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Patients with nonalcoholic steatohepatitis were randomly assigned to receive subcutaneous semaglutide or placebo. The incidence of NASH resolution was significantly higher with semaglutide than with placebo, but the between-group difference in the incidence of an improvement in fibrosis stage was not significant.

In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4–36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6–not estimable] vs 26·6 months [22·1–33·4]; hazard ratio [HR] 0·66 [95% CI 0·54–0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9–10·0] vs 8·3 months [7·0–8·8]; HR 0·77 [95% CI 0·65–0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2–not estimable]; HR 0·71 [95% CI 0·59–0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1–11·1] vs 9·7 months [8·3–11·1]; HR 0·85 [95% CI 0·73–0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3–4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. Bristol-Myers Squibb and ONO Pharmaceutical.

Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development. This open-label, single-centre, phase 1a, dose-escalation trial (part of the JAVELIN Solid Tumor trial) assessed four doses of avelumab (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort expansions to provide additional safety, pharmacokinetics, and target occupancy data. This study used a standard 3 + 3 cohort design and assigned patients sequentially at trial entry according to the 3 + 3 dose-escalation algorithm and depending on the number of dose-limiting toxicities during the first 3-week assessment period (the primary endpoint). Patient eligibility criteria included age 18 years or older, Eastern Cooperative Oncology Group performance status 0–1, metastatic or locally advanced previously treated solid tumours, and adequate end-organ function. Avelumab was given as a 1-h intravenous infusion every 2 weeks. Patients in the dose-limiting toxicity analysis set were assessed for the primary endpoint of dose-limiting toxicity, and all patients enrolled in the dose-escalation part were assessed for the secondary endpoints of safety (treatment-emergent and treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0), pharmacokinetic and pharmacodynamic profiles (immunological effects), best overall response by Response Evaluation Criteria, and antidrug antibody formation. The population for the pharmacokinetic analysis included a subset of patients with rich pharmacokinetic samples from two selected disease-specific expansion cohorts at the same study site who had serum samples obtained at multiple early timepoints. This trial is registered with ClinicalTrials.gov, number NCT01772004. Patient recruitment to the dose-escalation part reported here is closed. Between Jan 31, 2013, and Oct 8, 2014, 53 patients were enrolled (four patients at 1 mg/kg, 13 at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg). 18 patients were analysed in the dose-limiting toxicity analysis set: three at dose level 1 (1 mg/kg), three at dose level 2 (3 mg/kg), six at dose level 3 (10 mg/kg), and six at dose level 4 (20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. In all 53 enrolled patients (the safety analysis set), common treatment-related adverse events (occurring in >10% of patients) included fatigue (21 patients [40%]), influenza-like symptoms (11 [21%]), fever (8 [15%]), and chills (6 [11%]). Grade 3–4 treatment-related adverse events occurred in nine (17%) of 53 patients, with autoimmune disorder (n=3), increased blood creatine phosphokinase (n=2), and increased aspartate aminotransferase (n=2) each occurring in more than one patient (autoimmune disorder in two patients at 10 mg/kg and one patient at 20 mg/kg, increased blood creatine phosphokinase in two patients at 20 mg/kg, and increased aspartate aminotransferase in one patient at 1 mg/kg, and one patient at 10 mg/kg). Six (11%) of 53 patients had a serious treatment-related adverse event: autoimmune disorder (two [13%]), lower abdominal pain (one [7%]), fatigue (one [7%]), and influenza-like illness (one [7%]) in three patients treated at 10 mg/kg dose level, and autoimmune disorder (one [5%]), increased amylase (one [5%]), myositis (one [5%]), and dysphonia (one [5%]) in three patients who received the 20 mg/kg dose. We recorded some evidence of clinical activity in various solid tumours, with partial confirmed or unconfirmed responses in four (8%) of 53 patients; 30 (57%) additional patients had stable disease. Pharmacokinetic analysis (n=86) showed a dose-proportional exposure between doses of 3 mg/kg and 20 mg/kg and a half-life of 95–99 h (3·9–4·1 days) at the 10 mg/kg and 20 mg/kg doses. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Antidrug antibodies were detected in two (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. 31 (58%) of 53 patients in the overall safety population died; no deaths were related to treatment on study. Avelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. National Cancer Institute and Merck KGaA.

