict outcomes and treatment responsiveness are areas of active investigation. Here we review the epidemiologic and pathobiologic features of AIDS-related lymphoma along with clinical evaluation and treatment options in patients with this disease.

PURPOSE OF REVIEW Kaposi sarcoma, which has reached epidemic proportions in parts of Africa and in the Western world, continues to pose a problem in patients with AIDS receiving highly active antiretroviral therapy (HAART). This article reviews the new and important information regarding the epidemiology, biology, and management of Kaposi sarcoma that was published in the last year. RECENT FINDINGS Worldwide Kaposi sarcoma herpesvirus/human herpesvirus 8 (HHV8) seropositivity has been found to exceed the incidence of Kaposi sarcoma. Therefore, investigators have justifiably implicated other cofactors (eg, blood-sucking arthropods, angiotensin converting enzyme inhibitors, hemodialysis, and iron) in the development of Kaposi sarcoma. In the transplant setting, Kaposi sarcoma lesions have been shown to originate from the engraftment of donor tumor cells. The detection of HHV8 in Kaposi sarcoma lesions has provided a new diagnostic tool to help differentiate Kaposi sarcoma from its mimics. Kaposi sarcoma lesional cells, now confirmed to be of lymphatic origin, have been shown to express several chemokine receptors, some of which may help explain the predilection for skin. Regression of Kaposi sarcoma has been characterized histologically for the first time. The finding that some tumor cells can remain in an atrophic state even in completely regressed lesions suggests that they have the potential to recur. Protease inhibitor-based and nonnucleoside reverse transcriptase inhibitor-based HAART regimens have been verified to be similarly effective. Although antiretrovirals have been noted to favorably alter the clinical characteristics of Kaposi sarcoma favorably, they seem not to alter the natural history of this disease. In the HAART era, because CD4 cell count was shown no longer to provide prognostic information about AIDS-related Kaposi sarcoma, the traditional classification system for staging AIDS-related Kaposi sarcoma has been refined. Also, a new staging system for classic Kaposi sarcoma has been proposed. SUMMARY Numerous advances have emerged regarding Kaposi sarcoma during the last year, many of which still need to be translated into clinically useful information. The results of new clinical trials involving antivirals purposely directed against HHV8 and antiretrovirals for HIV-uninfected people are anticipated. Finally, although investigators during this period did provide us with additional potential therapeutic targets, more novel approaches such as RNA interference and gene therapy have been also proposed as options in the future management of Kaposi sarcoma.

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.

Kaposi sarcoma (KS) is the most common tumor arising in HIV-infected patients and is considered an AIDS-defining illness by CDC guidelines. Recent advances in the elucidation of the pathogenesis of KS continue to uncover potential targets for therapies. Such targets include the KS herpesvirus/human herpesvirus 8 and the processes of angiogenesis and cellular differentiation. Five agents are currently approved by the FDA for the treatment o KS: alitretinoin gel for topical administration and liposomal daunorubicin, liposomal doxorubicin, paclitaxel, and interferon-alpha for systemic administration. Many more agents, particularly angiogenesis inhibitors and other pathogenesis-targeted therapies, are in clinical development. With increasing recognition that effective antiretroviral regimens are associated with both a decreased proportion of new AIDS-defining KS cases and a regression in the size and number of existing KS lesions, most, if not all, patients with KS should be advised to take antiretroviral drugs that will maximally decrease HIV-1 RNA levels.

Kaposi sarcoma is considered a neoplasm of lymphatic endothelium infected with Kaposi sarcoma-associated herpesvirus. It is characterized by the expression of lymphatic lineage-specific genes by Kaposi sarcoma tumor cells. Here we show that infection of differentiated blood vascular endothelial cells with Kaposi sarcoma-associated herpesvirus leads to their lymphatic reprogramming; induction of approximately 70% of the main lymphatic lineage-specific genes, including PROX1, a master regulator of lymphatic development; and downregulation of blood vascular genes.

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.

