Citations

Abstract Bortezomib is highly effective in the treatment of multiple myeloma; however, emergent drug resistance is common. Consequently, we employed CRISPR targeting 19,052 human genes to identify unbiased targets that contribute to bortezomib resistance. Specifically, we engineered an RPMI8226 multiple myeloma cell line to express Cas9 infected by lentiviral vector CRISPR library and cultured derived cells in doses of bortezomib lethal to parental cells. Sequencing was performed on surviving cells to identify inactivated genes responsible for drug resistance. From two independent whole-genome screens, we selected 31 candidate genes and constructed a second CRISPR sgRNA library, specifically targeting each of these 31 genes with four sgRNAs. After secondary screening for bortezomib resistance, the top 20 “resistance” genes were selected for individual validation. Of these 20 targets, the proteasome regulatory subunit PSMC6 was the only gene validated to reproducibly confer bortezomib resistance. We confirmed that inhibition of chymotrypsin-like proteasome activity by bortezomib was significantly reduced in cells lacking PSMC6. We individually investigated other members of the PSMC group (PSMC1 to 5) and found that deficiency in each of those subunits also imparts bortezomib resistance. We found 36 mutations in 19S proteasome subunits out of 895 patients in the IA10 release of the CoMMpass study (https://themmrf.org). Our findings demonstrate that the PSMC6 subunit is the most prominent target required for bortezomib sensitivity in multiple myeloma cells and should be examined in drug-refractory populations. Mol Cancer Ther; 16(12); 2862–70. ©2017 AACR.

Purpose The relationship between syringomyelia and presyrinx, characterized by edema in the spinal cord, has not been firmly established. Patients with syringomyelia have abnormal spinal canal tapering that alters cerebrospinal fluid flow dynamics, but taper ratios in presyrinx have never been reported. We tested the hypothesis that presyrinx patients have abnormal spinal canal tapering. Materials and methods At six medical institutions, investigators searched the PACS system for patients with Chiari I and spinal cord edema unassociated with tumor, trauma, or other evident cause. In each case taper ratios were calculated for C1 to C4 and C4 to C7. In two age- and gender-matched control groups, Chiari I patients with no syringomyelia and patients with normal MR scans, the same measurements were made. Differences between groups were tested for statistical significance with t tests. Results The study enrolled 21 presyrinx patients and equal numbers of matched Chiari I and normal controls. C4 to C7 taper ratios were positive and steeper in presyrinx patients than in the normal controls ( p = 0.04). The upper cervical spine, C1 to C4, tapered negatively in cases and controls without significant differences between the groups. The difference in degree of tonsillar herniation was statistically significant between presyrinx patients and Chiari I controls ( p = 0.01). Conclusions Presyrinx patients have greater than normal positive tapering in the lower cervical spine and greater degree of tonsillar herniation than the controls.

AbstractBackground and AimFeedback has been shown to improve performance in colonoscopy including adenoma detection rate (ADR). The frequency at which feedback should be given is unknown. As part of a quality improvement program, we sought to measure the outcome of providing quarterly and monthly feedback on colonoscopy quality measures.MethodsAll screening colonoscopies performed at endoscopy unit at Mayo Clinic Arizona by gastroenterologists between October 2010 and December 2012 were reviewed. Quality indicators, including ADR, were extracted for each individual endoscopist, and feedback was provided. The study period was divided into four distinct groups: pre‐intervention that served as baseline, quarterly feedback, monthly feedback, and post‐intervention. Based on ADR, endoscopists were grouped into “low detectors” (≤ 25%), “average detectors” (26–35%), and “high detectors” (> 35%).ResultsA total of 3420 screening colonoscopies were performed during the study period (555 patients during pre‐intervention, 1209 patients during quarterly feedback, 599 during monthly feedback, and 1057 during the post‐intervention period) by 16 gastroenterologists. The overall ADR for the group improved from 30.5% to 37.7% (P = 0.003). Compared with the pre‐interventional period, all quality indicators measured significantly improved during the monthly feedback and post‐intervention periods but not in the quarterly feedback period.ConclusionsIn our quality improvement program, monthly feedback significantly improved colonoscopy quality measures, including ADR, while quarterly feedback did not. The impact of the intervention was most prominent in the “low detectors” group. Results were durable up to 6 months following the intervention.

BACKGROUNDBody weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long‐term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival.METHODSCRC cases diagnosed from 1997 to 2008 were identified through 4 population‐based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow‐up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC‐specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti‐inflammatory drug use, smoking, time between diagnosis and enrollment, and study site.RESULTSAt the 5‐year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median ‐4 kg) weight. Over a median of 5.1 years of subsequent follow‐up (range, 0.3‐9.9 years), 344 participants died (91 of CRC). Long‐term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07‐1.21) and CRC‐specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13‐1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight).CONCLUSIONSWeight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long‐term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017;123:4701‐4708. © 2017 American Cancer Society.

Abstract Significant endocrine therapy–resistant tumor proliferation is present in ≥20% of estrogen receptor–positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor–resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care. Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy–resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168–83. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047

Objective To describe self-reported disease understanding for newly diagnosed patients with atrial fibrillation (AF) and assess (1) how disease understanding changes over the first 6 months after diagnosis and (2) the relationship between patient understanding of therapies at baseline and treatment receipt at 6 months among treatment-naïve patients. Methods We analysed survey data from SATELLITE (Survey of Patient Knowledge and Personal Priorities for Treatment), a substudy of patients with new-onset AF enrolled in the national Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT) II registry across 56 US sites. Patients were surveyed at the baseline and 6-month follow-up clinic visits using Likert scales. Results Among 1004 baseline survey responses, patients’ confidence in their understanding of rhythm control, ablation, anticoagulation and cardioversion was suboptimal, with ‘high’ understanding ranging from 8.5% for left atrial appendage closure to 71.3% for rhythm therapy. Of medical history and demographic factors, education level was the strongest predictor of reporting ‘high’ disease understanding. Among the 786 patients with 6-month survey data, significant increases in the proportion reporting high understanding were observed (p<0.05) only for warfarin and direct oral anticoagulants (DOACs). With the exception of ablation, high understanding for a given therapeutic option was not associated with increased use of that therapy at 6 months. Conclusions About half of patients with new-onset AF understood the benefits of oral anticoagulant at the time of diagnosis and understanding improved over the first 6 months. However, understanding of AF treatment remains suboptimal at 6 months. Our results suggest a need for ongoing patient education. Clinical trial registration Clinicaltrials.gov. Identifier: NCT01701817.