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Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma. In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2–4a or ypN+ tumours following neoadjuvant chemotherapy or pT3–4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2–29·8). Median disease-free survival was 19·4 months (95% CI 15·9–24·8) with atezolizumab and 16·6 months (11·2–24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74–1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group. To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time. F Hoffmann-La Roche/Genentech.

Background Computed tomography measurements of total skeletal muscle area can detect changes and predict overall survival (OS) in patients with advanced ovarian cancer. This study investigates whether assessment of psoas muscle area reflects total muscle area and can be used to assess sarcopenia in ovarian cancer patients. Methods Ovarian cancer patients (n = 150) treated with induction chemotherapy and interval debulking were enrolled retrospectively in this longitudinal study. Muscle was measured cross sectionally with computed tomography in three ways: (i) software quantification of total skeletal muscle area (SMA); (ii) software quantification of psoas muscle area (PA); and (iii) manual measurement of length and width of the psoas muscle to derive the psoas surface area (PLW). Pearson correlation between the different methods was studied. Patients were divided into two groups based on the extent of change in muscle area, and agreement was measured with kappa coefficients. Cox‐regression was used to test predictors for OS. Results Correlation between SMA and both psoas muscle area measurements was poor (r = 0.52 and 0.39 for PA and PLW, respectively). After categorizing patients into muscle loss or gain, kappa agreement was also poor for all comparisons (all κ < 0.40). In regression analysis, SMA loss was predictive of poor OS (hazard ratio 1.698 (95%CI 1.038–2.778), P = 0.035). No relationship with OS was seen for PA or PLW loss. Conclusions Change in psoas muscle area is not representative of total muscle area change and should not be used to substitute total skeletal muscle to predict survival in patients with ovarian cancer.

The postmortem diagnosis of drowning death and understanding the mechanisms leading to drowning require a comprehensive judgment based on numerous morphological findings in order to determine the pathogenesis and epidemiological characteristics of the findings. Effortful breathing during the drowning process can result in intramuscular hemorrhage in respiratory and accessory respiratory muscles. However, the characteristics of this phenomenon have not been investigated. We analyzed the epidemiological characteristics of 145 cases diagnosed as drowning, in which hemorrhage, not due to trauma, was found in the respiratory muscles and accessory respiratory muscles. Hemorrhage was observed in 31.7% of these cases, and the incidence did not differ by gender or drowning location. The frequency of hemorrhage was significantly higher in months with a mean temperature below 20°C than in months above 20°C, suggesting a relationship between the occurrence of hemorrhage and low environmental temperature. Moreover, the frequency of hemorrhage was significantly higher in the elderly (aged ≥65 years) compared to those <65 years old. In the elderly, the weakening of muscles due to aging may contribute to the susceptibility for intramuscular hemorrhage. Moreover, these intramuscular hemorrhages do not need to be considered in cases of a potential bleeding tendency due to disease such as cirrhosis or medication such as anticoagulants. Our results indicate that intramuscular hemorrhage in respiratory and accessory respiratory muscles can serve as an additional criterion to differentiate between fatal drowning and other causes of death, as long as no cutaneous or subcutaneous hematomas above the muscles with hemorrhages are observed. In addition, the epidemiological features that such intramuscular hemorrhage is more common in cold environments and in the elderly may provide useful information for the differentiation.

Abstract Background The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11β-HSD1 inhibitors. We examined the impact of the reversible competitive 11β-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension (IIH). Methods We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry. Results Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, fat mass, and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass. Conclusions These beneficial metabolic changes represent a reduction in risk factors associated with raised intracranial pressure and represent further beneficial therapeutic outcomes of 11β-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia.

The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up. VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete. From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1–5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58–70] vs 56% [50–63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59–1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21–32] vs 40% [34–46], HRstrat 0·61 [95% CI 0·45–0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60–73] vs 57% [50–64], HR 0·71 [95% CI 0·52–0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18–30] vs 38% [32–45], HR 0·55 [0·39–0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]). Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer. French National Cancer Institute.

Cancer-induced muscle wasting begins early in the course of a patient's malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer. We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. This trial is registered with ClinicalTrials.gov, number NCT00467844. Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range −2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, −4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range −5·8 to 6·7) was not significant (p=0·88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6%vs one [2%] vs none). None of these events were deemed related to study drug. Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents. GTx.