Kaposi's sarcoma (KS) is an angioproliferative lesion that may regress or progress. Progression is related to spindle cell proliferation and the expression of human herpes virus-8 latency genes, including latent nuclear antigen-1 (LNA-1), cyclin-D1, and bcl-2. KS regression has not been well characterized histologically. Therefore, this study was undertaken to characterize the histopathology of pharmacologically induced regressed cutaneous KS.Skin punch biopsies from eight patients with acquired immunodeficiency syndrome (AIDS)-related KS, that regressed following chemotherapy with paclitaxel or the angiogenesis inhibitor Col-3, were investigated by light microscopy. Comparative immunophenotyping on pre- and post-treatment specimens for CD31, LNA-1, cyclin-D1, bcl-2, and CD117 (c-kit) was performed.Clinical and histologic features of regression were similar for paclitaxel and Col-3 treatment. On clinical examination, lesions flattened, became smaller, and lost their purple-red appearance, resulting in an orange-brown macule. Histological regression was divided into partial (n = 3) and complete (n = 5) regression. Partially regressed lesions had a significant reduction of spindle cells in the dermal interstitium, with residual spindle cells arranged around superficial and mid-dermal capillaries. Complete regression was characterized by an absence of detectable spindle cells, with a slight increase in capillaries of the superficial plexus. All regressed samples exhibited a prominent, superficial, perivascular, lymphocytic infiltrate and abundant dermal hemosiderin-laden macrophages. This clinicopathologic picture resembled the findings of pigmented purpura. CD31 staining correlated with the reduction of spindle cells. Regression was accompanied by a quantitative and qualitative decrease in LNA-1 and cyclin-D1 immunoreactivity, but no change in bcl-2 or c-kit expression.Pharmacologically induced regression of AIDS-related cutaneous KS is characterized by a complete loss or decrease of spindle cells, increased lymphocytes, and prominent dermal siderophage deposition. Without any prior knowledge of the history of KS regression following therapy, regressed KS lesions may be misdiagnosed clinically and histologically as pigmented purpuric dermatitis.

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.

The November 2002 COM. A 72-year-old immunocompetent woman presented with recent confusion, memory loss, visual and a gait disturbance. MRI scans demonstrated a T2 hypointense, gadolinium enhancing mass in her pineal region. A whole body CT scan identified a large retroperitoneal mass and significant lymphadenopathy. She underwent a biopsy of the pineal lesion. The intraoperative smear contained discohesive, basophilic malignant cells of moderate size that had only scant cytoplasm, an increased nuclear-to-cytoplasmic ratio and irregular, hyperchromatic nuclei containing prominent nucleoli. Mitotic figures, apoptotic and lymphoglandular bodies were frequent. Histologic examination showed malignant cells infiltrating and almost completely replacing the residual pineal gland. The tumor cells immunoreacted with LCA and CD-20. Scattered CD3 and UCHL-1 positive cells were also present. The diagnosis was stage IV, high grade, large B-cell lymphoma involving the pineal gland and retroperitoneum. Four cycles of systemic chemotherapy significantly reduced the patient's retroperitoneal mass. However, a repeat head MRI scan continued to show gadolinium-enhancement in the pineal region, now with extension into contiguous brain parenchyma and the subependymal region. The patient died 4 months after presentation. At autopsy, the lymphoma encased the pineal region and disseminated along the ventricular walls and into the subarachnoid spread. Pineal-region tumors are rare in the elderly population, and although unusual, lymphomas should be considered in this context. The behavior of this circumventricular organ lymphoma was comparable to both peripheral and primary central nervous system lymphomas.

Cytokine dysregulation in human immunodeficiency virus type 1 (HIV-1) infection has been documented in numerous studies and has been cited as an important component in the pathogenesis of this retroviral infection. Pharmacological modification of cytokine dysregulation, therefore, has been suggested as a therapeutic modality for HIV-1 infection. Dr. Dezube of Beth Israel Hospital (Boston) concisely reviews the state of our knowledge regarding the effects of pentoxifylline on expression of tumor necrosis factor-alpha, a cytokine known to influence HIV-1 replication and to play a possible role in the clinical manifestations of advanced infection with this virus. Pentoxifylline, a trisubstituted xanthine derivative, has been used to decrease blood viscosity and is reasonably well tolerated by most recipients of the drug. Results of preliminary studies, many of which were conducted by Dr. Dezube, suggest that use of this agent in combination with antiretroviral compounds may prove useful in the treatment of patients with HIV-1 infection.

