Research Spotlight

Conrad, C. and J. W. Fleshman, Jr. (2019). “Minimally Invasive Oncologic Surgery, Part I.” Surg Oncol Clin N Am 28(1): xv-xvii. Nov 12. [Epub ahead of print].

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This issue of Surgical Oncology Clinics of North America on Minimally Invasive Cancer Management, written by experts from around the world, provides an up-to-date overview on the tremendous progress that has been made in this field. Modern cancer surgery has the unique and unprecedented capacity to go beyond technical aspects of removing the tumor, focusing simultaneously on the cancer’s biology and its morbidity. For example, while Halsted’s radical mastectomy certainly helped many patients suffering from breast cancer, later attempts to reduce the morbidity in the context of progress in oncologic management led to a significant reduction of morbidity. Similarly, once surgeons such as Codivilla (1898), Kausch (1912), and Whipple (1935) pioneered the complex operation of a pancreaticoduodenectomy, attempts to perform the operation less invasively led to Gagner and Pomp reporting the first laparoscopic pancreaticoduodenectomy in 1994. In parallel, after the first successful liver resection by the German surgeon Langenbuch in 1888 (the specimen showed normal liver), the eagerness of performing liver surgery according to anatomic principles resulted in post-1950 reports of selective anatomic liver resection by Honjo (Japan), Lortat-Jacob (France), and Ton That Tung (Vietnam). Then, minimally invasive liver resection was introduced in the 1990s. Like many daring innovations, early attempts to develop minimally invasive surgery have not always drawn praise, or even approval. For example, after Semm performed the first laparoscopic appendectomy from the gynecological clinic of Kiel in 1981, the president of the German Surgical Society wrote to the Board of Directors of the German Gynecological Society requesting suspension of Semm from medical practice. Stories of such challenging environments are numerous and well known, and the ability of surgeons to push through those have paved the way for the exciting time in cancer surgery we live in today. This historic time includes standardizing minimally invasive operations and augmenting its potential by injecting high-tech applications, such as augmented reality or fluorescent-guided surgery. (Except from text, p. xv-xvi.)

Mao, J., R. F. Redberg, J. D. Carroll, D. Marinac-Dabic, J. Laschinger, V. Thourani, M. Mack and A. Sedrakyan (2018). “Association Between Hospital Surgical Aortic Valve Replacement Volume and Transcatheter Aortic Valve Replacement Outcomes.” JAMA Cardiol Oct 31. [Epub ahead of print].

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Importance: The Centers for Medicare & Medicaid Services national coverage determination for transcatheter aortic valve replacement (TAVR) includes volume requirements for surgical aortic valve replacement (SAVR) for hospitals seeking to initiate or continue TAVR programs. Evidence regarding the association between SAVR volume and TAVR outcomes is limited. Objective: To examine the association of hospital SAVR and combined SAVR and TAVR volumes with patient outcomes of TAVR procedures performed within 1 year, 2 years, and for the entire period after initiation of TAVR programs. Design, Setting, and Participants: This observational cohort study included 60538 TAVR procedures performed in 438 hospitals between October 1, 2011, and December 31, 2015, among Medicare beneficiaries. Main Outcomes and Measures: The associations between SAVR volume, SAVR and TAVR volumes, and risks of death, death or stroke, and readmissions within 30 days were determined using a hierarchical logistic regression model adjusting for patient and hospital characteristics. The association between SAVR and SAVR and TAVR volumes and 1-year and 2-year mortality after TAVR procedures was determined using a multivariable proportional hazard model with a robust variance estimator. The associations for procedures performed within 1 year, 2 years, and for the entire period after initiation of TAVR programs were examined. Results: Among the 60538 patients, 29173 were women and 31365 were men, with a mean (SD) age of 82.3 (8.0) years. Hospitals with high SAVR volume (mean annual volume, >/=97 per year) were more likely to adopt TAVR early and had a higher growth in TAVR volumes over time (median TAVR volume by hospitals with high SAVR volume and low SAVR volume: year 1, 32 vs 19; year 2, 48 vs 28; year 3, 82 vs 38; year 4, 118 vs 54; P < .001). In adjusted analysis, high hospital SAVR volume alone was not associated with better patient outcomes after TAVR. When hospital TAVR and SAVR volumes were jointly analyzed, patients treated in hospitals with high TAVR volume had lower 30-day mortality after TAVR (high TAVR and low SAVR vs low TAVR and low SAVR: odds ratio, 0.85; 95% CI, 0.72-0.99; high TAVR and high SAVR vs low TAVR and high SAVR: odds ratio, 0.81; 95% CI, 0.69-0.95), the effect of which was more pronounced when hospitals also had high SAVR volume. Patients treated in hospitals with high SAVR volume and high TAVR volume had the lowest 30-day mortality (vs hospitals with low SAVR volume and TAVR volume: odds ratio, 0.77; 95% CI, 0.66-0.89). Conclusions and Relevance: Hospitals with high SAVR volume are most likely to be fast adopters of TAVR. Hospital SAVR volume alone is not associated with better TAVR outcomes. Accumulating high volumes of TAVR is associated with lower mortality after TAVR, particularly when hospitals have high SAVR volumes. Hospitals with high caseloads of both SAVR and TAVR are likely to achieve the best outcomes.