Patients with cirrhosis often have functional limitations, decreased muscle mass, and a high risk of falls. These variables could improve with exercise. The aim was to study the effects of moderate exercise on functional capacity, body composition and risk of falls in patients with cirrhosis. Twenty-three cirrhotic patients were randomized to an exercise programme (n = 14) or to a relaxation programme (n = 9). Both programmes consisted of a one-hour session 3 days a week for 12 weeks. At the beginning and end of the study, we measured functional capacity using the cardiopulmonary exercise test, evaluated body composition using anthropometry and dual energy X-ray absorptiometry, and estimated risk of falls using the Timed Up&Go test. In the exercise group, cardiopulmonary exercise test showed an increase in total effort time (p<0.001) and ventilatory anaerobic threshold time (p = 0.009). Upper thigh circumference increased and mid-arm and mid-thigh skinfold thickness decreased. Dual energy X-ray absorptiometry showed a decrease in fat body mass (-0.94 kg, 95%CI -0.48 to -1.41, p = 0.003) and an increase in lean body mass (1.05 kg, 95%CI 0.27 to 1.82, p = 0.01), lean appendicular mass (0.38 kg, 95%CI 0.06 to 0.69, p = 0.03) and lean leg mass (0.34 kg, 95%CI 0.10 to 0.57, p = 0.02). The Timed Up&Go test decreased at the end of the study compared to baseline (p = 0.02). No changes were observed in the relaxation group. We conclude that a moderate exercise programme in patients with cirrhosis improves functional capacity, increases muscle mass, and decreases body fat and the Timed Up&Go time. ClinicalTrials.gov NCT01447537.

Fish oils (FOs) have anti-inflammatory effects and lower serum triglycerides. This study examined adipose and muscle inflammatory markers after treatment of humans with FOs and measured the effects of ω-3 fatty acids on adipocytes and macrophages in vitro. Insulin-resistant, nondiabetic subjects were treated with Omega-3-Acid Ethyl Esters (4 g/day) or placebo for 12 weeks. Plasma macrophage chemoattractant protein 1 (MCP-1) levels were reduced by FO, but the levels of other cytokines were unchanged. The adipose (but not muscle) of FO-treated subjects demonstrated a decrease in macrophages, a decrease in MCP-1, and an increase in capillaries, and subjects with the most macrophages demonstrated the greatest response to treatment. Adipose and muscle ω-3 fatty acid content increased after treatment; however, there was no change in insulin sensitivity or adiponectin. In vitro, M1-polarized macrophages expressed high levels of MCP-1. The addition of ω-3 fatty acids reduced MCP-1 expression with no effect on TNF-α. In addition, ω-3 fatty acids suppressed the upregulation of adipocyte MCP-1 that occurred when adipocytes were cocultured with macrophages. Thus, FO reduced adipose macrophages, increased capillaries, and reduced MCP-1 expression in insulin-resistant humans and in macrophages and adipocytes in vitro; however, there was no measureable effect on insulin sensitivity.

Low skeletal muscle, referred to as sarcopenia, has been shown to be an independent predictor of lower overall survival in various kinds of diseases. Several studies have evaluated the low skeletal muscle mass using computed tomography (CT) imaging. However, the cutoff values based on CT imaging remain undetermined in Asian populations. Preoperative plain CT imaging at the third lumbar vertebrae level was used to measure the psoas muscle mass index (PMI, cm2/m2) in 541 adult donors for living donor liver transplantation (LDLT). We analyzed PMI distribution according to sex or donor age, and determined the sex-specific cutoff values of PMI to define low skeletal muscle mass. PMI in men was significantly higher than observed in women (8.85 ± 1.61 cm2/m2 versus 5.77 ± 1.21 cm2/m2; P < 0.001). PMI was significantly lower in individuals ≥50 y than in younger donors in both men and women (P < 0.001 and P < 0.001, respectively). On the basis of the younger donor data, we determined the sex-specific cutoff values for the low skeletal muscle mass were 6.36 cm2/m2 for men and 3.92 cm2/m2 for women (mean − 2 SD). Data from healthy young Asian adults were used to establish new criteria for low skeletal muscle mass that would be applicable for defining sarcopenia in Asian populations. •Low muscle mass is an independent predictor of poor survival in various diseases.•We investigated the psoas muscle mass index (PMI) using computed tomography imaging in 541 healthy adults in Japan.•PMI was significantly lower in women and in individuals ≥50 y.•We established the sex-specific cutoff values of PMI to define low muscle mass.•This new criterion would be applicable for defining sarcopenia in Asia.

Optogenetic stimulation allows activation of cells with high spatial and temporal precision. Here we show direct optogenetic stimulation of skeletal muscle from transgenic mice expressing the light-sensitive channel Channelrhodopsin-2 (ChR2). Largest tetanic contractions are observed with 5-ms light pulses at 30 Hz, resulting in 84% of the maximal force induced by electrical stimulation. We demonstrate the utility of this approach by selectively stimulating with a light guide individual intralaryngeal muscles in explanted larynges from ChR2-transgenic mice, which enables selective opening and closing of the vocal cords. Furthermore, systemic injection of adeno-associated virus into wild-type mice provides sufficient ChR2 expression for optogenetic opening of the vocal cords. Thus, direct optogenetic stimulation of skeletal muscle generates large force and provides the distinct advantage of localized and cell-type-specific activation. This technology could be useful for therapeutic purposes, such as restoring the mobility of the vocal cords in patients suffering from laryngeal paralysis. Nerve damage can lead to skeletal muscle paralysis. The authors show that localized photostimulation of skeletal muscle expressing the light-sensitive channel Channelrhodopsin-2 generates contraction in the absence of neural impulses and prove that this strategy can be used for optogenetic opening of explanted murine vocal cords.