Kaposi's sarcoma-associated herpesvirus (KSHV) latently infects KS tumors, primary effusion lymphomas (PELs), and PEL cell lines. K12 (T0.7) is the most abundant transcript expressed in latent KSHV infection. We characterize here the K12 transcript from a PEL tumor prior to passage in cell culture. The PEL tumor KSHV K12 transcript contained additional complex nucleotide repeat elements compared to the previously described K12 message of the BCBL-1 PEL cell line. The PEL tumor lacked kaposin B, the predominant BCBL-1 K12 protein product, but encoded kaposins A and C. The K12 transcript was spliced and the splicing event occurred in all KSHV isolates tested. The 5′ end of the K12 transcript was mapped by 5′ RACE (rapid amplification of cDNA ends) and S1 nuclease protection assays and was at the site of an active promoter. This work demonstrates that the K12 transcript contains variable, complex repeat elements, is spliced and is expressed from a novel KSHV promoter.

Kaposi sarcoma–associated herpesvirus (KSHV)/human herpesvirus-8 (HHV-8) is causally associated with Kaposi sarcoma (KS). The absence of a cell culture system that effectively reproduces the composite mechanisms governing initiation and maintenance of HHV-8 infection (lytic and latent) in KS endothelial cells, however, has left important questions unanswered. Here, we report a culture system in which the earliest events that accompany HHV-8 infection could be surveyed in primary endothelial cells. Binding of HHV-8 to microvascular dermal endothelial cells (MVDECs) was directly compared with other primary target cells implicated in HHV-8–associated diseases. Virus attachment, fusion, internalization and transport within MVDECs was monitored by electron microscopy. Studies of genome configuration revealed that rapid circularization of the viral DNA occurred on entry, though by 72 hours after infection linear DNAs accumulated and early as well as late lytic RNAs (T1.1, K8.1) could be detected. The latency transcripts (LT1/LT2) were first detected on day 8, demonstrating that both lytic and latent infection were initiated. Although most lytic transcripts accrued until passage, open-reading frame–74 RNAs fluctuated with a fixed periodicity, suggesting that early replication after infection of MVDECs was synchronous.

Kaposi's sarcoma is the most common tumor arising in HIV-infected patients and is an AIDS-defining illness by the Centers for Disease Control guidelines. Recent advances in the elucidation of the pathogenesis of KS are uncovering potential targets for KS therapies. Such targets include the processes of angiogenesis and cellular differentiation and the Kaposi's sarcoma herpesvirus/human herpesvirus-8. With the increasing recognition that effective antiretroviral regimens are associated with both a decreased proportion of new AIDS-defining Kaposi's sarcoma cases and a regression in the size of existing Kaposi's sarcoma lesions, most, if not all, Kaposi's sarcoma patients should be advised to take antiretroviral drugs that will maximally decrease HIV-1 viral load. Five agents are currently approved by the US FDA for the treatment of Kaposi's sarcoma; alitretinoin gel for topical administration; and liposomal daunorubicin, liposomal doxorubicin, paclitaxel and interferon-alpha for systemic administration. Many more agents, particularly angiogenesis inhibitors and other pathogenesis-targeted therapies are in early clinical development. Over the next 5 years, we may see even more of these pathogenesis-targeted therapies in trials and just as important we may identify, develop and validate clinically practical tools for assessing the biological effects of these therapies. The next 5 years may also bring a better understanding of the pharmacokinetic interactions among the many agents in the Kaposi's sarcoma and AIDS armamentariums.

