Research Spotlight

Wolchok, J. D., V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J. J. Grob, C. L. Cowey, C. D. Lao, J. Wagstaff, D. Schadendorf, P. F. Ferrucci, M. Smylie, R. Dummer, A. Hill, D. Hogg, J. Haanen, M. S. Carlino, O. Bechter, M. Maio, I. Marquez-Rodas, M. Guidoboni, G. McArthur, C. Lebbe, P. A. Ascierto, G. V. Long, J. Cebon, J. Sosman, M. A. Postow, M. K. Callahan, D. Walker, L. Rollin, R. Bhore, F. S. Hodi and J. Larkin (2017). “Overall survival with combined nivolumab and ipilimumab in advanced melanoma.” N Engl J Med 377(14): 1345-1356.

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Background Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. Methods We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. Results At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. Conclusions Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone.

Douglas, P. S., M. B. Leon, M. J. Mack, L. G. Svensson, J. G. Webb, R. T. Hahn, P. Pibarot, N. J. Weissman, D. C. Miller, S. Kapadia, H. C. Herrmann, S. K. Kodali, R. R. Makkar, V. H. Thourani, S. Lerakis, A. M. Lowry, J. Rajeswaran, M. T. Finn, M. C. Alu, C. R. Smith and E. H. Blackstone (2017). “Longitudinal hemodynamics of transcatheter and surgical aortic valves in the partner trial.” JAMA Cardiol: 2017 Sep [Epub ahead of print].

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Importance: Use of transcatheter aortic valve replacement (TAVR) for severe aortic stenosis is growing rapidly. However, to our knowledge, the durability of these prostheses is incompletely defined. Objective: To determine the midterm hemodynamic performance of balloon-expandable transcatheter heart valves. Design, Setting, and Participants: In this study, we analyzed core laboratory-generated data from echocardiograms of all patients enrolled in the Placement of Aortic Transcatheter Valves (PARTNER) 1 Trial with successful TAVR or surgical AVR (SAVR) obtained preimplantation and at 7 days, 1 and 6 months, and 1, 2, 3, 4, and 5 years postimplantation. Patients from continued access observational studies were included for comparison. Interventions: Successful implantation after randomization to TAVR vs SAVR (PARTNER 1A; TAVR, n = 321; SAVR, n = 313), TAVR vs medical treatment (PARTNER 1B; TAVR, n = 165), and continued access (TAVR, n = 1996). Five-year echocardiogram data were available for 424 patients after TAVR and 49 after SAVR. Main Outcomes and Measures: Death or reintervention for aortic valve structural indications, measured using aortic valve mean gradient, effective orifice area, Doppler velocity index, and evidence of hemodynamic deterioration by reintervention, adverse hemodynamics, or transvalvular regurgitation. Results: Of 2795 included patients, the mean (SD) age was 84.5 (7.1) years, and 1313 (47.0%) were female. Population hemodynamic trends derived from nonlinear mixed-effects models showed small early favorable changes in the first few months post-TAVR, with a decrease of -2.9 mm Hg in aortic valve mean gradient, an increase of 0.028 in Doppler velocity index, and an increase of 0.09 cm2 in effective orifice area. There was relative stability at a median follow-up of 3.1 (maximum, 5) years. Moderate/severe transvalvular regurgitation was noted in 89 patients (3.7%) after TAVR and increased over time. Patients with SAVR showed no significant changes. In TAVR, death/reintervention was associated with lower ejection fraction, stroke volume index, and aortic valve mean gradient up to 3 years, with no association with Doppler velocity index or valve area. Reintervention occurred in 20 patients (0.8%) after TAVR and in 1 (0.3%) after SAVR and became less frequent over time. Reintervention was caused by structural deterioration of transcatheter heart valves in only 5 patients. Severely abnormal hemodynamics on echocardiograms were also infrequent and not associated with excess death or reintervention for either TAVR or SAVR. Conclusions and Relevance: This large, core laboratory-based study of transcatheter heart valves revealed excellent durability of the transcatheter heart valves and SAVR. Abnormal findings in individual patients, suggestive of valve thrombosis or structural deterioration, were rare in this protocol-driven database and require further investigation.

Keller, D. S., T. Ishizawa, R. Cohen and M. Chand (2017). “Indocyanine green fluorescence imaging in colorectal surgery: Overview, applications, and future directions.” Lancet Gastroenterol Hepatol 2(10): 757-766.

