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Sitagliptin has been suggested as a treatment option for older adults with type 2 diabetes (T2D). However, no randomized controlled trial has been performed to evaluate the efficacy and safety of sitagliptin treatment in older Japanese patients with T2D. The STREAM study was a multicenter, open-label, randomized controlled trial. T2D outpatients aged 65–80 years with moderately controlled glycemic levels (HbA1c 7.4–10.4%) under lifestyle interventions without or with oral anti-diabetic drugs excluding DPP4 inhibitors or GLP-1 receptor agonists were recruited (n = 176). The participants were randomized into sitagliptin group (n = 88) who received sitagliptin as an initial or an additive anti-diabetic drug and control group (n = 88) who did not. The treatment goal was HbA1c level < 7.4%. Efficacy and safety during 12-month treatment period were investigated. The mean (± SD) ages were 70.6 ± 3.9 and 71.9 ± 4.4 years old in sitagliptin and control groups, respectively. According to a mixed-effects model analysis, average changes from baseline over the treatment period in fasting plasma glucose (FPG), HbA1c, and glycated albumin (GA) were − 27.2 mg/dL, − 0.61%, and − 2.39%, respectively, in sitagliptin group, and 0.50 mg/dL, − 0.29%, and − 0.93%, respectively, in control group. The reductions in FPG, HbA1c, and GA were significantly greater in sitagliptin group (P < 0.0001, P < 0.01, and P < 0.0001, respectively). There were no differences in the incidence of adverse effects, except for cystatin C elevation and platelet count reduction in sitagliptin group. Sitagliptin treatment effectively improved the glycemic profile without any serious adverse effects in older T2D patients. Trial registration number: UMIN000010376.

Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18·6 months (IQR 11–25) in the trastuzumab plus chemotherapy group and 17·1 months (9–25) in the chemotherapy alone group. Median overall survival was 13·8 months (95% CI 12–16) in those assigned to trastuzumab plus chemotherapy compared with 11·1 months (10–13) in those assigned to chemotherapy alone (hazard ratio 0·74; 95% CI 0·60–0·91; p=0·0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. F Hoffmann-La Roche.

Background: This randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer. Methods: Patients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day −1 based on body surface area (BSA), orally, days 1–28, every 6 weeks) or SOX (S-1 80/100/120 mg day −1 based on BSA, orally, days 1–14, plus oxaliplatin 100 mg m −2 , intravenously, day 1, every 3 weeks). The primary end point was PFS. Results: Between January 2009 and July 2010, 271 patients were randomly allocated to either S-1 ( n =135) or SOX ( n =136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65–1.08; stratified log-rank test P =0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79–1.34; stratified log-rank test P =0.82). The response rate (RR) was 11.5% vs 20.9% ( P =0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%). Conclusions: Although SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.

Background Robotic-assisted minimally invasive esophagectomy (RAMIE) has become an increasingly adopted approach for the treatment of esophageal cancer. However, the impact of intraoperative fluid therapy on postoperative outcomes remains poorly defined. Whereas fluid overload has been linked to pulmonary and anastomotic complications, restrictive strategies may impair tissue perfusion and organ function. This study investigates the association between intraoperative fluid balance and postoperative morbidity in patients undergoing RAMIE. Methods We conducted a retrospective single-center cohort study including 254 consecutive patients who underwent elective RAMIE between 2019 and 2024. Intraoperative fluid balance was calculated in mL/kg/h and analyzed as a continuous variable. Primary endpoints included pulmonary complications, anastomotic leakage, postoperative atrial fibrillation (POAF), and acute kidney injury (AKI). Secondary endpoints comprised ICU length of stay (LOS), postoperative delirium, delayed gastric emptying (DGE), and complication severity according to the Clavien-Dindo classification. Multivariable regression models were adjusted for age, sex, BMI, and ASA status. Results Pulmonary complications (23.2%) were significantly associated with higher intraoperative fluid volumes (mean: 5.2 vs. 4.4 ml/kg/h; p  = 0.027; OR: 1.24, 95% CI: 1.05–1.46). Anastomotic leakage (18.5%) exhibited an inverted U-shaped relationship, with the highest risk at fluid levels of 4.7–8.1 ml/kg/h). POAF (16.1%) and AKI (5.5%) were not significantly associated with fluid volume in multivariable analysis. POAF showed no significant association with intraoperative fluid volume in adjusted models. Predicted probabilities illustrated a fivefold increase in pulmonary risk across the 0 to 10 ml/kg/h range, whereas POAF declined steadily over this interval. Postoperative delirium showed a trend toward association with fluid volume (OR: 1.34; p  = 0.056), while DGE, ICU-LOS, and major complications demonstrated no significant associations. Subgroup analyses suggested stronger associations between fluid volume and pulmonary complications in elderly patients, and a more pronounced POAF risk in males, indicating potential effect modification by age and sex. Conclusion Intraoperative fluid volume during RAMIE is variably associatiated with postoperative outcomes. While higher volumes are linked to increased pulmonary morbidity, lower volumes may predispose patients to arrhythmias. Anastomotic complications appear to peak at moderate fluid levels. These findings challenge binary fluid strategies and support a more individualized, risk-adapted approach to intraoperative fluid management in esophageal surgery.