Breast enlargement, a condition that was rarely reported in the era before highly active antiretroviral therapy, is emerging as a problem in the treatment of male human immunodeficiency virus (HIV)-infected patients. Evaluation of this condition must distinguish between gynecomastia (proliferation of ducts and periductal stroma), lipomastia (adipose-tissue deposition), and malignancy. We describe 13 HIV-infected men, all of whom had exposure to antiretroviral therapy, who presented with breast enlargement. Nine of these patients had gynecomastia, only 1 had lipomastia, and 3 had lymphoma (2 had non-Hodgkin lymphoma and 1 had Hodgkin disease). Gynecomastia was unilateral in all but a single case. In addition, all but 1 of our patients with gynecomastia had prolonged exposure to protease inhibitors. Six patients had potential causes of gynecomastia other than antiretroviral therapy, including liver disease (in 2 patients), mild hypogonadism (in 1), long-term marijuana use (in 2), and use of medications that have known associations with gynecomastia (in 3). Although most causes of breast enlargement in HIV-infected men are likely to be benign, malignancies other than carcinoma are of concern.

Myelodysplasia is a frequent consequence of HIV infection, but acute myeloid leukemia (AML) is rare. Clinical presentations and outcomes of patients with HIV and subsequent AML are reviewed.Five HIV-infected individuals who were subsequently diagnosed with AML were evaluated and treated. A further 42 cases of AML among patients with antecedent HIV infection were identified using MEDLINE, AIDSLINE, and CancerLit searches.HIV infection was present for a median of 48 months (71-180) before AML was diagnosed and the median reported CD4 cell count was 210 x 106 cells/l. In five instances, a delay in diagnosis occurred when cytopenias were initially attributed to HIV or zidovudine-based therapy. In 45 patients, diagnosis was according to the French-American-British (FAB) leukemia classification schema and in two the FAB type was not specified. M2 (n = 15) and M4 (n = 14) subtypes represented 64% (29/45) of reported cases. Patients with a CD4 cell count200 x 106 cells/l (n = 11) had a median survival time of 7 weeks, while patients with a CD4 cell countor= 200 x 106 cells/l (n = 7) had a median survival of 7 months (P = 0.005). Although long-lasting chemotherapy-induced responses were rare, the majority of treated patients did achieve complete hematologic remissions. Treatment-related morbidity did not appear to be excessive.In the absence of randomized and prospective clinical studies to guide decision making, this analysis indicates that induction chemotherapy may be a reasonable option for selected HIV-infected patients with AML and adequate immune function.

Pilonidal disease is a common acquired condition believed to arise from penetration of short hairs into the subcutaneous tissue that induces a cyst or sinus formation. Malignant degeneration is rare and is typically seen only after decades of antecedent disease presence. Condylomata acuminatum in association with pilonidal disease have been described in two prior case reports, however, the coexistence of condyloma with pilonidal disease complicated by malignant degeneration has not been previously reported. Condylomata have known potential for malignant degeneration and are correlated with human papilloma virus infection, with certain serotypes of higher oncogenic potential. Coinfection with human immunodeficiency virus and human papilloma virus is associated with higher rates of anal neoplasia. We report two cases of human immunodeficiency virus-infected patients with the constellation of pilonidal disease, condylomata acuminatum, and subsequent malignant degeneration into squamous-cell carcinoma. In contrast to other case reports in the literature, these two patients had considerably shorter antecedent periods of pilonidal disease before malignant degeneration was detected. Both cases also had intractable courses. We conclude that the existence of condylomata acuminatum and pilonidal disease in an immunocompromised patient may represent a more ominous condition than solitary pilonidal disease. Therefore, careful inspection of the pilonidal area in human immunodeficiency virus-infected patients presenting with condylomata is important and earlier intervention should be considered. Moreover, further evaluation of the prevalence of squamous-cell carcinoma arising from pilonidal disease complicated by condylomata, particularly in the immunosuppressed, is warranted.

