BACKGROUND-Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.

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 ∼70% of the main lymphatic lineage-specific genes, including PROX1, a master regulator of lymphatic development; and downregulation of blood vascular genes.Kaposi sarcoma is the most frequently occurring malignant tumor in individuals infected with the human immunodeficiency (HIV) virus and also occurs in HIV-negative immunosuppressed individuals. Kaposi sarcoma mainly affects the skin and forms lesions of various types, including early inflammatory and patch stage lesions, and tumors with a predominant population of spindle cells. Infection with Kaposi sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus-8) is essential for the formation of Kaposi sarcoma tumors 1,2 . Both latent viral genes, such as latency-associated nuclear antigen (LANA), and lytic viral genes, such as viral G-protein-coupled receptor, have been implicated in KSHV-mediated tumorigenesis 3 . In Kaposi sarcoma lesions, cells infected with KSHV characteristically appear spindle-shaped and are associated with slit-like spaces that sometimes contain red blood cells. Kaposi sarcoma is considered to be a neoplasm of KSHV-infected lymphatic endothelium, due to the morphological characteristics of the tumor cells and the expression of several lymphatic lineage-specific proteins, including VEGFR-3 and podoplanin [4][5][6][7] .The homeobox gene PROX1 is a master gene that controls lymphatic vessel development and differentiation 8 , and ectopic expression of PROX1 in differentiated blood vascular endothelial cells leads to lymphatic endothelial reprogramming of these cells 9,10 . Because KSHV can infect blood vascular endothelium, such as human umbilical vein endothelial cells, in vitro, we wondered whether KSHV infection might result in lymphatic reprogramming of blood vascular endothelium, potentially involving upregulation of PROX1.We first characterized the lineage-specific gene expression of cultured human lymphatic endothelial cells (LECs) versus blood vascular endothelial cells (BECs) 11 by Affymetrix HU133A gene arrays. We found that LECs, but not BECs, expressed PROX1, XLKD1 (encoding the hyaluronan receptor LYVE-1) and a number of other lymphatic lineage-specific genes ( Table 1). We then infected human dermal microvascular endothelial cells (HDMECs) with KSHV and carried out two independent transcriptional profiling studies 7 d later. Efficient KSHV infection was confirmed by high levels of expression of LANA mRNA in infected HDMECs. We found that 3-7% of infected HDMECs were ORF59-positive and 1.5-3% were K8.1 positive, in agreement with previous results [12][13][14] . This indicates that <10% of the cells were undergoing lytic reac...

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.

Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.

Plasmablastic lymphoma (PBL) is a distinct subtype of non-Hodgkin B-cell lymphoma, originally described with a strong predilection to the oral cavity of human immunodeficiency virus (HIV)-infected individuals. Data regarding patient age and gender, HIV status, initiation of and response to highly active antiretroviral therapy (HAART), tumor extent, pathology, treatment, and outcome were extracted from 112 cases of PBL identified in the literature. The median age at presentation was 38 years with a male predominance of 7:1, and the median CD41 count was 178 cells/mm 3 . PBL presented on average 5 years after diagnosis of HIV. Common primary sites of presentation included the oral cavity, gastrointestinal tract, and lymph nodes. Most cases presented with either stage I or stage IV disease. There was a variable expression of B-cell markers in tumor cells, but plasma cell markers were expressed in all cases. EBV was detected in 74%. Chemotherapy was used to treat 55% patients and was combined with radiotherapy in 21% cases. Complete response was obtained in 66% of treated cases; the majority of these responses were seen after CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). The refractory/relapsed disease rate was 54%. Death occurred in 53% of patients, with a median overall survival of 15 months. Sex, CD41 count, viral load, clinical stage, EBV status, primary site of involvement, and use of CHOP failed to show an association with survival. PBL is an aggressive B-cell lymphoma that presents in both oral and extra-oral sites of chronically HIV-infected immunosuppressed young men. Am. J. Hematol. 83:804-809, 2008. V

IMPORTANCE Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. OBJECTIVE To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. DESIGN, SETTING, AND PARTICIPANTS The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to Ն23.0 months). Data were collected from

BackgroundIn advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma.MethodsIn this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed.ResultsTwenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4–44.4 weeks).ConclusionsGC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments.Trial RegistrationClinicaltrials.gov NCT00356460

SummaryThis trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m 2 , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.