Effects of Standing after a Meal on Glucose Metabolism and Energy Expenditure.

In the past decade, university students have become more sedentary. A sedentary lifestyle is associated with an increased risk of obesity and cardiovascular disease. Methods that decrease sedentary lifestyles, such as the use of standing desks to increase physical activity, have been extensively examined. However, the effects of postprandial standing and sitting on energy metabolism have not yet been compared. Therefore, the present study investigated the effects of standing after a meal on energy expenditure and glucose metabolism. Ten males participated in the present study. The experiment was initiated with 300 g of rice ingested as a carbohydrate load. The subjects maintained a standing or sitting position for 120 min after the meal. Energy expenditure was calculated from VO2 and VCO2 using the indirect calorimetry method. Glucose metabolism was assessed by measuring blood glucose levels and the exogenous glucose metabolic rate. Energy expenditure through standing after eating was approximately 0.16 ± 0.08 kcal/min higher than that through sitting. Blood glucose dynamics did not significantly differ between the standing and sitting positions. Furthermore, no significant differences were observed in the dynamics of the exogenous glucose metabolic rate between the standing and sitting positions. Standing for 2 h after a meal increased energy expenditure by 10.7 ± 4.6% without affecting glucose metabolism.

Prediction of the Contribution Ratio of a Target Metabolic Enzyme to Clearance from Chemical Structure Information.

The contribution ratio of metabolic enzymes such as cytochrome P450 to in vivo clearance (fraction metabolized: fm) is a pharmacokinetic index that is particularly important for the quantitative evaluation of drug-drug interactions. Since obtaining experimental in vivo fm values is challenging, those derived from in vitro experiments have often been used alternatively. This study aimed to explore the possibility of constructing machine learning models for predicting in vivo fm using chemical structure information alone. We collected in vivo fm values and chemical structures of 319 compounds from a public database with careful manual curation and constructed predictive models using several machine learning methods. The results showed that in vivo fm values can be obtained from structural information alone with a performance comparable to that based on in vitro experimental values and that the prediction accuracy for the compounds involved in CYP induction or inhibition is significantly higher than that by using in vitro values. Our new approach to predicting in vivo fm values in the early stages of drug discovery should help improve the efficiency of the drug optimization process.

Real-world clinical outcomes in Japanese patients with locally advanced squamous cell carcinoma of the head and neck treated with radiotherapy plus cetuximab: a prospective observational study (JROSG12-2).

BACKGROUND: Radiotherapy plus cetuximab (bioradiotherapy: BRT) is a standard option in the treatment of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Published data on its safety and efficacy in real-world settings is limited. Here, we conducted a prospective multi-institutional observational study to evaluate clinical outcomes of BRT in patients with LA-SCCHN. METHODS: We analyzed real-world data of all patients who underwent BRT from 2013 to 2016. The primary endpoint was 1-year progression-free survival (PFS). Secondary endpoints were 1-year locoregional PFS (LPFS), treatment completion rate (TCR), and adverse events (AEs). RESULTS: A total of 171 patients with a minimum 1-year follow-up were analyzed. Median age was 67 (36-85) years, and 37 patients (21.6%) were aged 75 years or older. 1-year PFS and LPFS were 51.5 and 56.1%, respectively. N stage (p = 0.049) was significantly associated with PFS. TCR was 77.2%. Cetuximab was definitively discontinued in 30 patients (17.5%), in 15 cases due to severe mucositis. N stage, T stage, and comorbidity were significantly associated with TCR. Major AEs of grade 3 or higher were pharyngeal mucositis (48.5%), radiation dermatitis (45.6%), and oral mucositis (40.4%). Pneumonitis was observed in 12 patients (7.0%); 6 cases (3.5%) were grades 3-4 and 2 (1.2%) were grade 5. CONCLUSION: As a result of the large number of elderly patients in clinical practice,　toxicity reduced TCR. BRT-induced pneumonitis, which is sometimes fatal, was found to be more frequent than with chemotherapy plus cetuximab.

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma.

BACKGROUND: The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer. METHODS: In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given. RESULTS: In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies. CONCLUSION: Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable.ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347).

