Abstract Background Familial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is ...not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations. Methods and Results We studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed ( MYH7 , TNNT2 , TNNI3 , TPM1 , MYBPC3 , ACTC , LMNA , PLN , TAZ , and LDB3 ), and 70% of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52% had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4% of patients, commonly involving MYH7 , LMNA , or TNNT2 (78%). An additional 10.6% of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing. Conclusions Using rigorous criteria for classifying DNA variants, mutations were identified in 17% of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.
Background Endoscopic resection and ablation have advanced the treatment of intramucosal esophageal adenocarcinoma and have been promoted as definitive therapy for selected superficial submucosal ...tumors. Controversy exists regarding the prevalence of nodal metastases at various depths of mucosal and submucosal invasion. Our aim was to clarify this prevalence and identify predictors of nodal spread. Study Design An expert gastrointestinal pathologist retrospectively reviewed 54 T1 adenocarcinomas from 258 esophagectomy specimens (2000 to 2008). Tumors were classified as intramucosal or submucosal, the latter being subclassified as SM1 (upper third), SM2 (middle third), or SM3 (lower third) based on the depth of tumor invasion. The depth of invasion was correlated with the prevalence of positive nodes. Fisher's exact test and univariate and multivariate logistic regression were used to identify variables predicting nodal disease. Results Nodal metastases were present in 0% (0 of 25) of intramucosal, 21% (3 of 14) of SM1, 36% (4 of 11) of SM2, and 50% (2 of 4) of SM3 tumors. The differences were significant between intramucosal and submucosal tumors (p < 0.0001), although not between the various subclassifications of submucosal tumors (p = 0.503). Univariate logistic regression identified poor differentiation (p = 0.024), lymphovascular invasion (p = 0.049), and number of harvested lymph nodes (p = 0.037) as significantly correlated with nodal disease. Multivariate logistic regression did not identify any of the tested variables as independent predictors of the prevalence of positive lymph nodes. Conclusions All depths of submucosal invasion of esophageal adenocarcinoma were associated with an unacceptably high prevalence of nodal metastases and a marked increase relative to intramucosal cancer. Accurate predictors of nodal spread, independent of tumor depth, are currently lacking and will be necessary before recommending endoscopic resection with or without concomitant ablation as curative treatment for even superficial submucosal neoplasia.
The current American Joint Committee on Cancer Seventh Edition (AJCC7) pathologic staging for esophageal adenocarcinoma (EAC) is derived from data assessing the outcomes of patients having undergone ...esophagectomy without neoadjuvant treatment and has unclear significance in patients who have received multimodality therapy. Lymph nodes with evidence of neoadjuvant treatment effect without residual cancer cells may be observed and are not traditionally considered in pathologic reports, but may have prognostic significance.
All patients who underwent esophagectomy after completing neoadjuvant therapy for EAC at our institution between 2006 and 2012 were reviewed. Slides of pathologic specimens were reexamined for locoregional treatment-response nodes lacking viable cancer cells but with evidence of acellular mucin pools, central fibrosis, necrosis, or calcifications suggesting prior tumor involvement. Kaplan-Meier survival functions were estimated, and Cox proportional hazards regression models were used to compare staging models.
Ninety patients (82 men) underwent esophagectomy after neoadjuvant therapy for EAC (mean age, 61.8 ± 8.9 years). All patients received preoperative chemotherapy, and 50 patients also underwent preoperative radiotherapy. Median Kaplan-Meier survival was 55.6 months, and 5-year survival was 35% (95% confidence interval, 19% to 62%). A total of 100 treatment-response nodes were found in 38 patients. For patients with limited nodal disease (62 ypN0-N1), the presence of treatment-response nodes was associated with significantly worse survival (p = 0.03) compared with patients lacking such nodes. Adjusting for patient age and AJCC7 pathologic stage showed the presence of treatment-response nodes significantly increased the risk of death (hazard ratio, 2.7; 95% confidence interval, 1.1 to 6.9; p = 0.04). When stage-adjusted survival was modeled, counting treatment-response nodes as positive nodes offered a better model fit than ignoring them.
Treatment-response lymph nodes detected from esophagectomy specimens in patients having undergone neoadjuvant chemotherapy or combined chemoradiation for EAC provide valuable prognostic information, particularly in patients with limited nodal disease. The current practice of considering lymph nodes lacking viable cancer cells, but with evidence of tumor necrosis, as pathologically negative likely results in understaging. Future efforts at revising the staging system for EAC should consider incorporating treatment-response lymph nodes in the analysis.
