Citations

Bendamustine is a multifunctional alkylating agent with single agent activity in myeloma. We designed the current phase 1/2 trial to determine the maximum tolerated doses (MTD) of bendamustine that can be safely combined with lenalidomide and dexamethasone and to assess the safety and efficacy of the combination. Patients with relapsed MM following at least 1 prior therapy, but no more than four lines of prior therapy and with measurable disease were enrolled. Bendamustine 75 mg/m2 given on days 1 and 2, lenalidomide 25 mg given days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22, was the recommended Phase 2 dose. Seventy‐one patients were accrued: 21 on Phase 1 and 50 on Phase 2. The median age was 62.3 years; patients had a median of three prior lines of therapy (range 1–4), with over 70% of the patients having received prior lenalidomide, bortezomib, and/or peripheral blood stem cell transplant. Thirty‐four of 70 (49%) patients had a confirmed partial response or better, including 20 patients (29%) with a very good partial response or better. An additional 4 patients had a minor response, translating to an overall 55% clinical benefit rate. Grade 3 or higher toxicity was seen in 96% of patients, with ≥grade 3 hematologic in 94% and nonhematologic in 50%. The median progression free survival was 11.8 months and the median duration of response was 23 months. The combination of bendamustine, lenalidomide, and dexamethasone is very effective in relapsed multiple myeloma with high response rates and durable responses Am. J. Hematol. 90:1106–1110, 2015. © 2015 Wiley Periodicals, Inc.

Purpose: This project examined potential changes in health behaviors following wellness coaching. Design: In a single cohort study design, wellness coaching participants were recruited in 2011, data were collected through July 2012, and were analyzed through December 2013. Items in the study questionnaire used requested information about 11 health behaviors, self-efficacy for eating, and goalsetting skills. Setting: Worksite wellness center. Participants: One-hundred employee wellness center members with an average age of 42 years; 90% were female and most were overweight or obese. Intervention: Twelve weeks of in-person, one-on-one wellness coaching. Method: Participants completed study questionnaires when they started wellness coaching (baseline), after 12 weeks of wellness coaching, and at a 3-month follow-up. Results: From baseline to week 12, these 100 wellness coaching participants improved their self-reported health behaviors (11 domains, 0- to 10-point scale) from an average of 6.4 to 7.7 ( p < .001), eating selfefficacy from an average of 112 to 142 (on a 0- to 180-point scale; p < .001), and goal-setting skills from an average of 49 to 55 (on a 16- to 80-point scale; p < .001). Conclusion: These results suggest that participants improved their current health behaviors and learned skills for continued healthy living. Future studies that use randomized controlled trials are needed to establish causality for wellness coaching.

Purpose Given that the clinical course of oxaliplatin-induced neuropathy is not well defined, the current study was performed to better understand clinical parameters associated with its presentation. Methods Acute and chronic neuropathy was evaluated in patients receiving adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) on study N08CB (North Central Cancer Treatment Group, Alliance). Acute neuropathy was assessed by having patients complete daily questionnaires for 6 days with each cycle of FOLFOX. Before each dose of FOLFOX and as long as 18 months after chemotherapy cessation, chronic neurotoxicity was assessed with use of the 20-item, European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy. Results Three hundred eight (89%) of the 346 patients had at least one symptom of acute neuropathy with the first cycle of FOLFOX; these symptoms included sensitivity to touching cold items (71%), sensitivity to swallowing cold items (71%), throat discomfort (63%), or muscle cramps (42%). Acute symptoms peaked at day 3 and improved, although they did not always resolve completely between treatments. These symptoms were about twice as severe in cycles 2 through 12 as they were in cycle 1. For chronic neurotoxicity, tingling was the most severe symptom, followed by numbness and then pain. During chemotherapy, symptoms in the hands were more prominent than they were in the feet; by 18 months, symptoms were more severe in the feet than they were in the hands. Patients with more severe acute neuropathy during the first cycle of therapy experienced more chronic sensory neurotoxicity (P < .0001). Conclusion Acute oxaliplatin-induced neuropathy symptoms do not always completely resolve between treatment cycles and are only half as severe on the first cycle as compared with subsequent cycles. There is a correlation between the severities of acute and chronic neuropathies.