Background We evaluated the safety and efficacy of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients previously treated for advanced gastric or gastroesophageal junction adenocarcinoma in Japanese and Western subgroups from the RAINBOW trial. Methods Patients received ramucirumab at 8 mg/kg or placebo (days 1 and 15) plus paclitaxel at 80 mg/m 2 (days 1, 8, and 15 of a 28-day cycle). End points were compared between treatment arms within Japanese ( N  = 140) and Western ( N  = 398) populations. Results The incidence of adverse events of grade 3 or higher was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 83.8 % vs 52.1 %; Western population, 79.1 % vs 61.9 %). Neutropenia was the commonest adverse event of grade 3 or higher, with a higher incidence for ramucirumab plus paclitaxel (Japanese population, 66.2 % vs 25.4 %; Western population, 32.1 % vs 14.7 %). The incidence of febrile neutropenia was low and was similar between treatment arms in both populations. The overall survival hazard ratio was 0.88 (95 % confidence interval, 0.60–1.28) in the Japanese population and 0.73 (95 % confidence interval, 0.58–0.91) in the Western population. The progression-free survival hazard ratio was 0.50 (95 % confidence interval, 0.35–0.73) in the Japanese population and 0.63 (95 % confidence interval, 0.51–0.79) in the Western population. The objective response rate was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 41.2 % vs 19.4 %; Western population, 26.8 % vs 13.0 %), as was the 6-month survival rate (Japanese population, 94.1 % vs 71.4 %; Western population, 66.0 % vs 49.0 %). Conclusions Safety profiles of the ramucirumab plus paclitaxel arm were similar between populations, though there was a higher incidence of neutropenia in Japanese patients. Progression-free survival and objective response rate improvements were observed for ramucirumab plus paclitaxel in both populations. ClinicalTrials.gov identifier: NCT01170663

BackgroundAVAGAST was an international, randomized, placebo-controlled phase III study of chemotherapy with or without bevacizumab as first-line therapy for patients with advanced gastric cancer. We performed exploratory analyses to evaluate regional differences observed in the trial.MethodsAnalyses were performed in the placebo plus chemotherapy arm (intention-to-treat population). Chemotherapy was cisplatin 80 mg/m2 for six cycles plus capecitabine (1000 mg/m2 orally bid days 1–14) or 5-fluorouracil (800 mg/m2/day continuous IV infusion days 1–5) every 3 weeks until disease progression or unacceptable toxicity.ResultsOverall, 387 patients were assigned to placebo plus chemotherapy (eastern Europe/South America, n = 118; USA/western Europe, n = 81; Korea/other Asia, n = 94; Japan, n = 94). At baseline, poor performance status, liver metastases, and larger tumors were most frequent in eastern Europe/South America and least frequent in Japan. Patients received subsequent chemotherapy after disease progression as follows: eastern Europe/South America (14%); USA/western Europe (37%); Korea/other Asia (61%); and Japan (77%). Hazard ratios for overall survival versus USA/western Europe were 1.47 (95% CI, 1.09–1.99) for eastern Europe/South America, 0.91 (95% CI, 0.67–1.25) for Korea/other Asia, and 0.87 (95% CI, 0.64–1.19) for Japan.ConclusionsRegional differences in the healthcare environment may have contributed to the differences in overall survival observed in the AVAGAST study.