Physiological role of anticipatory cardiorespiratory responses to exercise.

This study aimed to investigate whether anticipatory cardiorespiratory responses vary depending on the intensity of the subsequent exercise bout, and whether anticipatory cardiorespiratory adjustments contribute importantly to enhancing exercise performance during high-intensity exercise. Eleven healthy men were provided advance notice of the exercise intensity and a countdown to generate anticipation during 10 min prior to exercise at 0, 50, 80 or 95% maximal work-rate (Experiment 1). A different group of subjects (n = 15) performed a time to exhaustion trial with or without anticipatory countdown (Experiment 2). In Experiment 1, heart rate (HR), oxygen uptake (VO2 ) and minute ventilation (VE ) during pre-exercise resting period increased over time and depended on the subsequent exercise intensity. Specifically, there was already a 7.4% increase in HR from more than 5 min prior to the start of exercise at 95% maximal work-rate, followed by progressively augmented increases of 12.5% between 2 and 3 min before exercise, 24.4% between 0 and 1 min before exercise. In Experiment 2, the initial HR for the first 10 s of exercise in the task with anticipation was 11.4% larger compared to without anticipation (p < 0.01), and the difference in HR between the two conditions decreased in a time-dependent manner. In contrast, the initial increases in VO2 and VE were significantly lower in the task with anticipation than that without anticipation. The time to exhaustion during high-intensity exercise was 14.6% longer under anticipation condition compared to no anticipation (135 ± 26 s vs. 119 ± 26 s, p = 0.003). In addition, the enhanced exercise performance correlated positively with increased HR response just before and immediately after exercise onset (p < 0.01). These results showed that anticipatory cardiorespiratory adjustments (feedforward control) via the higher brain that operate before starting exercise may play an important role in minimizing the time delay of circulatory response and enhancing performance after onset of high-intensity exercise in man.

Arterial Administration of DNA Crosslinking Agents with Restraint of Homologous Recombination Repair by Intravenous Low-Dose Gemcitabine Is Effective for Locally Advanced Pancreatic Cancer.

(1) Background: Pretreatment by Rad51-inhibitory substances such as gemcitabine followed by arterial chemotherapy using antineoplastic agents causing DNA crosslink might be more beneficial for patients with locally advanced pancreatic cancers than conventional treatments. The efficacy of arterial administration of DNA crosslinking agents with pretreatment of intravenous low-dose gemcitabine for patients with unresectable locally advanced or metastatic pancreatic cancer (LAPC or MPC) is evaluated. (2) Methods: A single-arm, single-center, institutional review board-approved prospective study was conducted between 2005 and 2015. Forty-five patients (23 LAPC, 22 MPC) were included. Patients received a weekly low dose of gemcitabine intravenously for three weeks followed by arterial administration of mitomycin C and epirubicin hydrochloride at tumor-supplying arteries on the fifth or sixth week. This treatment course was repeated at 1.5-to-2-month intervals. Overall survival (OS), local progression-free survival (LPFS), and therapeutic response were evaluated. LAPC or MPC were divided according to treatment compliance, excellent or poor (1 or 2), to subgroups L1, L2, M1, and M2. (3) Results: OS of LAPC and MPC were 23 months and 13 months, respectively. The OS of LAPC with excellent treatment compliance (subgroup L1, 10 patients) was 33 months with 31 months of LPFS, and four patients (40%) had a complete response (CR). The OS of the L1 subgroup was significantly longer than those of other subgroups L2, M1, and M2, which were 17 months, 17 months, and 8 months, respectively. As Grade 3 adverse effects, severe bone marrow suppression, interstitial pneumonitis, and hemolytic uremic syndrome were observed in six (13.0%), three (6.5%), and three (6.5%) patients, respectively. (4) Conclusions: Arterial DNA crosslinking with the systemic restraint of homologous recombination repair can be a new treatment option for LAPC.

Effects of pre-exercise acupuncture stimulation on heart rate response during short-duration exercise.