Background The purpose of this study was to determine the intra- and inter-rater reliability of detecting full- and partial-thickness tears of the supraspinatus intramuscular central tendon on ...magnetic resonance imaging (MRI) by orthopaedic shoulder surgeons. Full-thickness tears of this tendon have previously been associated with the failure of nonsurgical management of rotator cuff tears. Methods Shoulder MRIs from 40 patients entered into a prospective rotator cuff disease database were independently reviewed by two musculoskeletal (MSK) radiologists in order to determine if there was a partial- or full-thickness tear of the supraspinatus central tendon. The MRIs were randomly sorted and distributed to 16 fellowship-trained shoulder surgeons. The surgeons then similarly diagnosed each patient. After a 1-month interval, surgeons repeated the evaluation with the same set of randomly reordered MRIs. Surgeon intra- and inter-rater reliability was determined with the kappa statistic. Agreement and inter-rater reliability were also determined between the shoulder surgeons and MSK radiologists. Results For full-thickness tears, the intra-rater reliability was excellent (0.86 ± 0.1, 95% confidence interval (CI): 0.81, 0.91) and the agreement was 93.4% ± 4.6, 95% CI: 91.1, 95.8. Inter-rater reliability for both rounds was also excellent (0.77 and 0.74). The agreement between the shoulder surgeons and MSK radiologists was 92.9% ± 3.9, 95% CI: 90.9, 94.9, and the kappa was 0.85 ± 0.08, 95% CI: 0.81, 0.89. Including partial-thickness tears resulted in agreement of 65-92% and kappa values of 0.59-0.72. Conclusion The reliability for the MRI detection of full thickness tears of the supraspinatus central tendon among shoulder surgeons and between shoulder surgeons and MSK radiologists was excellent.
Purpose Screening for esophageal adenocarcinoma (EAC) has not become policy in part over concerns in identifying the high-risk group. It is often claimed that a significant proportion of patients ...developing EAC do not report preexisting reflux symptoms or prior treatment for gastroesophageal reflux disease (GERD). As such, our aim was to assess the prevalence of GERD symptoms, proton pump inhibitor (PPI) use and Barrett's esophagus (BE) and their impact on survival in patients undergoing esophagectomy for EAC. Methods The study population consisted of 345 consecutive patients who underwent esophagectomy for EAC between 2000 and 2011 at a university-based medical center. Patients with a diagnosis of esophageal squamous cell carcinoma and those who underwent esophagectomy for benign disease were excluded. The prevalence of preoperative GERD symptoms, defined as presence of heartburn, regurgitation or epigastric pain, PPI use (>6 months) and BE, defined by the phrases “Barrett's esophagus,” “intestinal epithelium,” “specialized epithelium,” or “goblet cell metaplasia” in the patients' preoperative clinical notes were retrospectively collected. Overall long-term and stage-specific survival was compared in patients with and without the presence of preoperative GERD symptoms, PPI use, or BE. Results The majority of patients (64%; 221/345) had preoperative GERD symptoms and a history of PPI use (52%; 179/345). A preoperative diagnosis of BE was present in 34% (118/345) of patients. Kaplan–Meier survival analysis revealed a marked survival advantage in patients undergoing esophagectomy who had preoperative GERD symptoms, PPI use or BE diagnosis ( P ≤ .001). The survival advantage remained when stratified for American Joint Committee on Cancer stage in patients with preoperative PPI use ( P = .015) but was less pronounced in patients with GERD symptoms or BE ( P = .136 and P = .225, respectively). Conclusion These data show that the oft-quoted statistic that the majority of patients with EAC do not report preexisting GERD or PPI use is false. Furthermore, a diagnosis of BE is present in a surprisingly high proportion of patients (34%). There is a distinct survival advantage in patients with preoperative GERD symptoms, PPI use, and BE diagnosis, which may not be simply owing to earlier stage at diagnosis. Screening may affect survival outcomes in more patients with EAC than previously anticipated.
Background Statin and ezetimibe combination therapy may be insufficient to improve lipid and nonlipid parameters beyond low-density lipoprotein cholesterol (LDL-C) in patients with mixed ...dyslipidemia. Methods In this phase 3, multicenter, double-blind study, a total of 543 patients with triglycerides ≥150 mg/dL and <400 mg/dL, high-density lipoprotein cholesterol (HDL-C) <40 mg/dL (<50 mg/dL for women), and LDL-C ≥130 mg/dL were randomized to 12 weeks of treatment with fenofibric acid 135 mg (FA) or placebo, each coadministered with atorvastatin 40 mg + ezetimibe 10 mg (Atorva/Eze). Results Both treatment regimens lowered LDL-C by >50%; however, FA + Atorva/Eze resulted in significantly ( P < .001) greater improvements in HDL-C (13.0% vs 4.2%), triglycerides (−57.3% vs −39.7%), non–HDL-C (−55.6% vs −51.0%), and apoprotein B (−49.1% vs −44.7%) compared with Atorva/Eze. Overall, adverse events were similar in the 2 treatment groups. No unexpected muscle, hepatic, or renal safety signals were identified with either treatment combination. Conclusions In patients with mixed dyslipidemia, the combination of FA + Atorva/Eze significantly improved lipid and nonlipid parameters compared with Atorva/Eze and was generally well tolerated.