We sought to develop estimates of biological variation (BV) for 9 enzymes in blood serum as part of the European Biological Variation Study. Ninety-one healthy study participants (38 male and 53 female, 21-69 years old) were phlebotomized in each of 10 consecutive weeks at 6 European laboratories. The same preanalytical sample-handling protocol was followed at each center before transport to San Raffaele Hospital, Milan, Italy, for analysis. Sera were stored at -80 °C before analysis in duplicate within a single run on an ADVIA 2400 Clinical Chemistry System (Siemens Healthcare) following a protocol designed to minimize analytical imprecision. Assay traceability was established using frozen sera with target values assigned by reference methods. The results were subjected to outlier analysis before CV-ANOVA to deliver valid BV estimates. Results for 9 enzymes were subsequently partitioned for graphical display allowing visual assessment of the effects of country of origin, sex, and age on BV estimates. We found no effect of country upon the observed variation, but overall sex-related differences were evident for alanine amino transferase (ALT), γ-glutamyl transferase (GGT), and creatine kinase (CK). The following estimates for within-subject BV (CV ) and between-subject BV (CV ), respectively, were obtained: ALT: 9.3%, 28.2%; aspartate aminotransferase: 9.5%, 20.3%; GGT: 8.9%, 41.7%; alkaline phosphatase : 5.3%, 24.9%; lactate dehydrogenase: 5.2%, 12.6%; CK: 14.5%, 31.5%; amylase: 6.8%, 30.4%; pancreatic α-amylase: 6.3%, 24.9%; and lipase (LIP): 7.7%, 23.8%. All CV and some CV estimates were lower than those reported in the online BV 2014 updated database. Analytical performance specifications derived from BV can be applied internationally.

Background Cardiovascular disease (CVD) remains the largest cause of death in breast cancer survivors. The aim of this study was to explore the impact of exercise intensity on aerobic fitness and autonomic cardiac regulation (heart rate variability (HRV)) and salivary biomarkers of the stress systems (HPA-axis, cortisol; sympathetic nervous system, α-amylase) and mucosal immunity (secretory(s)-IgA), markers of increased risk of CVD in breast cancer survivors. Methods Participants were randomly assigned to; 1) high intensity interval training (HIIT); 2) moderate-intensity, continuous aerobic training (CMIT); or 3) a wait-list control (CON) for a 12-week (36 session) stationary cycling intervention. Cardiorespiratory fitness (VO 2peak ), resting HRV and salivary biomarkers were measured at baseline 2–4 d pre-intervention and 2–4 d post the last exercise session. Results Seventeen participants were included in this study (62 ± 8 years, HIIT; n  = 6, CMIT; n  = 5, CON; n = 6). A significant improvement ( p  ≤ 0.05) was observed for VO 2peak in the HIIT group; 19.3% (B = 3.98, 95%CI = [1.89; 4.02]) and a non-significant increase in the CMIT group; 5.6% (B = 1.96, 95%CI = [− 0.11; 4.03]), compared with a 2.6% (B = − 0.64, 95%CI = [− 2.10; 0.82]) decrease in the CON group. Post intervention improvements in HRV markers of vagal activity (log (ln)LF/HF, LnRMSSD) and sympathetic nervous system (α-amylase waking response) occurred for individuals exhibiting outlying (> 95% CI) levels at baseline compared to general population. Conclusion High intensity interval training improved cardiovascular fitness in breast cancer survivors and improved cardiac regulation, and sympathetic nervous system (stress) responses in some individuals. High-intensity interval training was safe and effective for breast cancer survivors to participate in with promising results as a time efficient intensity to improve physical health and stress, reducing CVD risk. Trial registration This pilot study was retrospectively registered through the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12620000684921 .

INTRODUCTION:Aggressive hydration using lactated Ringer's solution prevents postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Concerns of this strategy are large volume and lengthy hydration. Our study aimed to evaluate the efficacy of tailored aggressive hydration (TAH) for PEP prevention.METHODS:In this prospective, multicenter, double-blinded, randomized trial conducted across 3 tertiary Korean hospitals, patients who underwent ERCP for the first time were randomly assigned (1:1) to the tailored standard hydration (TSH) and TAH groups. The TSH group received 1.5 mL/kg/hr lactated Ringer's solution during and after ERCP, whereas the TAH group was administered a 20 mL/kg bolus post-ERCP and 3 mL/kg/hr during and after the procedure. Both groups were assessed for elevated serum amylase levels and pain 4-6 hours after ERCP. If both were absent, hydration was discontinued. If either was present, hydration was continued at the original rate until 8 hours. The primary end point was PEP development and was analyzed on an intention-to-treat analysis.RESULTS:A total of 344 patients were randomly assigned to treatment groups (171 to the TSH group and 172 to the TAH group). PEP was observed in 9.4% (16/171) in the TSH group and 3.5% (6/172) in the TAH group (relative risk 0.37, 95% confidence interval 0.15-0.93, P = 0.03). No difference was identified between the 2 groups in PEP severity (P = 0.80) and complications related to volume overload (P = 0.32).DISCUSSION:TAH according to the presence of abdominal pain or elevated serum amylase levels at 4-6 hours after ERCP is safe and prevents PEP development.