Kaposi sarcoma (KS) is the most common tumor arising in HIV-infected patients and is an AIDS-defining illness by the Centers for Disease Control guidelines. The clinical course of AIDS-related KS is highly variable, ranging from minimal stable disease to explosive growth. Recent advances in the elucidation of the pathogenesis of KS are uncovering many potential targets for KS therapies. Such targets include the processes of angiogenesis and cellular differentiation, sex hormones, and the KS herpesvirus/human herpesvirus-8. With the increasing recognition that effective antiretroviral regimens are associated with both a decreased proportion of new AIDS-defining KS cases and a regression in the size of existing KS lesions, most, if not all, KS patients should be advised to take antiretroviral drugs that will maximally decrease HIV-1 viral load. Five agents are currently approved by the Food and Drug Administration for the treatment of KS: alitretinoin gel for topical administration; and liposomal daunorubicin, liposomal doxorubicin, paclitaxel, and interferon-alpha for systemic administration. Many more agents, particularly angiogenesis inhibitors, are in early clinical development. The potential interaction between anti-KS agents and antiretroviral agents needs to be kept in mind. Virtually all patients with KS can derive benefit from the many approved and investigational agents developed through years of collaborative translational and clinical research.

The angiopoietins are recently described growth factors for vascular endothelium. The Tie1 and Tie2 receptors are expressed by endothelium. Acquired immune deficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS) and cutaneous angiosarcoma are malignancies of endothelial origin. KS involves primarily the skin and mucosal surfaces and is common in AIDS patients. In an effort to determine whether the angiopoietins and Tie receptors play a role in the pathobiology of angiosarcoma and KS, we studied the expression of angiopoietin-1, angiopoietin-2, angiopoietin-4, Tie1, and Tie2 mRNAs in biopsies of KS from 12 AIDS patients, in biopsies of cutaneous angiosarcoma from two patients, and in control biopsies of normal skin from three volunteers by in situ hybridization. Strong expression of angiopoietin-2, Tie1, and Tie2 mRNAs was detected in the tumor cells of KS and cutaneous angiosarcomas, in contrast to the focal low-level expression in normal skin biopsies. Focal low-level expression of angiopoietin-1 was seen in KS, cutaneous angiosarcomas, and in normal skin. Focal low-level expression of angiopoietin-4 was identified in a minority of KS lesions. These findings suggest that the angiopoietins and Tie receptors may play an important role in the pathobiology of KS and cutaneous angiosarcoma and identify additional potential targets for therapeutic intervention in these vascular malignancies.

Background A retrospective examination of the utility of bone marrow sampling for identification of microorganisms was performed in an urban tertiary care hospital. Methods A retrospective review of culture and histology data from bone marrow specimens was performed for a 10-year period. Results Neither bone marrow culture nor special stains for microorganisms provided incremental benefit in identifying microbial agents compared with other methods such as blood culture. Conclusion Bone marrow aspiration/biopsy should only be performed selectively for diagnosis of an infectious etiology.

Cytokine and immune activation marker levels in plasma are valuable measurements of immune status and treatment effects in human immunodeficiency virus (HIV) infection and AIDS. Five populations representing various stages of disease were studied: controls, 2 AIDS groups with50/mm3 CD4 cells, and 2 groups of HIV-positive subjects-1 with stable CD4 T cells (median, 545/mm3) and 1 with100/mm3 CD4 cell decline in 1 year. Relatively stable levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptor (R)II, soluble interleukin-2R, neopterin, and beta2-microglobulin (beta2M) were documented over 5-8 weeks in patients with AIDS and for 1-4 years in the other groups. beta2M was generally the most stable marker. Interferon-gamma levels, however, fluctuated substantially. Individuals, whether normal or HIV-positive, maintain characteristic plasma levels of cytokines and immune activation markers. Thus, documented changes, in excess of the variability observed in this study, are likely to be significant indicators of change in disease status or effects of therapy.

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.