The objectives of the Wakefield RoundTable Discussion were defined as follows: (1) Discuss theories regarding the origins and etiology of complex scale-invariant variability; (2) examine and refine ...the methodology of continuous variability analysis; (3) review and discuss the clinical applications of complex systems science; and (4) discuss and foster transdisciplinary collaborative research projects.
Objectives To describe adverse events (AEs) and noteworthy clinical or ocular findings associated with retinopathy of prematurity (ROP) evaluation procedures. Study design Descriptive analysis of ...predefined AEs and noteworthy findings reported in a prospective observational cohort study of infants <1251 g birth weight who had ROP study visits consisting of both binocular indirect ophthalmoscopy (BIO) and digital retinal imaging. We compared infant characteristics during ROP visits with and without AEs. We compared respiratory support, nutrition, and number of apnea, bradycardia, or hypoxia events 12 hours before and after ROP visits. Results A total of 1257 infants, mean birth weight 802 g, had 4263 BIO and 4048 imaging sessions (total 8311 procedures). No serious AEs were related to ROP visits. Sixty-five AEs were reported among 61 infants for an AE rate of 4.9% infants (61/1257) or 0.8% total procedures (65/8311 BIO + imaging). Most AEs were due to apnea, bradycardia, and/or hypoxia (68%), tachycardia (16%), or emesis (8%). At ROP visit, infants with AEs, compared with those without, were more likely to be on mechanical ventilation (26% vs 12%, P = .04) even after adjustment for weight and postmenstrual age. Noteworthy clinical findings were reported during 8% BIO and 15% imaging examinations. Respiratory and nutrition support were not significantly different before and after ROP evaluations. Conclusions Retinal imaging by nonphysicians combined with BIO was safe. Noteworthy clinical findings occurred during both procedures. Ventilator support was a risk factor for AEs. Monitoring rates of AEs and noteworthy findings are important to the safe implementation of ROP imaging protocols. Trial registration Clinicaltrials.gov : NCT01264276.
Over the past several years, endoscopic ablation and resection have become a new standard of care in the management of Barrett esophagus (BE) with high-grade dysplasia (HGD) or intramucosal ...adenocarcinoma (IMC). Risk factors for failure of endoscopic therapy and the need for subsequent esophagectomy have not been well elucidated. The aims of this study were to determine the efficacy of radiofrequency ablation (RFA) with or without endoscopic mucosal resection (EMR) in the management of BE with HGD or IMC, to discern factors predictive of endoscopic treatment failure, and to assess the effect of endoscopic therapies on esophagectomy volume at our institution. Data were obtained retrospectively for all patients who underwent endoscopic therapies or esophagectomy for a diagnosis of BE with HGD or IMC in our department between January 1, 2004, and December 31, 2012. Complete remission (CR) of BE or HGD or IMC was defined as 2 consecutive biopsy sessions without BE or HGD or IMC and no subsequent recurrence. Recurrence was defined by the return of BE or HGD or IMC after initial remission. Progression was defined as worsening of HGD to IMC or worsening of IMC to submucosal neoplasia or beyond. Overall, 57 patients underwent RFA with or without EMR for BE with HGD ( n = 45) or IMC ( n = 12) between 2007 and 2012, with a median follow-up duration of 35.4 months (range: 18.5-52.0 months). The 57 patients underwent 181 ablation sessions and more than half (61%) of patients underwent EMR as a component of treatment. There were no major procedural complications or deaths, with only 2 minor complications including 1 symptomatic stricture requiring dilation. Multifocal HGD or IMC was present in 43% (25/57) of patients. CR of IMC was achieved in 100% (12/12) at a median of 6.1 months, CR of dysplasia was achieved in 79% (45/57) at a median of 11.5 months, and CR of BE was achieved in 49% (28/57) at a median of 18.4 months. Following initial remission, 28% of patients (16/57) had recurrence of dysplasia ( n = 12) or BE ( n = 4). Progression to IMC occurred in 7% (4/57). All patients without CR continue endoscopic treatment. No patient required esophagectomy or developed metastatic disease. Overall, 6 patients died during the follow-up interval, none from esophageal cancer. Factors associated with failure to achieve CR of BE included