Estimates of the prevalence and importance of significant tricuspid regurgitation (STR) related to implantable device leads are based mainly on case reports, small observational studies, or mixed ...samples that include defibrillators. We sought to assess whether patients with permanent pacemaker (PPM) leads have an increased risk of STR and to determine mortality associated with PPM-related TR in a large longitudinal single-center cohort. We examined the prevalence of STR (defined as moderate-severe or ≥3+) among all echocardiograms performed from 2005 to 2011 excluding those with defibrillators. We then examined mortality risk according to the prevalence of PPM and STR after adjusting for cardiac co-morbidities, left ventricular systolic/diastolic function, and pulmonary artery hypertension. We screened 93,592 echocardiograms (1,245 with PPM) in 58,556 individual patients (634 with PPM). The prevalence of STR was higher in patients after PPM placement (mean age 79 ± 3 years; 54% men) compared with those without a PPM (adjusted odds ratio 2.32; 95% confidence interval CI 1.54 to 3.49; p <0.0001). Among patients with a PPM lead, the presence of STR was associated with increased mortality (adjusted hazard ratio 1.40; 95% CI 1.04 to 2.11, p = 0.027, vs no STR). Compared with having neither a PPM lead nor STR, adjusted hazard ratios for death were 2.13 (95% CI 1.93 to 2.34) for STR but no PPM, 1.04 (0.89 to 1.22) for PPM without STR, and 1.55 (1.13 to 2.14) for PPM with STR. In conclusion, in a sample comprising >58,000 individual patients, PPM leads are associated with higher risk of STR after adjustment for left ventricular systolic/diastolic function and pulmonary artery hypertension; similarly to STR from other cardiac pathologies, PPM-related STR is associated with increased mortality.
Background TNFeradeBiologic (AdGVEGR.TNF.11D) is a replication-deficient adenoviral vector that expresses tumor necrosis factor-α (TNF-α) under the control of the Egr-1 promoter, which is inducible ...by chemotherapy and radiation. Objective This study was conducted to determine the maximal tolerated dose of TNFeradeBiologic with standard chemoradiotherapy and preliminary activity and safety of the combination in the treatment of locally advanced pancreatic cancer (LAPC). Design TNFeradeBiologic was injected into locally advanced pancreatic carcinomas by using EUS or percutaneous administration once a week for 5 weeks together with 50.4 Gy radiation and 5-fluorouracil (5-FU) 200 mg/m2 daily over 5.5 weeks. Dose levels from 4 × 109 to 1 × 1012 particle units (PU) were studied. Setting Multicentered, academic institutions. Patients Fifty patients with LAPC were treated. Interventions Doses of TNFerade Biologic were administered to patients. Main Outcome Measurements Toleration of TNFerade Biologic was measured through toxicity and tumor response, by using the criteria of the Response Evaluation Criteria in Solid Tumors and the World Health Organization, and was reviewed by a central radiology facility. Overall survival and progression-free survival were also measured. Results Dose-limiting toxicities of pancreatitis and cholangitis were observed in 3 patients at the 1 × 1012 PU dose, making 4 × 1011 PU the maximum tolerated dose. One complete response, 3 partial responses, and 12 patients with stable disease were noted. Seven patients eventually went to surgery, 6 had clear margins, and 3 survived >24 months. Limitations This is a Phase1/2 non-randomized study. Conclusions Intratumoral delivery of TNFerade Biologic by EUS with fine-needle viral injection or percutaneously, combined with chemoradiation, shows promise in the treatment of LAPC. There appeared to be better clinical outcome at the maximal tolerated dose than at lower doses. The dose of 4 ×1011 PU TNFerade Biologic was generally well tolerated, with encouraging indications of activity, and will be tested in the randomized phase of this study. Delivery of TNFerade Biologic did not interfere with subsequent surgical resection.