Dear Editor, Splenectomy is a clinically effective therapeutic intervention against chronic immune thrombocytopenic purpura (ITP) [1]. Severe, potentially life-threatening infections are a major long-term complication of splenectomy [2]. Certain infections may present with thrombocytopenia, which, in the case of splenectomized patients with a history of ITP, may be mistaken for ITP recurrence. We report what is, to the best of our knowledge, the first case of babesiosis in a patient with stable chronic ITP who had previously undergone splenectomy. The patient was a 66-year-old woman from Nantucket Island, MA, USA, with a known diagnosis of ITP, who was treated with prednisone, intravenous immunoglobulin, and rituximab before eventually undergoing splenectomy. Her postsplenectomy platelet count remained stable in the 60,000–70,000 range, without treatment. Two years following splenectomy, she presented with fever (temperature 101°F), chills, myalgias, and arthralgias. She denied any bleeding or bruising. Physical examination was unremarkable. Complete blood count demonstrated a hematocrit of 45.5 vol%, a white blood cell count of 4,600 cells/μL, and a platelet count of 10,000 platelets/μL. Liver function tests were notable for a slightly elevated alanine transaminase of 64 and aspartate transaminase of 49. Peripheral smear showed characteristic Howell-Jolly bodies and rare intraerythrocytic parasite ring forms in normal-sized red blood cells (Fig. 1). Babesiosis was confirmed by extremely high IgG and IgM titers to Babesia of 1:1,024 and 1:1,280, respectively, and a positive polymerase chain reaction (PCR). Importantly, there were no detectable antibodies for Lyme disease and ehrlichiosis. The patient was started on azithromycin and atovaquone and on a tapering dose of prednisone. She received 4 weeks of antibiotic therapy and her platelet count increased to 325,000 platelets/μL. Four weeks after completing the course of antibiotics, the platelet count dropped again to 24,000 platelets/μL. She continued to have circulating intracellular parasites on peripheral smear, and Babesia PCR and serologies were still positive. Atovaquone, azithromycin, and prednisone treatments were restarted. Her platelet count steadily improved, and only after 4 months of antibiotic therapy did the PCR for Babesia normalize. Steroids were discontinued. Her platelet count returned to her baseline value of 60,000–70,000, off immunosuppressive and anti-infective therapies. The approach to thrombocytopenia should always include an accurate history, physical examination, and examination of the peripheral blood smear. Splenectomy predisposes to infections that may present with thrombocytopenia, including ehrlichiosis, Colorado tick fever, Rocky Mountain spotted fever, babesiosis, and malaria. While patients can have a recurrence of ITP, other causes of thrombocytopenia need to be excluded. Babesiosis is a worldwide tick-borne disease caused by the intraerythrocytic protozoan Babesia [3]. Humans are infected by various tick vectors (Ixodes scapularis and Ixodes ricinus) and rarely by transfusions. In the USA, endemic areas include the islands off the coasts of MA and NY [4]. Symptoms include fever, chills, weakness, and myalgias. Babesiosis may present with hemolytic anemia, lymphopenia, and thrombocytopenia. Splenectomized patients may develop a fulminant infection with massive intravascular hemolysis [5]. The peripheral blood smear reveals small coccoid and dumbbell-shaped organisms. The trophozoites are small rings similar to those of Plasmodium falciparum. The parasites can be pyriform (pear shaped). Babesia microti is associated with Maltese cross forms and ring forms. IgM or P. A. Konstantinopoulos . K. B. Miller . B. J. Dezube (*) Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA e-mail: bdezube@bidmc.harvard.edu Tel.: +1-617-6677082 Fax: +1-617-9758030

Proinflammatory cytokines may be important in the pathogenesis of human immunodeficiency virus type 1 (HIV-1) disease. Tenidap decreases interleukin (IL)-6, IL-1, and tumor necrosis factor (TNF) production by peripheral blood mononuclear cells and decreases IL-6 plasma levels in rheumatoid arthritis patients. In this randomized double-blind study, 43 HIV-1-infected patients received tenidap (120 mg) or placebo daily for 6 weeks and then crossed over to the alternative therapy for an additional 6 weeks. Mean entry CD4 cell count was 140/microL. Analyses were performed on cytokines, acute-phase proteins, virus load, and CD4 cell counts. With the exception of small differences in plasma TNF levels, tenidap had no significant effect on these indices. Significant correlations of plasma IL-6 and TNF levels with HIV-1 RNA were noted. Six patients discontinued tenidap due to rash. The effects of tenidap in HIV-1 infection contrast to results in arthritis patients, in whom tenidap decreased plasma levels of IL-6 and acute-phase proteins.