increasing length of BE (6.0 ± 0.6 vs 4.0 ± 0.6 cm, P = 0.03) and shorter duration of follow-up (28.5 ± 3.8 months vs 49.0 ± 5.8 months, P = 0.004). Shorter surveillance duration (17.8 ± 7.6 months vs 63.9 ± 14.4 months, P = 0.009) and shorter follow-up (21.1 ± 6.1 months vs 43.2 ± 4.1 months) were the only significant factors associated with failure to eradicate dysplasia. Our use of esophagectomy as primary therapy for BE with HGD or IMC has diminished since we began using endoscopic therapies in 2007. From a maximum of 16 esophagectomies per year for early Barrett neoplasia in 2006, we performed only 3 esophageal resections for such early disease in 2012, all for IMC, and we have not performed an esophagectomy for HGD since 2008. Although recurrence of BE or dysplasia/IMC was not uncommon, RFA with or without EMR ultimately resulted in CR of IMC in all patients, CR of HGD in the majority (79%), and CR of BE in nearly half (49%). No patient treated endoscopically for HGD or IMC subsequently required esophagectomy. In patients with BE with HGD or IMC, RFA and EMR are safe and highly effective. The use of endoscopic therapies appears justified as the new standard of care in most cases of BE with early esophageal neoplasia.
Idelalisib, a selective inhibitor of PI3Kδ, is approved for the treatment of patients with relapsed chronic lymphocytic leukaemia (CLL) in combination with rituximab. We aimed to assess the efficacy ...and safety of idelalisib in combination with a second-generation anti-CD20 antibody, ofatumumab, in a similar patient population.
In this global, open-label, randomised, controlled phase 3 trial, we enrolled patients with relapsed CLL progressing less than 24 months from last therapy. Patients refractory to ofatumumab were excluded. Patients were stratified by relapsed versus refractory disease, presence or absence of del(17p) or TP53 mutation, or both, and IGHV mutated versus unmutated. We randomised patients in a 2:1 ratio using a web-based interactive system that generated a unique treatment code, and assigned patients to receive either idelalisib plus ofatumumab (oral idelalisib 150 mg twice daily continuously plus ofatumumab 300 mg intravenously in week 1, then 1000 mg intravenously weekly for 7 weeks, and every 4 weeks for 16 weeks) or ofatumumab alone (ofatumumab dosing as per the combination group, except 2000 mg was substituted for the 1000 mg dose). An independent review committee assessed response, including progressive disease, based on imaging using modified International Workshop on Chronic Lymphocytic Leukaemia 2008 criteria. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. We did a primary analysis (data cutoff Jan 15, 2015) and an updated analysis (data cutoff Sept 1, 2015). This trial is registered with Clinicaltrials.gov, number NCT01659021.
Between Dec 17, 2012, and March 31, 2014, we enrolled 261 patients (median age 68 years IQR 61-74, median previous therapies three IQR 2-4). At the primary analysis, median progression-free survival was 16·3 months (95% CI 13·6-17·8) in the idelalisib plus ofatumumab group and 8·0 months (5·7-8·2) in the ofatumumab group (adjusted hazard ratio HR 0·27, 95% CI 0·19-0·39, p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib plus ofatumumab group were neutropenia (59 34% patients vs 14 16% in the ofatumumab group), diarrhoea (34 20% vs one 1%), and pneumonia (25 14% vs seven 8%). The most frequent grade 3 or worse adverse events in the ofatumumab group were neutropenia (14 16%), pneumonia (seven 8%), and thrombocytopenia (six 7% vs 19 11% in the idelalisib plus ofatumumab group). Serious infections were more common in the idelalisib plus ofatumumab group and included pneumonia (23 13% patients in the idelalisib plus ofatumumab group vs nine 10% in the ofatumumab group), sepsis (11 6% vs one 1%), and Pneumocystis jirovecii pneumonia (eight 5% vs one 1%). 22 treatment-related deaths occurred in the idelalisib plus ofatumumab group (the most common being sepsis, septic shock, viral sepsis, and pneumonia). Six treatment-related deaths occurred in the ofatumumab group (the most common being progressive multifocal leukoencephalopathy and pneumonia).
The idelalisib plus ofatumumab combination resulted in better progression-free survival compared with ofatumumab alone in patients with relapsed CLL, including in those with high-risk disease, and thus might represent a new treatment alternative for this patient population.
Gilead Sciences, Inc.
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