Citations

ABSTRACTIntroduction: Valosin‐containing protein (VCP) is a ubiquitously expressed, multifunctional AAA‐ATPase protein. Its dominant mutations cause hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) or amyotrophic lateral sclerosis. The pattern of muscle weakness in IBMPFD patients is variable and includes limb‐girdle, scapuloperoneal, distal, or axial distributions. Case Report: We report a 63‐year‐old man with progressive scapuloperoneal weakness, head drop, and hyperCKemia since age 40 years. Electromyography showed myopathic changes and rare myotonic discharges. Muscle biopsy revealed numerous lobulated fibers, few fibers with glycogen accumulation, and rare fibers with polyglucosan bodies. Rimmed vacuoles and congophilic inclusions, often seen in IBMPFD, were absent. VCP sequencing identified a novel heterozygous c. 1160G>A mutation resulting in p.Asn387Ser substitution. Conclusions: Our patient broadens the pathological spectrum of VCP‐myopathy and emphasizes the importance of VCP analysis in patients with scapuloperoneal muscular dystrophy despite the absence of Paget disease, dementia, rimmed vacuoles, or intracellular amyloid deposition. Muscle Nerve 50:295–299, 2014

ABSTRACTPurposeThis analysis from Avastin® Registries: Investigation of Effectiveness and Safety (ARIES) examined the association between exposure to bevacizumab after disease progression (PD) and postprogression survival (PPS) in bevacizumab‐exposed metastatic colorectal cancer (mCRC) through the application of time‐dependent and time‐fixed analytical methods.MethodsPatients with mCRC who were treated with first‐line bevacizumab and who survived first PD (PD1) were included. A time‐dependent Cox regression model was fitted to assess the effect of cumulative bevacizumab exposure on PPS, while controlling for potential confounders. In addition to support findings from previous studies, a modified intent‐to‐treat (mITT) analysis compared PPS in patients who received bevacizumab beyond disease progression (BBP) with those who did not (No‐BBP).ResultsOf 1550 patients, 1199 survived PD1 and had a median PPS of 13.4 months. Cumulative bevacizumab exposure was associated with improved PPS (p = 0.0040). After adjusting for confounders, the hazard ratios (HRs) for PPS decreased, on average, by 1.2% (range, 1.1–1.3%) with each additional dose of bevacizumab. In the mITT analysis, the median PPS for BBP (n = 438) was 14.4 months vs 10.6 months with for No‐BBP (n = 667). BBP was found to be independently associated with longer PPS in a multivariable Cox regression analysis (HR, 0.84; 95% confidence interval, 0.73–0.97). Protocol‐specified adverse events suspected to be associated with bevacizumab occurred in 13.0% of patients with BBP.ConclusionThis analysis supports the observation that bevacizumab exposure after PD1 is associated with longer PPS in mCRC. Copyright © 2014 John Wiley & Sons, Ltd.

Background— Exercise intolerance is a hallmark of heart failure, but factors associated with impaired exercise capacity in heart failure with preserved ejection fraction are unclear. We hypothesized that in heart failure with preserved ejection fraction, the severity of resting ventricular and vascular dysfunction are associated with impairment in exercise tolerance as assessed by peak oxygen consumption. Methods and Results— Subjects with heart failure with preserved ejection fraction enrolled in the PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX) clinical trial (n=216) underwent baseline Doppler echocardiography, cardiopulmonary exercise testing, and cardiac MRI. RELAX participants were elderly (median age 69 years) and 48% were women. Ejection fraction (60%) and stroke volume (77 mL) were normal, while diastolic dysfunction (medial E / e ′, 16; deceleration time, 185 ms; left atrial volume, 44 mL/m 2 ) and increased arterial load (arterial elastance, 1.51 mm Hg/mL) were evident. Peak oxygen consumption was reduced (11.7 mLkg −1 min −1 , 1141 mL/min) and age, sex, body mass index, hemoglobin, and chronotropic response collectively explained 64% of the variance in raw peak oxygen consumption (mL/min). After adjustment for these variables, left ventricular structure (diastolic dimension [1.5%, P =0.008] and left ventricular mass [1.6%, P =0.008]), resting stroke volume (2.0%, P =0.002), left ventricular diastolic dysfunction (deceleration time [0.9%, P =0.03] and E / e ′ [1.4%, P =0.009]), and arterial function (arterial elastance [2.1%, P =0.002] and systemic arterial compliance [1.5%, P =0.007]), each explained only a small additional portion of the variance in peak oxygen consumption. Conclusions— In heart failure with preserved ejection fraction, potentially modifiable factors (obesity, anemia, and chronotropic incompetence) are strongly associated with exercise capacity, whereas resting measures of ventricular and vascular structure and function are not. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867