Topotecan (TPT), a known inhibitor of topoisomerase I, has previously been shown to inhibit the replication of several viruses. The mechanism of inhibition was proposed to be the inhibition of topoisomerase I. We report that TPT decreased replication of human immunodeficiency virus type 1 (HIV-1) in CPT-K5, a cell line with a topoisomerase I mutation. TPT inhibited production of HIV-1 RNA and p24 in CPT-K5 and wild-type cells equally effectively. The antiviral effects of TPT were observed not only in the topoisomerase-mutated CPT-K5 line but also in peripheral blood mononuclear cells (PBMC) acutely infected with clinical isolates and in OM10.1 cells latently infected with HIV and activated by tumor necrosis factor alpha. Little toxicity from TPT was noted in HIV-1-infected PBMC and in CPT-K5 and OM10.1 cells as measured by cell growth and proliferation assays. These observations suggest that TPT targets factors in virus replication other than cellular topoisomerase I and inhibits cytokine-mediated activation in latently infected cells by means other than cytotoxicity. These results suggest a potential for TPT and for other camptothecins in anti-HIV therapy alone and in combination with other antiretroviral drugs.

Interleukin-6 (IL-6) may be important in the pathogenesis of HIV-1 because of its ability to induce HIV-1 expression in infected cells in vitro. Tenidap, a structurally and functionally novel antirheumatic drug affecting diverse biologic processes, has been shown to reduce IL-6 production by peripheral blood mononuclear cells stimulated with lipopolysaccharide. Tenidap also inhibits the activity of chloride-bicarbonate exchangers and causes acidification of the cytoplasmic compartment that is similar to the effect of the anion transport inhibitor UK5099. Furthermore, tenidap inhibits the cyclooxygenase-mediated pathway of arachidonic acid metabolism as do the nonsteroidal antiinflammatory drugs (NSAIDs). Here we show that tenidap decreased HIV-1 replication as measured by p24 core antigen in the acutely infected CD4+ T-lymphocyte lines H9 and Jurkat, in the acutely infected monocyte line U937, and in its chronically infected subclone U1.8/HIV. These effects were seen at concentrations in the range of 3 to 15 microM, well below those toxic to cells. The antiviral effects of tenidap may be independent of its ability to reduce IL-6 production based on the observations that these effects were as prominent in IL-6 nonresponsive lines as in IL-6 responsive lines and that the inhibition of p24 production was not reversed by exogenous IL-6.

