PURPOSE Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited. PATIENTS AND METHODS In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus–positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1–positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death. CONCLUSION Here, we present the longest observation to date of patients with aMCC receiving first-line anti–programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.

Obesity is associated with early cardiovascular dysfunction and reduced muscle strength. Whole-body vibration (WBV) training may improve arterial function and muscle strength. The effects of WBV training on arterial stiffness (brachial-ankle pulse wave velocity, baPWV), wave reflection (augmentation index, AIx), brachial systolic blood pressure (bSBP), aortic systolic blood pressure (aSBP), heart rate variability, and muscle strength (one-repetition maximum, 1RM) were examined in 10 young (21 ± 2 year) overweight/obese women (body mass index, BMI¼29.9 ± 0.8 kg m -2 ). Participants were randomized to a 6-week WBV training or non-exercising control (CON) period in a crossover design. WBV training (3 daysÂweek) consisted of static and dynamic squats and calf raises with vibration intensity at 25-30 Hz and 1-2 mm amplitude (2.83-4.86 G). There were significant (Po0.05) decreases in baPWV (À0.9±0.3 m s -1 ), AIx (À8.0±2.2 %), bSBP (À5.3±1.5 mm Hg), aSBP (À5.2 ± 2.1 mm Hg), low-frequency power (À0.13 ± 0.05 nu) and sympathovagal balance (LF/HF, À0.42 ± 0.16) after WBV training compared with CON. Significant (Po0.05) increases in high-frequency power (HF, 0.19 ± 0.04 nu) and leg extension 1RM (8.2±2.3 kg) occurred after WBV training compared with CON. Six weeks of WBV training decreased systemic arterial stiffness and aSBP via improvements in wave reflection and sympathovagal balance in young overweight/obese normotensive women. WBV training may benefit arterial function and muscle strength in deconditioned individuals who cannot perform conventional exercise.

Our findings indicate that a 12-week moderate-intensity combined circuit RE and EE training improves arterial stiffness, hemodynamics, and muscle strength in previously sedentary postmenopausal women. This study provides evidence that combined training may have important health implications for the prevention of hypertension and frailty in postmenopausal women.

SUMMARY This study sought to investigate the effects of mechanical unloading on myocardial energetics and the metabolic perturbation of heart failure (HF) in an effort to identify potential new therapeutic targets that could enhance the unloading-induced cardiac recovery. The authors prospectively examined paired human myocardial tissue procured from 31 advanced HF patients at left ventricular assist device (LVAD) implant and at heart transplant plus tissue from 11 normal donors. They identified increased post-LVAD glycolytic metabolites without a coordinate increase in early, tricarboxylic acid (TCA) cycle intermediates. The increased pyruvate was not directed toward the mitochondria and the TCA cycle for complete oxidation, but instead, was mainly converted to cytosolic lactate. Increased nucleotide concentrations were present, potentially indicating increased flux through the pentose phosphate pathway. Evaluation of mitochondrial function and structure revealed a lack of post-LVAD improvement in mitochondrial oxidative functional capacity, mitochondrial volume density, and deoxyribonucleic acid content. Finally, post-LVAD unloading, amino acid levels were found to be increased and could represent a compensatory mechanism and an alternative energy source that could fuel the TCA cycle by anaplerosis. In summary, the authors report evidence that LVAD unloading induces glycolysis in concert with pyruvate mitochondrial oxidation mismatch, most likely as a result of persistent mitochondrial dysfunction. These findings suggest that interventions known to improve mitochondrial biogenesis, structure, and function, such as controlled cardiac reloading and conditioning, warrant further investigation to enhance unloading-induced reverse remodeling and cardiac recovery.