SummaryBackgroundTemporary faecal diversion is sometimes used for management of refractory perianal Crohn's disease (CD) with variable success.AimsTo perform a systematic review with meta‐analysis to evaluate the effectiveness, long‐term outcomes and factors associated with success of temporary faecal diversion for perianal CD.MethodsThrough a systematic literature review through 15 July 2015, we identified 16 cohort studies (556 patients) reporting outcomes after temporary faecal diversion. We estimated pooled rates [with 95% confidence interval (CI)] of early clinical response, attempted and successful restoration of bowel continuity after temporary faecal diversion (without symptomatic relapse), and rates of re‐diversion (in patients with attempted restoration) and proctectomy (with or without colectomy and end‐ileostomy). We identified factors associated with successful restoration of bowel continuity.ResultsOn meta‐analysis, 63.8% (95% CI: 54.1–72.5) of patients had early clinical response after faecal diversion for refractory perianal CD. Restoration of bowel continuity was attempted in 34.5% (95% CI: 27.0–42.8) of patients, and was successful in only 16.6% (95% CI: 11.8–22.9). Of those in whom restoration was attempted, 26.5% (95% CI: 14.1–44.2) required re‐diversion because of severe relapse. Overall, 41.6% (95% CI: 32.6–51.2) of patients required proctectomy after failure of temporary faecal diversion. There was no difference in the successful restoration of bowel continuity after temporary faecal diversion in the pre‐biological or biological era (13.7% vs. 17.6%, P = 0.60), in part due to selection bias. Absence of rectal involvement was the most consistent factor associated with restoration of bowel continuity.ConclusionsTemporary faecal diversion may improve symptoms in approximately two‐thirds of patients with refractory perianal Crohn's disease, but bowel restoration is successful in only 17% of patients.

AbstractAbstract In a nested, matched case-cohort design of 384 anesthesia residents who developed substance use disorder (SUD) and 768 controls who did not, receiving medical education in the United States, but not anesthesia knowledge early in residency, was associated with risk of developing SUD. By the end of follow-up, 54 anesthesiology residents (14.1%) with SUD and 10 controls (1.3%) were dead. Those with SUD were 15-, 10-, and 7-fold more likely to not complete residency, to not become board certified, or have adverse medical licensure actions, respectively. Background: The goal of this work is to evaluate selected risk factors and outcomes for substance use disorder (SUD) in physicians enrolled in anesthesiology residencies approved by the Accreditation Council for Graduate Medical Education. Methods: For each of 384 individuals with evidence of SUD while in primary residency training in anesthesiology from 1975 to 2009, two controls (n = 768) who did not develop SUD were identified and matched for sex, age, primary residency program, and program start date. Risk factors evaluated included location of medical school training (United States vs. other) and anesthesia knowledge as assessed by In-Training Examination performance. Outcomes (assessed to December 31, 2013, with a median follow-up time of 12.2 and 15.1 yr for cases and controls, respectively) included mortality and profession-related outcomes. Results: Receiving medical education within the United States, but not performance on the first in-training examination, was associated with an increased risk of developing SUD as a resident. Cases demonstrated a marked increase in the risk of death after training (hazard ratio, 7.9; 95% CI, 3.1 to 20.5), adverse training outcomes including failure to complete residency (odds ratio, 14.9; 95% CI, 9.0 to 24.6) or become board certified (odds ratio, 10.4; 95% CI, 7.0 to 15.5), and adverse medical licensure actions subsequent to residency (hazard ratio, 6.8; 95% CI, 3.8 to 12.2). As of the end of follow-up, 54 cases (14.1%) were deceased compared with 10 controls (1.3%); 28 cases and no controls died during residency. Conclusion: The attributable risk of SUD to several adverse outcomes during and after residency training, including death and adverse medical license actions, is substantial.

Abstract Single-positive thymocytes that successfully complete positive and negative selection must still undergo one final step, generally termed T cell maturation, before they gain functional competency and enter the long-lived T cell pool. Maturation initiates after positive selection in single-positive thymocytes and continues in the periphery in recent thymic emigrants, before these newly produced T cells gain functional competency and are ready to participate in the immune response as peripheral naive T cells. Recent work using genetically altered mice demonstrates that T cell maturation is not a single process, but a series of steps that occur independently and sequentially after positive selection. This review focuses on the changes that occur during T cell maturation, as well as the molecules and pathways that are critical at each step.