Background NEDD8-activating enzyme (NAE) regulates the NEDD8 conjugation pathway, and is required for activity of the cullin-RING E3 ligases (CRLs). CRLs control proteasomal degradation of several substrates involved in cell-cycle regulation, signal transduction, DNA replication and stress response including proteins important for survival of AML cells. MLN4924, a first-in-class NAE inhibitor, has shown antitumor activity in preclinical AML models. This study evaluated safety and tolerability of MLN4924 given on multiple dosing schedules. A maximum tolerated dose (MTD) of 59 mg/m2 given on days 1, 3 and 5 of a 21-day cycle (schedule A) was previously reported (Erba et al, EHA 2011); complete responses were observed in 4/27 patients for this schedule (most common AE: diarrhea [44%], most common Gr ≥3 AE: febrile neutropenia [33%]). Here we report on two additional schedules. Methods Adults with AML or MDS and good performance status received MLN4924 as a 60-min IV infusion on one of two schedules for up to 1 year or until disease progression. Schedule B patients received escalating doses of MLN4924 on days 1, 4, 8 and 11 every 21 days. Schedule E patients received a fixed dose of MLN4924 on days 1, 3 and 5 every 21 days. Adverse events (AEs) and responses were graded according to published guidelines. Serial blood samples were obtained during cycle 1 for pharmacokinetic (PK) and pharmacodynamic analyses. Results On schedule B: 26 patients were enrolled (77% male), median age was 70.5 yrs, 23 had AML and 3 had MDS (2 had advanced disease with marrow blasts exceeding 10%). Patients received MLN4924 at 83 (n=19), 110 (n=4), and 147 mg/m2 (n=3). On Schedule E: 16 patients (69% male) received 50 mg/m2 MLN4924, median age was 70.5 yrs, 14 AML and 2 MDS (1 with advanced disease). Three patients on schedule B had dose-limiting toxicities (DLTs): 1 patient at 110 mg/m2; orthostatic hypotension (Gr 3); 2 patients at 147 mg/m2; cardiac failure (Gr 4; n=1), fatal lactic acidosis, hypotension, gastrointestinal necrosis, acute renal failure and myocardial ischemia (each Gr 4; n=1). On schedule E, 2 patients had DLTs: morbilliform rash (Gr 3; n=1); and increased aspartate/alanine aminotransferases (Gr 2/3; n=1). Most common all-grade and Gr ≥3 AEs are shown in the table. The MTD for Schedule B was determined as 83 mg/m2. On schedules B/E, 3/2 patients received ≥4 cycles, 0/4 remain on treatment; discontinuations were due to progressive disease (11/10), AEs (8/0), and other reasons (7/2) respectively. In 17 patients treated at 83 mg/m2 on schedule B and 16 patients on schedule E, individual PK profiles showed a biphasic disposition phase following completion of the first infusion. MLN4924 plasma concentrations were detectable 24–48 hours (schedule B) and 24 hours (schedule E) post dosing. Schedule B geometric mean (%CV) Cmax was 1255 ng/mL (25.1%), AUC24hr was 3936 ng•h/mL (22.6%); schedule E values were Cmax of 669 ng/mL (24.4%) and AUC24hr of 2614 ng•h/mL (21.4%). Observed increases in mean Cmax and AUC24hr were dose-proportional between 50 and 83 mg/m2 after single dosing. Pharmacodynamic data demonstrated evidence of target and pathway inhibition for all patients on both schedules. On schedule B, of 20 response-evaluable patients (18 AML, 2 MDS), 2 (11%) AML patients had partial responses (PR), 13 (72%) had stable disease. On schedule E, of 12 response-evaluable patients (11 AML, 1 MDS), 1 (8%) AML patient had a PR, 7 (59%) maintained stable disease and the MDS patient (8%) had a response. Conclusions Both schedules appeared to be generally well tolerated and NAE inhibition with MLN4924 resulted in clinical activity in highly refractory/multiply relapsed patients. Based on safety and observed clinical activity across schedules, the recommended phase 2 dose for single agent MLN4924 in AML/MDS is 50 mg/m2 given on days 1, 3 and 5 of a 21-day cycle. A study of MLN4924 with azacitidine in treatment-naïve AML patients older than 60 years is ongoing (NCT01814826). Disclosures: Off Label Use: Investigational agent MLN4924 for the treatment of patients with AML and high-grade or low-grade MDS. Hua:Millennium: The Takeda Oncology Company: Employment. Blakemore:Millennium: The Takeda Oncology Company: Employment. Faessel:Millennium: The Takeda Oncology Company: Employment. Dezube:Millennium: The Takeda Oncology Company: Employment. Medeiros:Millennium: The Takeda Oncology Company: Research Funding.

To the Editor: Various hematologic disorders, including plasma-cell dyscrasia,1 are increasingly being diagnosed in patients with human immunodeficiency virus (HIV) infection. Monoclonal gammopathy of undetermined significance (MGUS), generally considered to be a disease of the elderly, affects up to 3 percent of persons 50 years of age or older.2 Nevertheless, the presence of a monoclonal protein in HIV-positive persons is not a rare event.3 Since the standard care for MGUS is regular follow-up and monitoring for progression, patients in whom MGUS is the initial manifestation of HIV infection could miss out on the benefit of early antiretroviral therapy, should the . . .