BACKGROUND: The purpose of the present study was to investigate the effects of bradycardia induced by pre-exercise acupuncture on heart rate responses during short-duration exercise. METHODS: A total of 29 healthy subjects underwent two protocols: protocol 1 assessed the effects of manual acupuncture on heart rate response during rest, and protocol 2 tested the hypothesis that the bradycardic effects induced by pre-exercise acupuncture continue during low- and high-intensity exercise. Their average age, height, weight, and body mass index were 21.2 ± 2.0 years, 167.2 ± 8.8 cm, 63.8 ± 12.8 kg, and 22.7 ± 3.5 kg/m2, respectively. In acupuncture stimulations for protocols 1 and 2, an acupuncture needle was inserted into the lower leg and manual acupuncture stimulation was performed at 1 Hz. RESULTS: In protocol 1 (resting condition), acupuncture stimulation induced a bradycardic response, which continued for 4 min after the cessation of acupuncture stimulation (p < 0.05). In protocol 2, the bradycardic response induced by pre-exercise acupuncture stimulation remained during low-intensity exercise and in the beginning of high-intensity exercise performed immediately after the cessation of acupuncture stimulation (p < 0.05). However, the effects disappeared when post-acupuncture exercise was performed when the heart rate was approximately 140 beats/min during high-intensity exercise. The rating of perceived exertion after exercise differed significantly between the acupuncture stimulation task (7.9 ± 1.6) and no-stimulation task (8.5 ± 2.0) (p = 0.03) only in the low intensity group. CONCLUSION: This study may provide new insights into the effect of acupuncture stimulation on psycho-physiological conditions during exercise.

Phase II study of cetuximab plus S-1/cisplatin therapy in Japanese patients with advanced gastric cancer.

OBJECTIVE: We evaluated the efficacy and safety of first-line S-1 plus cisplatin in combination with cetuximab for Japanese patients with advanced gastric cancer, including gastroesophageal junction adenocarcinoma. METHODS: This open-label, single arm, multicenter, phase 2 trial was conducted to assess first-line cetuximab plus S-1 plus cisplatin for advanced gastric cancer. A total of 40 patients from 10 centers were enrolled. Cetuximab was administered weekly, with the initial infusion at 400 mg/m2 and then 250 mg/m2 each subsequent week. S-1 plus cisplatin chemotherapy was concomitantly conducted in a 5-week cycle: S-1 (40-60 mg, adjusted for body surface area) was given twice daily for 3 consecutive weeks, followed by a 2-week rest period, and cisplatin (60 mg/m2) was given on day 8 of each cycle for a maximum of 8 cycles. Treatment continued until the occurrence of radiographically confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The primary endpoint was the best overall response. Secondary endpoints included progression-free survival and safety. RESULTS: A total of 40 patients were evaluable. One patient (2.5%) had a complete response; 15 patients (37.5%) had a partial response. The observed overall response rate according to the independent review committee was 40.0% (95% confidence interval, 24.9-56.7; P = 0.7043 [one-sided null hypothesis: overall response rate ≤ 43%]); median PFS was 5.6 months (95% confidence intervals, 4.2-8.3). No adverse events leading to death were reported during the study, and no specific safety concerns were observed. CONCLUSIONS: Overall, the addition of cetuximab to S-1 plus cisplatin was well tolerated in patients with advanced gastric cancer but provided no additional clinical benefit in this study. ClinicalTrials.gov identifier: NCT01388790.

Real-world clinical outcomes and prognostic factors in Japanese patients with recurrent or metastatic squamous cell carcinoma of head and neck treated with chemotherapy plus cetuximab: a prospective observation study (JROSG12-2).

