Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.next-generation sequencing | cancer genetics | cancer heterogeneity D iffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults (1). Although nearly half the patients can be cured with standard regimens, the majority of relapsed patients succumb. Thus, there is an urgent need to identify the genetic underpinnings of the disease and to identify novel treatment strategies. Gene expression profiling (2, 3) has uncovered distinct molecular signatures for DLBCL subtypes that have unique biology and prognoses. High-throughput sequencing has provided rich opportunities for the comprehensive identification of the genetic causes of cancer (4-6). Whereas exhaustive portraits of individual cancer genomes are emerging, the degree to which these genomes represent the disease is unclear.We generated a detailed analysis of a DLBCL genome by sequencing a primary human tumor and paired normal tissue (Dataset S1). We further characterized the genetic diversity of DLBCL by sequencing the exomes of 73 DLBCL primary tumors (34 with matched normal DNA) and 21 DLBCL cell lines for comparative purposes. This in-depth sequencing identified 322 DLBCL cancer genes that were recurrently mutated in DLBCLs. We also experimentally validated the effects of genetic alteration of PIK3CD, an oncogene that we identified in DLBCL. Our work provides one of the largest genetic portraits yet of human DLBCLs and offers insights into the molecular heterogeneity of the disease, especially in the context of other recently published studies in DLBCL (7, 8).

Summary Background Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine (DAC) and deoxyguanosine that is resistant to degradation by cytidine deaminase. Methods This is a first-in-human pharmacokinetic (PK)- and pharmacodynamic (PD)-guided Phase 1 dose-escalation study in adults with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients with MDS or AML refractory to, or relapsed after, standard treatment were randomly assigned to one of two regimens of subcutaneous (SC) guadecitabine: Daily×5 or Once Weekly for three weeks. Stratification was based on disease (MDS vs. AML). Treatment assignment was not blinded. A Twice Weekly for three weeks regimen was later added to the study. All regimens were given in 28-day cycles. The primary objective was the safety profile of all regimens and the recommended dose and schedule for phase 2 by either maximum tolerated dose (MTD) or biologically effective dose (BED). All patients who received at least one treatment were included in the analyses. Enrollment is complete and all patients have finished treatment. This study is registered with ClinicalTrials.gov, number NCT01261312. Findings 93 patients were treated (74 AML and 19 MDS): 44 on Daily×5 (3–125 mg/m2/d), 34 on Once Weekly (6–125 mg/m2/d), and 15 on Twice Weekly (60 and 90 mg/m2/d). Guadecitabine SC produced a longer exposure window and half-life, and lower Cmax, of plasma DAC than intravenous DAC. The MTD was 90 mg/m2 in MDS on the Daily×5 regimen but was not reached in AML or on the other regimens. The most common Grade ≥3 adverse events were febrile neutropenia (38/93, 41%), pneumonia (27/93, 29%), thrombocytopenia and anemia (23/93, 25% each), and sepsis (16/93, 17%). The most common serious adverse events (SAEs) were febrile neutropenia (29/93, 31%), pneumonia (26/93, 28%), and sepsis (16/93, 17%). Potent dose-related DNA demethylation occurred on the daily regimen, reaching a plateau at 60 mg/m2 Daily×5 (designated as BED). Responses were seen in heavily pretreated patients including six responders (two complete response [CR], two CR with incomplete blood count recovery [CRi], one CR with incomplete platelet recovery [CRp], and one partial response [PR]) in AML patients and two marrow complete response (mCR) in MDS patients. Responders showed significantly more demethylation than non-responders. Interpretation Guadecitabine SC at 60 mg/m2 Daily×5 is well-tolerated, easily administered, and biologically and clinically active in both MDS and AML; it warrants testing in phase 2 studies.

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SUMMARY Background Hypomethylating agents azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia (AML), but responses are limited and of short duration, possibly due to short half-lives and suboptimal bone marrow exposure. Guadecitabine (SGI-110), a dinucleotide of decitabine and deoxyguanosine, is resistant to degradation by cytidine deaminase thus achieving longer half-life and exposure of its active metabolite, decitabine. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in treatment-naïve older patients with AML who were not candidates for intensive chemotherapy. Methods In this multicentre, open-label, phase 2 study, treatment-naïve older patients from 14 North American medical centres with AML who were not candidates for intensive chemotherapy were randomly assigned (1:1, using a computer algorithm) to subcutaneous guadecitabine at 60 or 90 mg/m2 on days 1–5 (5-day schedule) of a 28-day treatment cycle. Subsequently, patients were assigned sequentially to subcutaneous guadecitabine at 60 mg/m2 in a 10-day schedule (at least 2 cycles administered on days 1–5 and 8–12, with subsequent cycles given on a 5-day schedule). The objective was to evaluate and compare the activity and safety of two doses and schedules of guadecitabine, with a primary endpoint of composite complete response (including complete response [CR], CR with incomplete platelet recovery [CRp], and CR with incomplete neutrophil recovery regardless of platelets [CRi]). Response was evaluated in all patients (as-treated) as long as a patient received at least one guadecitabine treatment. Secondary endpoints included safety, survival, and pharmacodynamics. We present the final trial analyses, although at time of database lock, 15 patients were still being monitored for survival including six continuing treatment. This study is registered with ClinicalTrials.gov, number NCT01261312 Findings Between Aug 24, 2012, and Sep 15, 2014, 103 patients received treatment: 51 on a 5-day schedule of guadecitabine (24 received 60 mg/m2, 27 received 90 mg/m2) and 52 on the 10-day schedule. Median age was 77 years. Poor prognostic features included ECOG status ≥2 (39 [38%]), poor-risk cytogenetics (43 [42%]), and secondary AML (37 [36%]). Characteristics were generally balanced across doses and schedules. CRc rates were 54% (13 patients), 59% (16 patients), and 50% (26 patients) for the 5-day 60, 5-day 90, and 10-day 60 mg/m2 regimens, respectively. The most common grade 3 or higher adverse events, regardless of relationship to treatment, for the 5- and 10-day schedules, respectively, included febrile neutropenia (31 [61%] and 36 [69%]), thrombocytopenia (25 [49%] and 22 [42%]), neutropenia (20 [39%] and 18 [35%]), pneumonia (15 [29%] and 19 [37%]), anaemia (15 [29%] and 12 [23%]), and sepsis (8 [16%] and 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5- and 10-day schedules, respectively, were febrile neutropenia (2...

Men outperform women on the Iowa Gambling Task (IGT; A. Bechara, H. Damasio, D. Tranel, & A. R. Damasio, 1997). In this study, the authors show that sex differences are not due to differences in general emotional arousal or the abilities to calculate or reverse responses. Imaging studies have shown that, during the IGT, men increase activity in the right dorsolateral prefrontal cortex (PFC) and lateral orbital PFC, whereas women increase activity in the left medial orbital PFC. Deliberation of personal moral (PM) dilemmas also increases activity in medial and lateral dorsal PFC, whereas deliberation of moral impersonal (MI) dilemmas increases activity in lateral dorsal PFC. In the present study, men and women performed the IGT during PM, MI, or control deliberations. Deliberation of only PM dilemmas increased women's IGT performance to the level of men.