Abstract Purpose: Clustering of neural autoantibodies in patients with paraneoplastic neurologic disorders may predict tumor type. A mathematical analysis of neural autoantibody clusters was performed in 78,889 patients undergoing evaluation for a suspected paraneoplastic autoimmune neurologic disorder. Tumor predictive autoantibody profiles were confirmed in sera from patients with histologically proven tonsillar cancer, thymoma, and lung cancer. Patients and Methods: Of note, 78,889 patient sera were tested for 15 defined neural autoantibodies (1.2 million tests). The observed and hypothesized frequencies of autoantibody clusters were compared and their tumor associations defined. A tumor validation study comprised serum from 368 patients with a variety of tumors (thymoma, lung, or tonsil). Results: Informative oncological associations included (i) thymoma in 85% of patients with muscle striational, acetylcholine receptor antibodies plus CRMP5 autoantibodies; (ii) lung carcinoma in 80% with both P/Q-type and N-type calcium channel antibodies plus SOX1-IgG; and (iii) in men, prostate carcinoma frequency more than doubled when striational and muscle AChR specificities were accompanied by ganglionic AChR antibody. In women, amphiphysin-IgG alone was associated commonly with breast carcinoma, but amphiphysin-IgG, coexisting with antineuronal nuclear autoantibody-type 1 or CRMP5-IgG, was associated with lung cancer (P < 0.0001). In the validation cohorts, many tumor-associated profiles were encountered that matched the clusters identified in the screening study (e.g., 15% of thymoma patients had striational, acetylcholine receptor antibodies plus collapsin response-mediator protein-5 autoantibodies). Conclusions: Neural autoantibodies commonly coexist in specific clusters that are identifiable by comprehensive screening. Signature autoantibody clusters may predict a patient's cancer risk and type. Clin Cancer Res; 20(14); 3862–9. ©2014 AACR.

Abstract Background: With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology. Methods: We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements. Results: Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers. Conclusions: Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues—some of which are barriers to specific research questions—that require special attention. Impact: Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information. Cancer Epidemiol Biomarkers Prev; 23(8); 1598–608. ©2014 AACR.

AbstractBackgroundThe aim of the study was to assess which aspects of an enhanced recovery programme are associated with better outcomes following laparoscopic colorectal surgery.MethodsA database of laparoscopic colorectal procedures performed in 2011 was reviewed. Elements of the enhanced recovery programme and compliance were evaluated for short-term (30-day) outcomes. Individual elements included gabapentin, celecoxib, intrathecal analgesia, diet, postoperative fluids, and paracetamol/non-steroidal anti-inflammatory drug pain management.ResultsFive hundred and forty-one consecutive procedures were included. Compliance with the enhanced recovery programme elements ranged from 82·4 to 99·3 per cent. Median length of hospital stay was 3 (i.q.r. 2–5) days, with 25·9 per cent of patients discharged within 48 h. Patients without complications had a median length of stay of 3 (i.q.r. 2–4) days if compliant and 3 (3–5) days if not (P < 0·001). Low oral opiate intake (oral morphine equivalent of less than 30 mg) (odds ratio (OR) 1·97, 95 per cent confidence interval 1·29 to 3·03; P = 0·002), full compliance (OR 2·36, 1·42 to 3·90; P < 0·001) and high surgeon volume (more than 100 cases per year) (OR 1·50, 1·19 to 1·89; P < 0·001) were associated with discharge within 48 h. Compliance with the elements of oral intake and fluid management in the first 48 h was associated with a reduced rate of complications (8·1 versus 19·6 per cent; P = 0·001). Median oral opiate intake was 37·5 (i.q.r. 0–105) mg in 48 h, with 26·2 per cent of patients receiving no opiates.ConclusionCompliance with an enhanced recovery pathway was associated with less opiate use, fewer complications and a shorter hospital stay.