BACKGROUND: The aims of this study are to evaluate the efficacy and safety of first-line treatment with chemotherapy plus cetuximab in real-world patients with recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) and to identify prognostic factors for overall survival (OS). METHODS: This is a prospective observation study involving 20 oncology institutions in Japan. Patients with RM-SCCHN treated with a first-line therapy consisting of cetuximab plus any chemotherapy regimen between December 2013 and February 2017 were enrolled. The primary objective of the study was 1-year OS. Secondary objectives included response rate and adverse events. RESULTS: Of 120 patients recruited, 114 patients were analyzed. Median age was 64 years. Cetuximab in combination with platinum plus 5-FU (EXTREME regimen) was chosen in 86 patients (75.4%). The median OS was 12.4 months. A point estimate of the 1-year survival rate was 51.1%. Overall response rate was 26.3%. Grade 3 or worse adverse events included neutropenia (22.8%), hypokalemia (9.6%), acneiform rash (7.0%), pneumonitis (1.8%), and infusion-related reaction (0.9%). On multivariate analysis, regional lymph node metastasis, absence of intervention by dermatologists, lack of response to therapy, skin metastasis, and non-EXTREME regimen were identified as independent unfavorable prognostic factors for OS. CONCLUSION: The combination of cetuximab plus chemotherapy was tolerable and efficacious in patients with RM-SCCHN in a real-world setting. Clinical outcomes and prognostic factors extracted from this study provide a reference of the current clinical practice as well as for the future development of novel therapy in RM-SCCHN.

Low Frequency Severe-Intensity Interval Training Markedly Alters Respiratory Compensation Point During Incremental Exercise in Untrained Male.

This study investigated the effect of low-frequency severe-intensity interval training on the respiratory compensation point (RCP) during incremental exercise test. Eighteen healthy males (age; 20.7 ± 2.2 years, range 18 to 29 years, height; 174.0 ± 5.6 cm, weight; 68.8 ± 13.5 kg) were randomly assigned to an interval training group or a control group. Interval training was conducted once weekly for 3 months. Each session consisted of three bouts of bicycle ergometer exercise at 80% maximum work rate until volitional fatigue. Before (baseline) and after the 3-month intervention, incremental exercise test was performed on a bicycle ergometer for determination of ventilatory threshold (VT), RCP, and peak oxygen consumption (V̇O 2 peak). The training program resulted in significant increases of V̇O 2 peak (+ 14%, p < 0.001, η p 2 = 0.437), oxygen consumption (V̇O 2) at VT (+ 18%, p < 0.001, η p 2 = 0.749) and RCP (+ 15%, p = 0.03, η p 2 = 0.239) during incremental exercise test in the training group. Furthermore, a significant positive correlation was observed between the increase in V̇O 2 peak and increase in V̇O 2 at RCP after intervention (r = 0.87, p = 0.002) in the training group. Tidal volumes at VT (p = 0.04, η p 2 = 0.270) and RCP (p = 0.01, η p 2 = 0.370) also increased significantly after intervention compared to baseline. Low-frequency severe-intensity interval training induced a shift in RCP toward higher work rate accompanied by higher tidal volume during incremental exercise test.

Morphologic response to chemotherapy containing bevacizumab in patients with colorectal liver metastases: A post hoc analysis of the WJOG4407G phase III study.

The phase III West Japan Oncology Group (WJOG) 4407G study showed noninferiority of folinic acid, bolus/continuous fluorouracil, and irinotecan plus bevacizumab to modified folinic acid, bolus/continuous fluorouracil, and oxaliplatin 6 plus bevacizumab in progression-free survival (PFS) as first-line chemotherapy for patients with metastatic colorectal cancer. The aim of this study was to evaluate the predictive and prognostic value of morphologic response in patients with colorectal liver metastases (CLM) as a post hoc analysis of the WJOG4407G study.Morphologic response was assessed by comparing contrast-enhanced computed tomography (CT) images at baseline and week 8. Three blinded radiologists evaluated CT images and classified their response as optimal, incomplete, or no response according to the morphologic criteria. Response evaluation criteria in solid tumors (RECIST) response, early tumor shrinkage (ETS), and depth of response (DpR) were also evaluated.Among 395 patients who were eligible for efficacy analysis in the WJOG4407G study, 70 patients had liver-limited disease. We finally evaluated 55 of these patients. Optimal morphologic response was identified in 19 of 55 patients (34.5%). The median PFS was 10.7 months for patients with optimal response and 10.1 months in those with incomplete/no response (log-rank, P = .96). The median overall survival (OS) was 26.2 and 35.5 months, respectively (log-rank, P = .062). According to univariate analysis, morphologic response was not associated with PFS or OS, whereas RECIST response was significantly associated with both PFS and OS, with ETS and DpR being associated with significantly longer PFS.Morphologic response might be neither a predictive nor a prognostic factor in patients with CLM undergoing chemotherapy containing bevacizumab, whereas RECIST response was significantly associated with both PFS and OS.