Objective To assess the dose-response, safety, and efficacy of circumferential endoscopic ablation of Barrett's esophagus (BE) by using an endoscopic balloon–based ablation device (HALO360 System). ...Design This study was conducted in 2 serial phases (dosimetry phase and effectiveness phase) to evaluate a balloon-based ablation device that delivers a pre-set amount of energy density (J/cm2 ) to BE tissue. The dosimetry phase evaluated the dose-response and the safety of delivering 6 to 12 J/cm2 . The effectiveness phase used 10 J/cm2 (delivered twice ×2) for all patients, followed by EGD with biopsies at 1, 3, 6, and 12 months. A second ablation procedure was performed if BE was present at 1 or 3 months. Patients received esomeprazole 40 mg twice a day for 1 month after ablation, and 40 mg every day thereafter. Postablation symptoms were quantified by using a 14-day symptom diary (scale, 0-100). A complete response (CR) was defined as all biopsy specimens negative for BE at 12 months. Setting Eight U.S. centers, between September 2003 and September 2005. Patients Patients were 18 to 75 years of age, with a diagnosis of BE (without dysplasia), with histopathology reconfirmation of the diagnosis within 6 months of enrollment. Results In the dosimetry phase, 32 patients (29 men; mean age, 56.8 years) were enrolled. Median symptom scores returned to a score of 0 of 100 by day 3. There were no dose-related serious adverse events, and the outcomes at 1 and 3 months permitted the selection of 10 J/cm2 (×2) for the subsequent effectiveness phase of the study. In the effectiveness phase, 70 patients (52 men, 18 women; mean age, 55.7 years) were enrolled. Median symptom scores returned to a score of 0 of 100 by day 4. At 12 months (n = 69; mean, 1.5 sessions), a CR for BE was achieved in 70% of patients. There were no strictures and no buried glandular mucosa in either study phase (4306 biopsy fragments evaluated). Conclusions Circumferential ablation of nondysplastic BE by using this balloon-based ablation device can be performed with no subsequent strictures or buried glands and with complete elimination of BE in 70% of patients at 1-year follow-up.
Background and Aims Targeting neoplasia in Barrett’s esophagus (BE) is challenging. Volumetric laser endomicroscopy (VLE) is a new imaging technique that allows for real time cross-sectional ...microstructure imaging that can detect BE neoplasia. The interobserver agreement among users in practice is unknown. Methods Eight high-volume users of VLE from different academic centers in the United States evaluated 120 stored VLE images blinded to the endoscopic and clinical findings. There were 30 images for each tissue type: gastric cardia, esophageal squamous mucosa, nonneoplastic BE, and neoplastic BE. Each image with BE had corresponding histology confirming the tissue diagnosis. Each normal esophagus and gastric cardia had matching endoscopic images confirming normal mucosa. These were considered the criterion standard. Respondents were asked to classify the images into 1 of each category. Agreement among the users was measured. Results The overall agreement among users was almost perfect (kappa = 0.81; 95% confidence interval CI, 0.79-0.83). For esophageal squamous and gastric cardia, the agreement was almost perfect (kappa 0.95 and 0.86, respectively 95% CI, 0.92-0.98 and 0.83-0.89). For nonneoplastic BE and neoplastic BE, the agreement was strong (kappa 0.66 95% CI, 0.63-0.69 and 0.79 95% CI, 0.75-0.82, respectively). When compared with the criterion standard, the median accuracy for identifying normal squamous mucosa, normal gastric mucosa, nonneoplastic BE, neoplastic BE, and all tissue types was 99% (95% CI, 98%-100%), 97% (95% CI, 95%-99%), 93% (95% CI, 88%-98%), 95% (95% CI, 91%-99%), and 96% (95% CI, 94%-99%), respectively. Conclusions VLE has a high level of agreement and accuracy among high-volume users.