Incidences of pancreatic cancer and acute and chronic pancreatitis are rising globally, and often no curative treatment is available at the time of diagnosis. We tested the hypothesis that low and high plasma concentrations of pancreatic amylase are associated with increased risk of pancreatic cancer, acute pancreatitis, and chronic pancreatitis in the general population. We included 101,765 individuals (55% women) aged 20–100 years from the Copenhagen General Population Study with baseline measurements of plasma pancreatic amylase. After recruitment in 2004–2015 during a median 9 years of follow-up (range 0–15), we collected information about diagnoses of pancreatic cancer, acute pancreatitis, and chronic pancreatitis from the national Danish Patient Registry, the national Danish Cancer Registry, and the national Danish Causes of Death Registry. The median age was 58 years (interquartile range: 48–67) and the median plasma pancreatic amylase 32 U/L (26–40). During follow-up, 442 individuals were diagnosed with pancreatic cancer, 282 with chronic pancreatitis, and 401 with acute pancreatitis. Compared to individuals with pancreatic amylase levels in the 41st–60th percentiles, those with extreme low (1st–2.5th percentiles) and extreme high (97.5th–100th percentiles) pancreatic amylase had hazard ratios of 2.4 (95% confidence interval; 1.6–3.6) and 2.2 (1.4–3.7) for pancreatic cancer, of 1.8 (1.1–3.3) and 3.2 (1.8–5.6) for chronic pancreatitis, and of 1.1 (0.6–1.8) and 1.5 (0.8–2.7) for acute pancreatitis, respectively. In apparently healthy individuals from the general population, extreme low and extreme high plasma pancreatic amylase were associated with 2–threefold higher risk of both pancreatic cancer and chronic pancreatitis.

Alpha-amylase in both blood and saliva has been used as a diagnostic parameter. While studies examining alpha-amylase activity in saliva have shown that it is sensitive to physiological and psychological challenge of the adrenergic system, no challenge studies have attempted to elucidate the role of the adrenergic system in alpha-amylase activity in blood. We set out to examine the impact of psychological and pharmacological challenge on alpha-amylase in blood in two separate studies. In study 1, healthy subjects were examined in a placebo-controlled, double-blind paradigm using yohimbine, an alpha2-adrenergic antagonist. In study 2, subjects were examined in a standardized rest-controlled psychosocial stress protocol. Alpha-amylase activity in blood was repeatedly measured in both studies. Results of study 1 showed that alpha-amylase in blood is subject to stronger increases after injection of yohimbine compared to placebo. In study 2, results showed that there was no significant effect of psychological stress compared to rest. Alpha-amylase in blood increases after pharmacological activation of the adrenergic pathways suggesting that sympathetic receptors are responsible for these changes. Psychological stress, however, does not seem to have an impact on alpha-amylase in blood. Our findings provide insight into the mechanisms underlying activity changes in alpha-amylase in blood in healthy individuals.

Background Physical activity has shown to be effective in anxiety disorders. For specific phobia, no studies are available that systematically examined the effects of an aerobic exercise intervention on phobic fear within a randomized‐controlled design. Therefore, we investigated the acute effect of a standardized aerobic training on clinical symptoms of dental phobia as well as on stress‐related neurobiological markers. Methods Within a crossover design, 30 patients with dental phobia (mean age: 34.1 years; mean score of the Dental Anxiety Scale: 18.8) underwent two minor dental interventions separated by 7 days. Dental treatment was performed after 30 min of physical activity at either 20% VO2 max (control) or 70% VO2 max (intervention), respectively. To control for habituation, patients were randomly assigned to one of the two conditions prior to the first intervention. Moreover, saliva samples were collected at five times in order to determine changes in salivary cortisol (sC) and alpha‐amylase (sAA) due to treatment. Results In comparison to baseline, aerobic exercise within 70% VO2 max significantly reduced clinical anxiety and sC concentrations before, during, and after the dental treatment. In contrast, the control condition led to decreased sAA levels at different time points of measurement. Habituation occurred at the second study day, independent of the order. Conclusions Our study provides evidence for an effect of moderate–intense exercise on clinical symptoms and sC in patients with dental phobia. Therefore, acute aerobic exercise might be a simple and low‐cost intervention to reduce disorder‐specific phobic fear.

The evidence for high-volume hemofiltration plus hemoperfusion (HVHF&HP) for hyperlipidemic severe acute pancreatitis (HL-SAP) is anecdotal. The purpose of our study was to evaluate the efficacy of HVHF&HP for HL-SAP in a prospective controlled study. Prospective controlled pilot study between May 2010 and May 2013 in a hospital intensive care unit. HL-SAP patients chose conventional treatment alone (the control group) or conventional treatment combined with the experimental protocol (the HVHF&HP group) and were prospectively followed in our hospital. APACHE II score, SOFA score, ICU and hospital stay duration, and serum biomarkers were considered endpoints. Ten HL-SAP patients accepted conventional treatment alone (the control group) and 10 patients underwent HVHF&HP combined with conventional treatment (the HVHF&HP group). The APACHE II score, SOFA score, systolic blood pressure, diastolic blood pressure, heart rate, serum amylase, and serum creatinine were significantly reduced after the HVHF&HP treatment. The changes in these variables were significantly different between the HVHF&HP and control group at 48 hours after the initiation of treatment. Patients in the HVHF&HP group had a significantly shorter ICU stay (P=.015). The reduction in serum triglyceride and cholesterol in the HVHF&HP group after 2, 6, 12, 24, and 48 hours was greater than the control group. All of the tested serum cytokines were significantly decreased after HVHF&HP treatment (P < .05). However, in patients who underwent conventional treatment alone, there was no significant change in the serum cytokines. This study suggests that the addition of HVHF&HP to conventional treatment for HL-SAP patients may be superior to conventional treatment alone for the improvement of serum biomarkers and clinical outcomes.