A Case of Pathological Complete Response Following FOLFIRINOX Therapy for Pancreatic Adenocarcinoma with Synchronous Distant Lymph Node Metastases.

INTRODUCTION: We report a case of conversion surgery for pancreatic ductal adenocarcinoma (PDAC) with synchronous distant metastases showing pathological complete response (pCR) after FOLFIRINOX therapy. PRESENTATION OF CASE: A 46-year-old woman with obstructive jaundice was referred to our hospital. A CT scan revealed a hypo-vascular mass in the head of the pancreas with multiple para-aortic lymph nodes and a Virchow's node swollen. The serum CA 19-9 level was 71795.1 U/mL. The result of tumor biopsy from the biliary stenotic site was concordant with adenocarcinoma. She was diagnosed with PDAC with distant metastases. After 10 courses of FOLFIRINOX followed by 4 courses of FOLFIRI, a CT scan showed that distant lymph node swellings disappeared, and CA19-9 level became almost normal. She underwent pancreaticoduodenectomy with dissection of para-aortic lymph nodes 8 months after the initiation of chemotherapy. Pathologically, no evidence of residual adenocarcinoma was observed in neither pancreas nor lymph nodes. Adjuvant chemotherapy using S-1 was administered for 6 months, and no recurrence has been observed 4 years after surgery. BRCA1/2 mutations were not detected in patient's DNA. DISCUSSION: With the induction of intensive chemotherapies such as FOLFIRINOX, an increasing number of patients with synchronous distant metastases could become suitable candidates for surgery of the primary lesion because of the potential complete response of metastatic lesions. CONCLUSION: This case presented a rare occurrence of pCR in a patient with unresectable PDAC with distant metastases who received FOLFIRINOX. The feasibility and benefits of conversion surgery in such patients must be investigated in future trials.

Population pharmacokinetic analysis of esomeprazole in Japanese subjects with various CYP2C19 phenotypes.

WHAT IS KNOWN AND OBJECTIVE: Esomeprazole, the S-isomer of omeprazole, is a proton pump inhibitor which has been approved by over 125 countries, also known as NEXIUM® . Esomeprazole was developed to provide further improvement on efficacy for acid-related diseases with higher systemic bioavailability due to the less first-pass metabolism and lower plasma clearance. Esomeprazole is primarily metabolized by CYP2C19. Approximately <1% of Caucasians and 5%-10% of Asians have absent CYP2C19 enzyme activity. Although the influence of various CYP2C19 phenotypes on esomeprazole pharmacokinetics has been studied, this is the first report in the Japanese population where 27 low CYP2C19 metabolizers were included. METHODS: In this study, a population PK model describing the PK of esomeprazole was developed to understand the difference of CYP2C19 phenotypes on clearance in the Japanese population. The model quantitatively assessed the influence of CYP2C19 phenotype on esomeprazole PK in healthy Japanese male subjects after receiving repeated oral dosing. The inhibition mechanism of esomeprazole on CYP2C19 activity was also included in the model. RESULTS AND DISCUSSION: CYP2C19 phenotype and dose were found as statistically significant covariates on esomeprazole clearance. The apparent clearance at 10-mg dose was 17.32, 9.77 and 7.37 (L/h) for homozygous extensive metabolizer, heterozygous extensive metabolizer and poor metabolizer subjects, respectively. And the apparent clearance decreased as dose increased. WHAT IS NEW AND CONCLUSION: The established population PK model well described the esomeprazole PK and model-predicted esomeprazole PK was in good agreement with external clinical data, suggesting the robustness and applicability of the current model for predicting esomeprazole PK.

Increase in diastolic blood pressure induced by fragrance inhalation of grapefruit essential oil is positively correlated with muscle sympathetic nerve activity.

