Citations

Background— Postmarket medical device surveillance in the United States depends largely on voluntary reporting of adverse events. Consequently, early safety signals may be missed, exposing patients to potentially hazardous products. The aim of this study was to assess the feasibility of using an automated safety surveillance tool to detect early signals that a marketed implantable cardiac device was underperforming. Methods and Results— For this purpose, we performed simulated prospective monthly full-cohort and propensity-matched comparative survival analyses on our 3-center database of Sprint Fidelis and Quattro Secure implantable cardioverter-defibrillator leads, using a commercially available automated surveillance tool that was preset to trigger an alert if the log rank probability value was <0.05. During the study, 84 of 1035 Fidelis (8.1%) and 23 of 1675 Quattro (1.4%) leads failed. The simulated full-cohort analysis triggered a sustained alert for Fidelis leads beginning 13 months after the first implant and 2 years before Fidelis leads were removed from the market. Of the 1035 patients who had Fidelis leads, up to 969 (93.6%) were successfully matched to Quattro patients. In the propensity-matched analysis, the alert triggered 22 months after the first Fidelis implant and more than 1 year before the lead was recalled. Conclusions— An active automated safety surveillance system could have identified this implantable cardiovascular device problem substantially sooner than was achieved through existing postmarket surveillance methods. Such a tool, when applied to clinical registries and remote monitoring databases, may limit the exposure of large populations to underperforming and potentially hazardous cardiovascular devices.

To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88 , CARD11 , EZH2 , and CREBBP . We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B , MLL2 , BTG1 , GNA13 , ACTB , P2RY8 , PCLO , and TNFRSF14 . Further, we show that BCL2 mutations commonly occur in patients with BCL2 / IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase–mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS , BRAF , and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease.

ObjectivesTo determine the cost of treatment of oropharyngeal squamous cell carcinoma (OP SCCA) with transoral surgery with concomitant neck dissection (TOS), TOS with adjuvant radiation therapy (TOS + RT), TOS with adjuvant chemoradiation therapy (TOS + CRT), and primary chemoradiation therapy (CRT).Study DesignCase series.SettingTwo tertiary care teaching hospitals.Subjects and MethodsUsing the databases of 2 teaching hospitals, patients were identified who had OP SCCA treated with TOS, TOS + RT, TOS + CRT, and primary CRT in 2009 to 2010. Costs were analyzed from an institutional perspective looking at reimbursement. Patients with government payers and patients with private payers in each group were identified, and net revenue data obtained for the 3‐month period from diagnosis were calculated and averaged for each group. Cost was defined as the reimbursement for all charges surrounding the 3‐month episode of treatment. All revenue associated with inpatient and outpatient care, including pharmacy charges, was included.ResultsThe mean cost of TOS (private payers/government payers) was $37,435/$15,664 (range, $22,486‐$48,746/$13,325‐$16,885). The mean cost of TOS + RT (private payers/government payers) was $74,484/$34,343 (range, $72,400‐$84,825/$31,565‐$40,810). The mean cost of TOS + CRT (private payers/government payers) was $191,780/$53,245 (range, $145,450‐$217,220/$49,400‐$58,325). The mean cost of CRT (private payers/government payers) was $198,285/$57,429 (range, $168,216‐$298,945/$52,900‐$59,545).ConclusionAn algorithm of transoral surgical treatment of OP SCCA with adjuvant treatment as indicated by pathology is more cost conscious than an algorithm of treatment of all OP SCCA with CRT.

Abstract The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.

It is widely accepted that traditional models of clinical investigation are becoming unsustainable in oncology and that trials must become more efficient in matching effective treatments to the patients most likely to benefit. In 2008, gastrointestinal oncologists from many countries began a collaboration to improve the design and conduct of clinical trials in their field, through the auspices of a French/U.S. charitable foundation, ARCAD. Whether this model of academic collaboration will be judged a success will depend on the quality of its scientific output during the next few years and whether this output, alongside that of other scientists, groups, and institutions, ultimately leads to more efficient trials and improved treatment options for patients.

Background: In multiple sclerosis (MS), the relapse rate declines during pregnancy and increases during the first three months post-partum before returning to the pre-pregnancy rate. It is unknown whether pregnancy impacts the risk of clinical conversion in those within the presymptomatic period. Objectives: We investigate the impact of pregnancy on developing a clinical event in women diagnosed with radiologically isolated syndrome (RIS). Methods: All women with RIS underwent clinical and radiological assessments as part of an observational, prospective, longitudinal study. Clinical and MRI outcomes were analyzed during and after pregnancy. Subjects who became pregnant were compared with an age-matched female RIS group who did not become pregnant during the same follow-up period. Results: A total of 60 women with RIS were followed for up to seven years. Among them, seven became pregnant and were compared with 53 age-matched control women with RIS who did not become pregnant during the observation period. A significantly shorter time of conversion to the first neurological event was observed in the pregnant group [15.3 months (10–18)] compared with the non-pregnant controls [35.7 months (8–76)], yielding an absolute difference of 20.4 months ( p<0.05). The mean (SD) number of active lesions on a subsequent brain MRI scan was significantly higher in the pregnant group [3.2 (±1.7)] compared with the control group [1.8 (±0.6)]. Conclusions: The risk for clinical conversion from RIS to a clinical event and new MRI disease activity seems to be influenced by pregnancy. Pregnancy related physiological changes could operate as early as the presymptomatic period in patients with MS.

Due to its excellent safety profile, ease of administration, and economic considerations, sublingual immunotherapy (SLIT) is becoming a preferred form of allergen specific immunotherapy. The efficacy of SLIT is still debated. The purpose of this act of practice trial is to evaluate quality of life outcomes in patients treated with SLIT. Fifty one patients with allergic rhinoconjunctivitis demonstrated by skin testing completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at initiation, at four months and at 10–12 months of SLIT. Significant improvement () on six of seven domain categories of the RQLQ questionnaire was noted. Total RQLQ scores also showed significant improvement. This study supports SLIT as a modality effective in controlling allergic symptoms.