We have previously shown that amino acid changes in the human Kruppel-Like Factor (KLF) 11 protein is associated with the development of maturity onset diabetes of the young VII, whereas complete inactivation of this pathway by the −331 human insulin mutation causes neonatal diabetes mellitus. Here, we report that Klf11−/− mice have decreased circulating insulin levels, alterations in the control of blood glucose and body weight, as well as serum dyslipidemia, but do not develop diabetes. Functional assays using ex vivo liver tissue sections demonstrate that Klf11−/− mice display increased insulin sensitivity. Genome-wide experiments validated by pathway-specific quantitative PCR arrays reveal that the Klf11−/− phenotype associates to alterations in the regulation of gene networks involved in lipid metabolism, in particular those regulated by peroxisome proliferator-activated receptor-γ. Combined, these results demonstrate that the major phenotype given by the whole-body deletion of Klf11 in mouse is not diabetes but increased insulin sensitivity, likely due to altered transcriptional regulation in target tissues. The absence of diabetes in the Klf11−/− mouse either indicates an interspecies difference for the role of this transcription factor in metabolic homeostasis between mouse and humans, or potentially highlights the fact that other molecular factors can compensate for its absence. Nevertheless, the data of this study, gathered at the whole-organism level, further support a role for KLF11 in metabolic processes like insulin sensitivity, which regulation is critical in several forms of diabetes.

Background and Purpose— The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography–based planimetry (CTP). Methods— In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. Results— In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC ( r 2 =0.93) than with site-ABC ( r 2 =0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm 3 ; CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (κ=0.75; P <0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. Conclusions— ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.

Abstract Several studies have identified common genetic factors that influence susceptibility to lung cancer but no large studies have systematically studied familial lung cancers. The Genetic Epidemiology of Lung Cancer Consortium completed a genome-wide association study (GWAS) using samples from 757 cases and 796 controls, all of European American ancestry, and frequency matched on age and sex. Genotyping was performed by the Center for Inherited Disease Research (CIDR) using an Illumina Human OmniExpressExome-8v1 array. The most significantly associated SNPs were identified in the cases as a whole, and were also stratified by histology (adenocarcinoma and squamous cell carcinoma) and family history (0-1 and 2-5 affected family members). Analysis of all cases and controls identified a large number of SNPs around the CFTR gene that are strongly associated with lung cancer risk. Upon imputation with European Ancestry 1000 genomes data, the most significant SNP in this region is rs43034 (p = 3.89E-07, OR = 0.657) in the promoter region. In addition, an exonic missense SNP, rs213950 (p = 6.32E-07, OR = 0.663), and an intronic SNP with a possible splicing effect, rs213935 (p = 5.20E-07, OR = 0.660) were also identified as possible protective alleles. Analysis by histological subtype identified several rare and exonic SNPs that were specific by histology. We highlight two SNPs, rs114719990 (p = 1.194E-04, OR = 336.8, SETD2, c.3229A&gt;G, p.Thr1077Ala) and rs199710487 (p = 1.124E-04, OR = 366, NTN5, c.656G&gt;A, p.Arg219Gln), that were identified as strongly associated SNPs in cases with histologically confirmed adenocarcinoma, and two SNPs, rs144465058 (p = 1.029E-04, OR = 484.6, ANK3, c.6555G&gt;T, p.Gln2185His) and rs140216112 (p = 1.087E-04, OR = 476, GRIK4, c.1013C&gt;G, p.Ala338Gly), that were identified as top SNPs in cases with histologically confirmed squamous cell carcinoma. The SETD2 gene is thought to be a tumor suppressor gene and variants in this gene have previously been associated with leukemia and glioma (Zhu X et al. 2014, Fontebasso AM et al. 2013), and may now have implications in lung cancer, specifically adenocarcinoma development. In conclusion, we identified SNPs in the CFTR gene that may have a protective effect on lung cancer and several rare and exonic variants that were specific to histology subtype. SNPChrPositionGeneGenomic/ Nucleotide/ Amino acid changeOdds Ratiop-valueCFTR Protective Allelesrs430347117108449CFTRg.117108449T&gt;C; 2.4kb upstream0.6573.89×10−7rs2139507117199533CFTRc.1408G&gt;A; p.Val470Met0.6636.32×10−7rs2139357117178208CFTRc.869+1481A&gt;G0.6605.20×10−7 Citation Format: Diana M. Toledo, Susan M. Pinney, Diptasri Mandal, Mariza de Andrade, Elena Kupert, Jennifer Franks, Colette Gaba, Claire L. Simpson, Ming You, Marshall W. Anderson, Joan E. Bailey-Wilson, Christopher I. Amos, Ann Schwartz. Genetic Epidemiology of Lung Cancer Consortium: genome-wide association study of familial lung cancer cases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-189. doi:10.1158/1538-7445.AM2015-LB-189