Purpose Pembrolizumab demonstrated antitumor activity in programmed death ligand 1 positive (combined positive score (CPS) ≥ 1) gastric/gastroesophageal junction cancer in KEYNOTE-059 (third line or beyond), KEYNOTE-061 (second line), and KEYNOTE-062 (first line). We characterized efficacy and safety of pembrolizumab monotherapy in Japanese patients across several lines of therapy in these studies. Methods This analysis was conducted in 34 patients from KEYNOTE-059 cohort 1 (all pembrolizumab), including 13 patients with CPS ≥ 1, 65 patients with CPS ≥ 1 from KEYNOTE-061 (pembrolizumab, n  = 27; chemotherapy, n  = 38), and 70 patients with CPS ≥ 1 from KEYNOTE-062 (pembrolizumab, n  = 38; chemotherapy, n  = 32). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated. Results In KEYNOTE-059, ORR with pembrolizumab was 9%, median PFS was 2 months, and median OS was 10 months. In KEYNOTE-061, median OS was 12 months with pembrolizumab versus 10 months with chemotherapy (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.39–1.15). Median PFS (pembrolizumab vs. chemotherapy) was 2 months versus 4 months (HR, 1.21; 95% CI, 0.69–2.13); ORR was 7% versus 18%. In KEYNOTE-062, median OS was 20 months with pembrolizumab versus 18 months with chemotherapy (HR, 0.76; 95% CI, 0.43–1.33). Median PFS (pembrolizumab vs. chemotherapy) was 6 months versus 7 months (HR, 1.03; 95% CI, 0.61–1.74); ORR was 29% versus 34%. Conclusions The current analysis provides valuable information that anti–PD-1 therapies are worthy of further assessment for gastric cancer. Trial Registration ClinicalTrials.gov: NCT02335411 (KEYNOTE-059), NCT02370498 (KEYNOTE-061), and NCT02494583 (KEYNOTE-062).

Identifying the major determinant of leg stiffness during hopping would be helpful in the development of more effective training methods. Despite the fact that overall leg stiffness depends on a combination of the joint stiffness, it is unclear how the major determinants of leg stiffness are influenced by hopping frequency. The purpose of this study was to identify the major determinant of leg stiffness over a wide range of hopping frequencies. Fourteen well-trained male athletes performed in a place hopping on two legs, at three frequencies (1.5, 2.2 and 3.0 Hz). We determined leg and joint stiffness of the hip, knee and ankle from kinetic and kinematic data. Multiple linear regression analysis revealed that knee stiffness could explain more of the variance of leg stiffness than could ankle or hip stiffness at 1.5 Hz hopping. Further, only ankle stiffness was significantly correlated with leg stiffness at both 2.2 and 3.0 Hz, and the standardized regression coefficient of ankle stiffness was higher than that of knee and hip stiffness. The results of the present study suggest that the major determinant of leg stiffness during hopping switches from knee stiffness to ankle stiffness when the hopping frequency is increased.

Purpose To evaluate the efficacy and safety of the combination of gemcitabine (GEM) and S-1 (GS) in comparison to GEM alone (G) for unresectable pancreatic cancer. Methods In this multicenter randomized phase II study, we randomly assigned unresectable pancreatic cancer patients to either the GS group or the G group. The GS group regimen consists of intravenous 1,000 mg/m 2 GEM during 30 min on days 1 and 8, combined with 80 mg/m 2 oral S-1 twice daily on days 1–14, repeated every 3 weeks. On the other hand, the G group regimen consists of intravenous 1,000 mg/m 2 GEM on days 1, 8, and 15, repeated every 4 weeks. The primary endpoint was objective response rate (ORR). Secondary end points included treatment toxicity, clinical response benefit, progression-free survival (PFS), and overall survival. Results We registered 117 patients from 16 institutions between June 2007 and August, 2010. The ORR of the GS group was 28.3%, whereas that of the G group was 6.8%. This difference was statistically significant ( P  = 0.005). The disease control rate was 64.2% in the GS group and 44.1% in the G group. Median PFS was 6.15 months in the GS group and 3.78 month in the G group. This was also statistically significant ( P  = 0.0007). Moreover, the median overall survival (OS) of the GS group was significantly longer than that of the G group (13.7 months vs. 8.0 months; P  = 0.035). The major grade 3–4 adverse events were neutropenia (54.7% in the GS group and 22.0% in the G group), thrombocytopenia (15.1% in the GS group and 5.1% in the G group), and skin rash (9.4% in the GS group). Conclusions The GS group showed stronger anticancer activity than the G group, suggesting the need for a large randomized phase III study to confirm GS advantages in a specific subset.

Glioma and brain metastasis can be difficult to distinguish on conventional magnetic resonance imaging (MRI) due to the similarity of imaging features in specific clinical circumstances. Multiple studies have investigated the use of machine learning (ML) models for non-invasive differentiation of glioma from brain metastasis. Many of the studies report promising classification results, however, to date, none have been implemented into clinical practice. After a screening of 12,470 studies, we included 29 eligible studies in our systematic review. From each study, we aggregated data on model design, development, and best classifiers, as well as quality of reporting according to the TRIPOD statement. In a subset of eligible studies, we conducted a meta-analysis of the reported AUC. It was found that data predominantly originated from single-center institutions (n = 25/29) and only two studies performed external validation. The median TRIPOD adherence was 0.48, indicating insufficient quality of reporting among surveyed studies. Our findings illustrate that despite promising classification results, reliable model assessment is limited by poor reporting of study design and lack of algorithm validation and generalizability. Therefore, adherence to quality guidelines and validation on outside datasets is critical for the clinical translation of ML for the differentiation of glioma and brain metastasis.