Fragrance inhalation of essential oils is widely used in aromatherapy, and it is known to affect blood pressure (BP) and heart rate (HR) via autonomic control of circulation. In this study, we aimed to test the hypothesis that the changes in hemodynamics with fragrance inhalation were observed along with changes in muscle sympathetic nerve activity (MSNA). In study 1, thirteen healthy men were exposed to fragrance stimulation of grapefruit essential oil for 10 min, and BP, HR, and MSNA were continuously measured. In study 2, another nine healthy men were exposed to the same fragrance stimulation; responses in BP and HR were continuously measured, and plasma noradrenaline and cortisol concentrations were determined. We found that diastolic BP increased significantly during fragrance inhalation, while the other variables remained unchanged in both studies. Although MSNA burst frequency, burst incidence, and total activity remained unchanged during fragrance inhalation, we found a significant linear correlation between changes in diastolic BP in the last 5 min of fragrance inhalation and changes in MSNA burst frequency. The plasma cortisol concentration decreased significantly at 10 min of fragrance inhalation, though the noradrenaline concentration remained unchanged. These results suggest, for the first time, that changes in BP with fragrance inhalation of essential oil are associated with changes in MSNA even with decreased stress hormone.

Optimal designs for regional bridging studies using the Bayesian power prior method.

As described in the ICH E5 guidelines, a bridging study is an additional study executed in a new geographical region or subpopulation to link or "build a bridge" from global clinical trial outcomes to the new region. The regulatory and scientific goals of a bridging study is to evaluate potential subpopulation differences while minimizing duplication of studies and meeting unmet medical needs expeditiously. Use of historical data (borrowing) from global studies is an attractive approach to meet these conflicting goals. Here, we propose a practical and relevant approach to guide the optimal borrowing rate (percent of subjects in earlier studies) and the number of subjects in the new regional bridging study. We address the limitations in global/regional exchangeability through use of a Bayesian power prior method and then optimize bridging study design with a return on investment viewpoint. The method is demonstrated using clinical data from global and Japanese trials in dapagliflozin for type 2 diabetes.

Acupoint dependence of depressor and bradycardic responses elicited by manual acupuncture stimulation in humans.

The cardiovascular effects of the autonomic nervous system (ANS) are modulated by inputs from peripheral sensors and other brain regions. However, it currently remains unknown whether the manual acupuncture (MA) stimulation of different acupuncture points evokes different responses by the heart and vasculature, a phenomenon known as "site specificity". Sixty healthy subjects were randomly divided into a control group and MA stimulation groups at the lower leg, ear, abdomen, and forearm. MA was performed at 1 Hz for 2 min. A depressor response was observed only in the lower leg stimulation group, in which mean blood pressure significantly decreased from 83.4 ± 10.1 to 80.9 ± 11.7 mmHg (p < 0.003). A bradycardic response was elicited in all MA stimulation groups. There was no significant differences in the magnitude of the bradycardic response between groups. MA-induced cardiovascular responses, which may be mediated by the modulation of ANS, differ depending on acupuncture points.

Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors.

Blockade of programmed cell death ligand-1 with durvalumab has shown efficacy and safety in large, international studies of patients with advanced solid tumors. A phase 1, non-randomized, open-label multicenter study was initiated to evaluate durvalumab in a Japanese population. The first part of this study used a standard 3 + 3 dose-escalation design to determine the optimal dosing schedule of durvalumab. Primary objective was evaluation of safety and tolerability of durvalumab monotherapy. Secondary objectives were to evaluate maximum tolerated dose (MTD), immunogenicity, pharmacokinetics, and efficacy. Twenty-two patients (median age, 61.5 years; range, 41-76; 64% male) received durvalumab at doses of 1, 3, or 10 mg/kg every 2 weeks (q2w), 15 mg/kg q3w, or 20 mg/kg q4w. Twenty patients discontinued before completing 12 months of treatment as a result of progressive disease and two due to adverse events (AE). The most common treatment-related AE (trAE) were rash (18%) and pruritus (14%); two patients had grade ≥3 trAE including one patient each with hyponatremia and hypothyroidism. No patient experienced a dose-limiting toxicity (DLT) during the DLT evaluation period and the MTD was not identified. There were no AE leading to a fatal outcome during study treatment. Durvalumab showed dose-proportional pharmacokinetics across the 1-20 mg/kg dose range; incidence of positive titers for antidrug antibodies was 9%. One patient with lung cancer had a partial response and disease control rate at 12 weeks was 36%. In conclusion, durvalumab at the doses and regimens evaluated was safe and well tolerated in Japanese patients with advanced solid tumors.