Hodi, F. S., V. Chiarion-Sileni, R. Gonzalez, J. J. Grob, P. Rutkowski, C. L. Cowey, C. D. Lao, D. Schadendorf, J. Wagstaff, R. Dummer, P. F. Ferrucci, M. Smylie, A. Hill, D. Hogg, I. Marquez-Rodas, J. Jiang, J. Rizzo, J. Larkin and J. D. Wolchok (2018). “Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.” Lancet Oncol Oct 18. [Epub ahead of print].

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BACKGROUND: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study. METHODS: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAF(V600) mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505. FINDINGS: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46.9 months (IQR 10.9-51.8) in the nivolumab plus ipilimumab group, 36.0 months (10.5-51.4) in the nivolumab group, and 18.6 months (7.6-49.5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38.2-not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3-not reached) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0.54 (95% CI 0.44-0.67; p<0.0001) and for nivolumab versus ipilimumab was 0.65 (0.53-0.79; p<0.0001). Median progression-free survival was 11.5 months (95% CI 8.7-19.3) in the nivolumab plus ipilimumab group, 6.9 months (5.1-10.2) in the nivolumab group, and 2.9 months (2.8-3.2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0.42 (95% CI 0.35-0.51; p<0.0001) and for nivolumab versus ipilimumab was 0.53 (0.44-0.64; p<0.0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis. INTERPRETATION: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma. FUNDING: Bristol-Myers Squibb.

Rangaswami, J. and P. A. McCullough (2018). “Heart Failure in End-Stage Kidney Disease: Pathophysiology, Diagnosis, and Therapeutic Strategies.” Semin Nephrol Nov. 11: 38(6): 600-617.

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Heart failure (HF) is a major comorbidity in patients with end-stage kidney disease (ESKD). The pathogenesis of HF in patients on renal replacement therapy represents the confluence of several traditional and nontraditional vascular risk factors, unique to the milieu of chronic kidney disease and the dialysis modality. The diagnosis of HF with ESKD is complicated by the background of frequent inevitable fluid shifts superimposed on underlying myocardial pump abnormalities and dialysis-induced myocardial stunning. A careful temporal assessment of symptoms and physical findings, cardiac imaging, hemodynamic data, and biomarkers help establish an accurate diagnosis of HF in ESKD. Accurate volume assessment and its tight management remains the cornerstone of treatment in HF in patients on dialysis. A multidisciplinary approach between the cardiologist and nephrologist in optimizing pharmacologic strategies for HF in this population, and dialysis-based options such as frequent dialysis, may help reduce the burden of HF in this vulnerable population. Finally, including patients with ESKD in clinical trials for HF therapies, and designing pragmatic trials that bring targeted strategies for HF into the daily clinical practice of dialysis, will shed light on the optimal management of the dual burden of cardiomyopathy and advanced kidney disease.

Vallabhajosyula, S., T. M. Haddad, P. R. Sundaragiri, A. A. Ahmed, M. S. Nawaz, H. A. A. Rayes, H. C. Devineni, A. Kanmanthareddy, D. A. McCann, C. S. Wichman, A. M. Modrykamien and L. E. Morrow (2018). “Role of B-Type Natriuretic Peptide in Predicting In-Hospital Outcomes in Acute Exacerbation of Chronic Obstructive Pulmonary Disease With Preserved Left Ventricular Function: A 5-Year Retrospective Analysis.” J Intensive Care Med 33(11): 635-644.

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BACKGROUND: The role of B-type natriuretic peptide (BNP) is less understood in the risk stratification of patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), especially in patients with normal left ventricular ejection fraction (LVEF). METHODS: This retrospective study from 2008 to 2012 evaluated all adult patients with AECOPD having BNP levels and available echocardiographic data demonstrating LVEF >/=40%. The patients were divided into groups 1, 2, and 3 with BNP /=501 pg/mL, respectively. A subgroup analysis was performed for patients without renal dysfunction. Outcomes included need for and duration of noninvasive ventilation (NIV) and mechanical ventilation (MV), NIV failure, reintubation at 48 hours, intensive care unit (ICU) and total length of stay (LOS), and in-hospital mortality. Two-tailed P < .05 was considered statistically significant. RESULTS: Of the total 1145 patients, 550 (48.0%) met our inclusion criteria (age 65.1 +/- 12.2 years; 271 [49.3%] males). Groups 1, 2, and 3 had 214, 216, and 120 patients each, respectively, with higher comorbidities and worse biventricular function in higher categories. Higher BNP values were associated with higher MV use, NIV failure, MV duration, and ICU and total LOS. On multivariate analysis, BNP was an independent predictor of higher NIV and MV use, NIV failure, NIV and MV duration, and total LOS in groups 2 and 3 compared to group 1. B-type natriuretic peptide continued to demonstrate positive correlation with NIV and MV duration and ICU and total LOS independent of renal function in a subgroup analysis. CONCLUSION: Elevated admission BNP in patients with AECOPD and normal LVEF is associated with worse in-hospital outcomes and can be used to risk-stratify these patients.