Background For patients with Barrett's esophagus (BE), life-long surveillance endoscopy is recommended because of an elevated risk for developing dysplasia and esophageal adenocarcinoma. Various ...endoscopic therapies have been used to eradicate BE. Recently circumferential radiofrequency ablation has been used with encouraging short-term results. Objective To provide longer follow-up and to assess the long-term safety and efficacy of step-wise circumferential ablation with the addition of focal ablation for BE. Design Prospective, multicenter clinical trial (NCT00489268). Setting Eight U.S. centers, between May 2004 and February 2007. Patients Seventy subjects with 2 to 6 cm of BE and histologic evidence of intestinal metaplasia (IM). Interventions Circumferential ablation was performed at baseline and repeated at 4 months if there was residual IM. Follow-up biopsy specimens were obtained at 1, 3, 6, 12, and 30 months. Specimens were reviewed by a central pathology board. Focal ablation was performed after the 12-month follow-up for histological evidence of IM at the 12-month biopsy (absolute indication) or endoscopic appearance suggestive of columnar-lined esophagus (relative indication). Subjects received esomeprazole for control of esophageal reflux. Main outcome measurements Complete absence of IM per patient from biopsy specimens obtained at 12 and 30 months, defined as complete remission–IM (CR-IM). Results At 12 months, CR-IM was achieved in 48 of 69 available patients (70% per protocol PP, 69% intention to treat ITT). At 30 months after additional focal ablative therapy, CR-IM was achieved in 60 of 61 available patients (98% PP, 97% ITT). There were no strictures or buried glandular mucosa detected by the standardized biopsy protocol at 12 or 30 months, and there were no serious adverse events. Limitations This was an uncontrolled clinical trial with 2.5-year follow-up. Conclusion Stepwise circumferential and focal ablation resulted in complete eradication of IM in 98% of patients at 2.5-year follow-up.
Background The management strategies for Barrett's esophagus (BE) that contains high-grade dysplasia (HGD) include intensive endoscopic surveillance, photodynamic therapy, thermal ablation, EMR, and ...esophagectomy. Objective To assess the safety and effectiveness of endoscopic circumferential balloon-based ablation by using radiofrequency energy for treating BE HGD. Design Multicenter U.S. registry. Setting Sixteen academic and community centers; treatment period from September 2004 to March 2007. Patients Patients with histologic evidence of intestinal metaplasia (IM) that contained HGD confirmed by at least 2 expert pathologists. A prior EMR was permitted, provided that residual HGD remained in the BE region for ablation. Intervention Endoscopic circumferential ablation with follow-up esophageal biopsies to assess the histologic response to treatment. Outcomes Histologic complete response (CR) end points: (1) all biopsy specimen fragments obtained at the last biopsy session were negative for HGD (CR-HGD), (2) all biopsy specimens were negative for any dysplasia (CR-D), and (3) all biopsy specimens were negative for IM (CR-IM). Results A total of 142 patients (median age 66 years, interquartile range IQR 59-75 years) who had BE HGD (median length 6 cm, IQR 3-8 cm) underwent circumferential ablation (median 1 session, IQR 1-2). No serious adverse events were reported. There was 1 asymptomatic stricture and no buried glands. Ninety-two patients had at least 1 follow-up biopsy session (median follow-up 12 months, IQR 8-15 months). A CR-HGD was achieved in 90.2% of patients, CR-D in 80.4%, and CR-IM in 54.3%. Limitations A nonrandomized study design, without a control arm, a lack of centralized pathology review, ablation and biopsy technique not standardized, and a relatively short-term follow-up. Conclusions Endoscopic circumferential ablation is a promising modality for the treatment of BE that contains HGD. In this multicenter registry, the intervention safely achieved a CR for HGD in 90.2% of patients at a median of 12 months of follow-up.
Background Detection of hepatic metastases during EUS is an important component of tumor staging. Objective To describe our experience with EUS-guided FNA (EUS-FNA) of solid hepatic masses and derive ...and validate criteria to help distinguish between benign and malignant hepatic masses. Design Retrospective study, survey. Setting Single, tertiary-care referral center. Patients Medical records were reviewed for all patients undergoing EUS-FNA of solid hepatic masses over a 12-year period. Interventions EUS-FNA of solid hepatic masses. Main Outcome Measurements Masses were deemed benign or malignant according to predetermined criteria. EUS images from 200 patients were used to create derivation and validation cohorts of 100 cases each, matched by cytopathologic diagnosis. Ten expert endosonographers blindly rated 15 initial endosonographic features of each of the 100 images in the derivation cohort. These data were used to derive an EUS scoring system that was then validated by using the validation cohort by the expert endosonographer with the highest diagnostic accuracy. Results A total of 332 patients underwent EUS-FNA of a hepatic mass. Interobserver agreement regarding the initial endosonographic features among the expert endosonographers was fair to moderate, with a mean diagnostic accuracy of 73% (standard deviation 5.6). A scoring system incorporating 7 EUS features was developed to distinguish benign from malignant hepatic masses by using the derivation cohort with an area under the receiver operating curve (AUC) of 0.92; when applied to the validation cohort, performance was similar (AUC 0.86). The combined positive predictive value of both cohorts was 88%. Limitations Single center, retrospective, only one expert endosonographer deriving and validating the EUS criteria. Conclusion An EUS scoring system was developed that helps distinguish benign from malignant hepatic masses. Further study is required to determine the impact of these EUS criteria among endosonographers of all experience.
To compare 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable early-stage lung cancer to determine which produces the lowest rate of grade ≥3 protocol-specified adverse ...events (psAEs) at 1 year.
Patients with biopsy-proven peripheral (≥2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors were eligible. Patients were randomized to receive either 34 Gy in 1 fraction (arm 1) or 48 Gy in 4 consecutive daily fractions (arm 2). Rigorous central accreditation and quality assurance confirmed treatment per protocol guidelines. This study was designed to detect a psAEs rate >17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included rates of primary tumor control (PC), overall survival (OS), and disease-free survival (DFS) at 1 year. Designating the better of the 2 regimens was based on prespecified rules of psAEs and PC for each arm.
Ninety-four patients were accrued between September 2009 and March 2011. The median follow-up time was 30.2 months. Of 84 analyzable patients, 39 were in arm 1 and 45 in arm 2. Patient and tumor characteristics were balanced between arms. Four (10.3%) patients on arm 1 (95% confidence interval CI 2.9%-24.2%) and 6 (13.3%) patients on arm 2 (95% CI 5.1%-26.8%) experienced psAEs. The 2-year OS rate was 61.3% (95% CI 44.2%-74.6%) for arm 1 patients and 77.7% (95% CI 62.5%-87.3%) for arm 2. The 2-year DFS was 56.4% (95% CI 39.6%-70.2%) for arm 1 and 71.1% (95% CI 55.5%-82.1%) for arm 2. The 1-year PC rate was 97.0% (95% CI 84.2%-99.9%) for arm 1 and 92.7% (95% CI 80.1%-98.5%) for arm 2.
34 Gy in 1 fraction met the prespecified criteria and, of the 2 schedules, warrants further clinical research.
Background The diagnosis of pancreatic cystic neoplasms (PCNs), which now depends on morphology, cytology, and fluid analysis, is still challenging. A novel confocal laser endomicroscopy probe that ...can be inserted through a 19-gauge FNA needle allows needle-based confocal laser endomicroscopy (nCLE), and the feasibility of nCLE has been reported in PCNs. The combination of cystoscopy by using a through-the-needle fiberoptic probe in combination with nCLE under EUS guidance may improve the diagnosis of PCNs. Objective To assess the feasibility, safety, and diagnostic yield of the combination of cystoscopy and nCLE in the clinical diagnosis of PCNs. Design A prospective feasibility study. Setting An academic tertiary referral center. Patients Thirty patients with PCNs. Interventions EUS-guided dual through-the-needle imaging (cystoscopy and nCLE) for PCNs. Main Outcome Measurements Technical feasibility and safety. Associations of cystoscopy and nCLE findings with clinical diagnosis of PCNs. Results The procedure was technically successful with the exception of 1 probe exchange failure. In 2 patients (7%), postprocedure pancreatitis developed. Specific features associated with the clinical diagnosis of mucinous cysts were identified: mucin on cystoscopy and papillary projections and dark rings on nCLE. The sensitivity of cystoscopy was 90% (9/10), and that of nCLE was 80% (8/10), and the combination was 100% (10/10) in 18 high-certainty patients. Limitations A single-center study and lack of complete pathologic correlation. Conclusion The combination of dual through-the-needle imaging (cystoscopy and nCLE) of pancreatic cysts appears to have strong concordance with the clinical diagnosis of PCN. (Clinical trial registration number: NCT01447238 .)
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