Pharmacokinetics and pharmacodynamics of dapagliflozin in combination with insulin in Japanese patients with type 1 diabetes.

AIMS: To assess the pharmacokinetics/pharmacodynamics (PK/PD) of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor that increases urinary glucose excretion (UGE) and its major metabolite, dapagliflozin-3-O-glucuronide (D3OG), in Japanese patients with type 1 diabetes (T1D) and inadequate glycaemic control (HbA1c 7%-10%). MATERIALS AND METHODS: Japanese patients (18-65 years) with inadequately controlled T1D were randomized 1:1:1 to dapagliflozin 5 mg, 10 mg or placebo (n = 14 each) once daily for 7 days, with adjustable insulin. The PK/PD characteristics of dapagliflozin and D3OG were assessed on Day 7. Patients underwent follow-up evaluation on Days 8 and 14. Adverse events (AEs), hypoglycaemic episodes and events of diabetic ketoacidosis (DKA) were recorded over the treatment and follow-up periods. RESULTS: A total of 42 randomized patients received dapagliflozin or placebo. PK variables increased in a dose-dependent manner. D3OG was generated rapidly, with a median time to maximum plasma concentration of 2.0 hours (1.0-3.0). The dapagliflozin dose-UGE relationship was attenuated, with larger insulin dose reductions than anticipated. Mean percent (standard error) changes in total daily insulin dose from baseline to Day 7 were - 36.86% (3.32), -39.13% (2.68) and - 4.97% (5.28) for dapagliflozin 5 mg and 10 mg and for placebo, respectively. No DKA was reported. AEs were consistent with the established dapagliflozin safety profile. There was no increase in hypoglycaemia. CONCLUSIONS: The PK and safety profiles of dapagliflozin in Japanese patients with T1D were consistent with previous studies, but with an unanticipated attenuation of the PD dose-response measured as UGE.

aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer.

BACKGROUND: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC. MATERIALS AND METHODS: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG). RESULTS: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS). CONCLUSION: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC. IMPLICATIONS FOR PRACTICE: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.

Urinary glucose excretion after dapagliflozin treatment: An exposure-response modelling comparison between Japanese and non-Japanese patients diagnosed with type 1 diabetes mellitus.

AIMS: To assess the dapagliflozin exposure-response relationship in Japanese and non-Japanese patients with type 1 diabetes mellitus (T1DM) and investigate if a dose adjustment is required in Japanese patients. MATERIALS AND METHODS: Data from two clinical studies were used to develop a non-linear mixed effects model describing the relationship between dapagliflozin exposure (area under the concentration curve) and response (24-hour urinary glucose excretion [UGE]) in Japanese and non-Japanese patients with T1DM. The effects of patient-level characteristics (covariates; identified using a stepwise procedure) on response was also assessed. Simulations were performed using median-normalized covariate values. RESULTS: Data from 84 patients were included. Average self-monitored blood glucose (SMBG) at day 7, change from baseline in total insulin dose at day 7, and baseline estimated glomerular filtration rate (eGFR) all had a significant effect on 24-hours UGE, with SMBG being the most influential. Dapagliflozin systemic exposure for matching doses and baseline eGFR was similar between Japanese and non-Japanese patients; however, higher SMBG and a greater reduction in total insulin dose was observed in the Japanese population. When the significant covariates were included, the model fit the data well for both populations, and accurately predicted exposure-response in the Japanese and non-Japanese populations, in agreement with the observed data. CONCLUSIONS: There was no difference in dapagliflozin exposure-response in Japanese and non-Japanese patients with T1DM once differences in renal function, glycaemic control and insulin dose reductions between studies were considered. Therefore, no dose adjustment is recommended in Japanese patients with T1DM.