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Indocyanine green fluorescence imaging is a surgical tool with increasing applications in colorectal surgery. This tool has received acceptance in various surgical disciplines as a potential method to enhance surgical field visualisation, improve lymph node retrieval, and decrease the incidence of anastomotic leaks. In colorectal surgery specifically, small studies have shown that intraoperative fluorescence imaging is a safe and feasible method to assess anastomotic perfusion, and its use might affect the incidence of anastomotic leaks. Controlled trials are ongoing to validate these conclusions. The number of new indications for indocyanine green continues to increase, including innovative options for detecting and guiding management of colorectal metastasis to the liver. These advances could offer great value for surgeons and patients, by improving the accuracy and outcomes of oncological resections.

Sannino, A., R. L. Smith, 2nd, G. G. Schiattarella, B. Trimarco, G. Esposito and P. A. Grayburn (2017). “Survival and cardiovascular outcomes of patients with secondary mitral regurgitation: A systematic review and meta-analysis.” JAMA Cardiol: 2017 Sep [Epub ahead of print].

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Importance: The outcomes of patients with left ventricular (LV) dysfunction and secondary mitral regurgitation (SMR) are still controversial. Objective: To clarify the role of SMR in the outcomes of patients with ischemic or idiopathic cardiomyopathies. Data Sources: MEDLINE, ISI Web of Science, and Scopus databases were searched for studies published up to March 2017. Study Selection: Studies reporting data on outcomes in patients with SMR were included. Duplicate publication data, studies lacking data on SMR grade and its correlation with outcomes, mixed data on SMR and primary mitral regurgitation, studies not clearly reporting the outcome of interest, and studies with fewer than 100 patients were excluded. Of the initial 3820 articles identified, 1.4% were finally included. Data Extraction and Synthesis: The study met PRISMA requirements. Two of us independently screened articles for fulfillment of inclusion criteria. Main Outcomes and Measures: The primary outcome, set after data collection, was the incidence of all-cause mortality in patients with and without SMR. Secondary outcomes included hospitalization for heart failure (HF), cardiac mortality, and a composite end point of death, HF hospitalization, and cardiac transplant. Results: Fifty-three studies and 45900 patients were included in the meta-analysis. The mean (SD) length of follow-up was 40.8 (22.2) months. In 26 of 36 studies reporting LV function by SMR grade, increasing SMR severity was associated with worse LV function. When SMR was categorized as present or absent, all-cause mortality was significantly higher in the patients with SMR (17 studies, 26359 patients; risk ratio [RR],1.79; 95% CI, 1.47-2.18; P < .001, I2 = 85%); when SMR was qualitatively graded, the incidence of all-cause mortality was significantly increased in patients having any degree of SMR compared with patients not having SMR (21 studies, 21081 patients; RR, 1.96; 95% CI, 1.67-2.31; P < .001, I2 = 74%). Finally, when SMR was quantitatively graded, it remained associated with an increased all-cause mortality rate (9 studies, 3649 patients; RR, 1.97; 95% CI, 1.71-2.27; P < .001, I2 = 0%). Moreover, SMR was associated with an increased risk of hospitalization for HF (16 studies, 10171 patients; RR, 2.26; 95% CI, 1.92-2.67; P < .001, I2 = 41%), cardiac mortality (12 studies, 11896 patients; RR, 2.62; 95% CI, 1.87-3.69; P < .001, I2 = 74%), and death, HF, and transplant (11 studies, 8256 patients; RR, 1.63; 95% CI, 1.33-1.99; P < .001, I2 = 78%). Conclusions and Relevance: To our knowledge, this study is the first meta-analysis to date to demonstrate that SMR, even when mild, correlates with adverse outcomes in patients with ischemic or idiopathic cardiomyopathies. Because SMR is an intrinsic consequence of LV dysfunction, causality between SMR and mortality should not be implied.

Spechler, S. J. (2017). “The durability of antireflux surgery.” Jama 318(10): 913-915.

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Patients who have mild, nonerosive gastroesophageal reflux disease (GERD) have many valid treatment options, but patients with severe erosive GERD (those with endoscopy showing large esophageal mucosal breaks extending between mucosal folds) have only 2: take proton pump inhibitors (PPIs) indefinitely or have antireflux surgery with fundoplication.1 No medication other than PPIs (and potassium-competitive acid blockers, which are not available in the United States) reliably heals reflux esophagitis; once healed, that esophagitis will return quickly and severely in most cases if PPIs are stopped.2