The combination of a DNA hypomethylating agent with a histone deacetylase inhibitor has synergistic antileukemia activity and may restore sensitivity to all-trans retinoic acid (ATRA). We conducted a phase 1/2 study of the combination of 5-azacitidine (5-AZA), valproic acid (VPA), and ATRA in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. 5-AZA was administered subcutaneously at a fixed dose of 75 mg/m 2 daily for 7 days. VPA was dose-escalated and given orally daily for 7 days concomitantly with 5-AZA. ATRA was given at 45 mg/m 2 orally daily for 5 days, starting on day 3. A total of 53 patients were treated. Their median age was 69 years (range, 5-84 years). The maximum tolerated dose of VPA in this combination was 50 mg/kg daily for 7 days. Dose-limiting toxicity was reversible neurotoxicity. The overall response rate was 42%. In previously untreated older patients, the response rate was 52%. Median number of courses to response was 1 (range, 1-3 courses). Median remission duration was 26 weeks, and median survival has not been reached. A significant decrease in global DNA methylation and induction of histone acetylation were achieved. VPA blood levels were higher in responders (P < .005). In conclusion, the combination studied is safe and has significant clinical activity. This clinical trial was registered at www.clinicaltrials.gov as no. NCT00326170.(Blood.

Marked activation of endothelium, platelets, and leukocytes occurs in VTE, and VTE, or the accompanying inflammatory process, involves the release of EMP and formation of EMP-monocyte conjugates and PLC. These findings support prior studies suggesting that release of EMP and their binding to monocytes are key events in thrombogenesis. Our findings also support the concept that the formation of PLC regulates leukocyte activation and participates in linking thrombosis with inflammation.

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Follicular dendritic cell sarcomas (FDCS) are grouped with the histiocytic and dendritic cell neoplasms. The natural history and response to different treatments have not been well established. The cases of 14 patients with FDCS who were seen at M. D. Anderson between 1995 and 2005 were reviewed. Median patient age was 48 years (range, 25-69 years). Histologically, four cases showed low-grade features, three cases showed low-grade features with focal high-grade features, and five cases showed high-grade features. Tumors were positive for CD21, CD23, and CD35 in 83, 90, and 44% of cases, respectively. Twelve (92%) of 13 tumors were strongly positive for epidermal growth factor receptor. Information on initial treatment was available in 11 patients, which included surgery alone in one patient, surgery and radiation in two, surgery and chemotherapy in one, chemotherapy alone in three, chemotherapy and radiation in one, surgery followed by radiation and chemotherapy in three patients. In eight patients the initial chemotherapy regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone. Complete remission was achieved in 7 (63%) of 11 patients. Ten patients were alive at a median follow up of 22 months, 3 (23%) of 13 had no evidence of disease, and 7 (53%) of 13 patients were alive with disease. Follicular sarcoma is an aggressive neoplasm. Although most of the patients initially responded to treatment, the majority of them (81%) relapsed. A better understanding of the biology of FDCS could guide our efforts in the development of new treatment modalities for this rare disease. Am. J. Hematol. 82:725-728, 2007. V

Our data support the hypothesis that early increased, not decreased, inflammatory response as measured by our markers is associated with improved survival rate. A high negative correlation was found between some of these markers and Sequential Organ Failure Assessment score.

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Purpose: 5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, we conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers. Experimental Design: 5-AZA was administered s.c. daily for 10 days.Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 Ag/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m 2 and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1and 10 of each cycle when patients agreed to provide them. Results: Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m 2 of 5-AZA in combination with valproic acid. Doselimiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m 2 of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed. Conclusion: The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m 2 for 5-AZA in patients with advanced malignancies.

Introduction: Data of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)positive NSCLC (cohort E) are reported (NCT02443324). Methods: In this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cellinflamed, Gajewski, and effector T cells) and CD274 gene expression. Results: Cohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n ¼ 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ! 50%) and lower levels (TPS 1%-49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry. Conclusions: First-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression.