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Background: Regorafenib is a standard salvage line therapy used for advanced colorectal cancer (CRC). Recently, FTD/TPI plus bevacizumab also showed promising efficacy as a salvage line therapy for advanced CRC. However, the efficacy and safety of regorafenib for patients with advanced CRC who have previously received trifluridine/tipiracil (TFTD) plus bevacizumab is unclear.Results: We retrospectively collected clinicopathologic data from patients with advanced CRC who received regorafenib after TFTD plus bevacizumab in multiple institutions between April 2017 and June 2020.Thirty-four advanced CRC patients who received regorafenib were analyzed. The median age was 66.5 (range 43−81 years), 11 patients were male, and all had an ECOG performance status(PS) of 0 or 1. Twenty-two patients had left-sided tumors, 18 patients had RAS mutants, and 1 patient had a BRAF V600E mutation. The response rate was 0%, and the disease control rate was 31%. The median progression-free survival was 70 days (95% CI: 56−91), and the overall survival was 233 days (95% CI: 188−324). Treatment was discontinued in 32 patients, and 28 (82%) discontinued treatment due to progressive disease. The major grade 3 and4 toxicities were proteinurea (29%), hypertension (26%), hand-foot syndrome(15%), and platelet decrease (6%).Conclusion: Regorafenib after TFTD plus bevacizumab showed efficacy similar to that of the previous study, and no new adverse events were observed.

Lessons Learned Background The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable colorectal cancer liver metastases (CLM) is still unclear. We evaluated the feasibility of 3-month adjuvant treatment with capecitabine plus oxaliplatin in combination (CAPOX) for postcurative resection of CLM. Methods Patients received one cycle of capecitabine followed by four cycles of CAPOX as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given as 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle, and CAPOX consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3-week cycle. Primary endpoint was the completion rate of adjuvant chemotherapy. Secondary endpoints included recurrence-free survival (RFS), overall survival (OS), dose intensity, and safety. Results Twenty-eight patients were enrolled. Median age was 69.5 years, 54% of patients had synchronous metastases, and 29% were bilobar. Mean number of lesions resected was two, and mean size of the largest lesion was 31 mm. Among patients, 20 (71.4%; 95% confidence interval, 53.6%–89.3%) completed the protocol treatment and met its primary endpoint. The most common grade 3 or higher toxicity was neutropenia (29%). Five-year recurrence-free survival and overall survival were 65.2% and 87.2%, respectively. Conclusion Three-month adjuvant treatment with CAPOX is tolerable and might be a promising strategy for postcurative resection of CLM.

Background RAS/BRAFV600E mutations are the most remarkable oncogenic driver mutations in colorectal cancer (CRC) and play an important role in treatment selection. No data are available regarding the clinical and prognostic features of patients with detailed RAS/BRAFV600E-mutant metastatic CRC (mCRC) in Japan. Methods A total of 152 chemotherapy-naïve patients with mCRC were included in this study between August 2018 and July 2019. Tumor samples were collected, and RAS/BRAFV600E status was investigated. RAS/BRAFV600E status was examined using a MEBGEN RASKET-B kit and polymerase chain reaction reverse sequence-specific oligonucleotide method. Results RAS/BRAFV600E mutations were detected in 54% of cases (KRAS codon 12, 26%; KRAS codon 13, 17%; KRAS non-Exon2, 5%; NRAS, 5%; and BRAFV600E, 7%). BRAFV600E-mutant CRC mainly existed in the right colon, whereas KRAS non-Exon2 and NRAS-mutant CRC was predominantly present in the left colon. KRAS non-Exon2 and NRAS-mutant CRC were associated with shorter survival time than RAS wild-type CRC (hazard ratio [HR], 2.26; 95% confidence interval [CI], 0.64–8.03; p = 0.19; HR, 2.42; 95% CI, 0.68–8.61; p = 0.16) and significantly shorter overall survival than KRAS Exon2-mutant CRC (HR, 3.88; 95% CI, 0.92–16.3; p = 0.04; HR, 4.80; 95% CI, 1.14–20.2; p = 0.02). Conclusions In our multicenter study, the findings elucidated the clinical and prognostic features of patients with detailed RAS/BRAFV600E-mutant mCRC in Japan.

Organisms living in temperate regions are sensitive to seasonal variations in the environment; they are known to accumulate energy as fat in their livers during the winter when days are shorter, temperatures are lower, and food is scarce. However, the effect of variations in photoperiod alone on hepatic lipid metabolism has not been well studied. Therefore, in this study, we analyzed lipid metabolism in the liver of medaka, Oryzias latipes, while varying the length of days at constant temperature. Larger amounts of fatty acids accumulated in the liver after 14 days under short‐day conditions than under long‐day conditions. Metabolome analysis showed no accumulation of long‐chain unsaturated fatty acids, but showed a significant accumulation of long‐chain saturated fatty acids. Short‐day conditions induced a reduction in the levels of succinate, fumarate, and malate in the tricarboxylic acid cycle, decreased expression of PPARα, and decreased accumulation of acylcarnitine, which suggested inhibition of lipolysis. In addition, transparent medaka fed on a high‐fat diet under short‐day conditions exhibited greater amounts of fat accumulation and developed fatty liver. The findings of our study will be useful for creating a medaka hepatic steatosis model for future studies of hepatic steatosis‐related diseases., In this study, we analyzed lipid metabolism in the liver of medaka, Oryzias latipes, while varying the length of days at constant temperature. Larger amounts of fatty acids accumulated in the liver after 14 days under short‐day conditions than under long‐day conditions. The findings of our study will be useful for creating a medaka hepatic steatosis model for future studies of hepatic steatosis‐related diseases.

Long-term use of benzodiazepine (BZD) is not recommended for the treatment of anxiety disorders. Cognitive behavioral therapy (CBT) is an effective treatment option for discontinuation of BZDs in patients with anxiety disorders. This systematic review and meta-analysis sought to clarify whether CBT is effective for discontinuing BZD anxiolytics in patients with anxiety disorders. This study was preregistered with PROSPERO (registration number: CRD42019125263). A literature search of major electronic databases was conducted in December 2018. Three randomized controlled trials were included in this review, and meta-analyses were performed. The proportion of discontinuing BZD anxiolytics was significantly higher in the CBT plus gradual tapering group than in the gradual tapering alone group, both in the short term (3 months after allocation; number needed to treat [NNT]: 3.2, 95% confidence interval: 2.1 to 7.1; risk ratio: 1.96, 95% confidence interval: 1.29 to 2.98, p=0.002, three studies) and long term (6 to 12 months after allocation; NNT: 2.8, 95% confidence interval: 1.9 to 5.3; risk ratio: 2.16, 95% confidence interval: 1.41 to 3.32, p=0.0004, three studies). CBT may be effective for discontinuing BZD anxiolytics, both in the short term and in the long term after the allocation. Further studies with larger sample sizes are necessary to draw definitive conclusions regarding the efficacy and safety of CBT for discontinuing BZD anxiolytics in patients with anxiety disorders. This article is protected by copyright. All rights reserved.

Background Consuming drugs in conjunction with sexual intercourse may shape the perceived interdependence of drug use and sexual intercourse (PIDS). Additionally, the severity of drug problems may have a significant impact on PIDS. However, this relationship remains unverified. Therefore, this study investigates whether the severity of drug problems is associated with PIDS among adult males in drug addiction rehabilitation centers (DARC) in Japan. Methods This study was a secondary analysis of the “DARC Follow-Up Study in Japan” conducted by the National Center of Neurology and Psychiatry in 2016, in which participants from 46 facilities completed a self-report questionnaire. A total of 440 males with drug dependence were included in the analysis. We analyzed participants’ demographic characteristics, history of sexually transmitted disease diagnoses, and responses to questions related to drug use (e.g., primary drug use and PIDS). Additionally, we measured the severity of drug problems using the Japanese version of the Drug Abuse Screening Test-20 (DAST-20). Results The median age of the participants was 42 years. The median DAST-20 score was 14.0, the primary drug was methamphetamine (61.4%) and new psychoactive substances (NPS: 13.6%). Multivariate analysis indicated that participants’ experiences with unprotected sexual intercourse (“mostly a non-condom user”: adjusted odds ratio (AOR) = 4.410), methamphetamine use (AOR = 3.220), new psychoactive substances use (AOR = 2.744), and the DAST-20 score (AOR = 1.093) were associated with PIDS. Conclusions This study indicated that the frequency of unprotected sexual intercourse under the influence of drugs, methamphetamine and NPS use were strongly associated with PIDS. The severity of drug problems was also significantly associated with PIDS. It is necessary to develop culturally appropriate treatment programs adapted to the needs of patients who experience strong PIDS.

There are a few studies on gender differences in terms of reasons and motives for methamphetamine use. Purpose/Objectives: To examine gender differences in triggers of methamphetamine use Methods: ...

Purpose FOLFOXIRI plus bevacizumab is regarded as a first-line therapeutic option for selected patients with metastatic colorectal cancer (mCRC). Our aim was to assess the efficacy and safety of induction treatment with FOLFOXIRI plus bevacizumab in patients with untreated mCRC harboring UGT1A1 wild (*1/*1), or single-hetero (*1/*6 or *1/*28) genotypes. Methods Twelve cycles of FOLFOXIRI plus bevacizumab were administered to patients with untreated mCRC. The primary endpoint was the overall response rate (ORR) assessed by central independent reviewers. Secondary endpoints included time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), relative dose intensity (RDI), R0 resection rate, and safety. The exploratory objectives were early tumor shrinkage (ETS) and depth of response (DoR). Results Of the 47 patients enrolled, 46 and 44 patients were eligible for the safety and efficacy analysis, respectively. The primary endpoint was met. The ORR was 63.6% (95% CI 47.8–77.6). At a median follow-up of 25.4 months, median TTF, PFS, and OS was 8.1, 15.5, and 34.4 months, respectively. The median RDI of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab was 72, 69, 62, and 71%, respectively. R0 resection rate was 22.7%. Grade 3 or higher adverse events (≥ 10%) included neutropenia (65.2%), febrile neutropenia (26.1%), leukopenia (23.9%), anorexia (10.9%), nausea (10.9%), and diarrhoea (10.9%). No treatment-related deaths were observed. ETS and DoR were 70.5 and 45.4%, respectively. Conclusions FOLFOXIRI plus bevacizumab induction treatment of Japanese patients was shown to be beneficial and manageable, although caution is required since the treatment causes febrile neutropenia.

Aim The objective of the current study was to identify risk factors that affect the onset of dependence and chronic psychosis due to cannabis use. Methods We examined clinical genetic factors, psychiatric disorders prior to cannabis use, starting age of cannabis use, duration and frequency of cannabis use, types of cannabis products used, combined use of other psychoactive substances, and the psychiatric diagnosis of 71 patients with cannabis‐related psychiatric disorders who underwent treatment at nine mental health hospitals in Japan. Information was collected from cross‐sectional interview surveys conducted by each patient's attending psychiatrist. Results For the diagnosis of dependence syndrome due to the use of cannabis, we found associations with the number of years of cannabis use and the use of cannabis products with a high Δ9‐tetrahydrocannabinol (THC) content. However, we found no association between diagnosis of residual and late‐onset psychotic disorders and clinical genetic factors, presence of preceding psychiatric disorders, duration and frequency of cannabis use, starting age of cannabis use, or combined use of other psychoactive substances; an association was found only for the absence of use of cannabis products other than dried cannabis. Conclusion The onset of cannabis dependence was related to long‐term cannabis use and the use of cannabis products with a high THC content. However, chronic psychosis was not associated with total THC intake or psychiatric vulnerability. Thus, unknown factors appear to be involved in the onset of chronic psychosis., The onset of cannabis dependence was related to long‐term cannabis use and the use of cannabis products with a high THC content. However, chronic psychosis was not associated with total THC intake or psychiatric vulnerability.

The incidence of nonalcoholic steatohepatitis-related liver cirrhosis is increasing. We used a steatohepatitis murine model fed a choline-deficient, l-amino acid-defined (CDAA) diet with a single injection of carbon tetrachloride (CCl4) to evaluate the efficacy of trans-portal hepatic infusion of bone marrow-derived mesenchymal stem cells (BMSCs) for liver fibrosis, liver steatosis, and oxidative stress. Mice were fed a CDAA diet and injected with a single intraperitoneal dose of CCl4 (0.5 ml/kg) after 4 weeks of CDAA diet. After 12 weeks of CDAA diet, 1 × 106 luciferase-positive syngeneic BMSCs (Luc-BMSCs) were infused into the animal spleen. An in vivo imaging system was used to confirm Luc-BMSC accumulation in the liver via the portal vein, and at 4 weeks after infusion, we compared liver fibrosis, liver steatosis, and oxidative stress. After the BMSC-infusion, serum albumin and serum total bilirubin were significantly improved. Liver fibrosis assessed by Sirius red staining, α-smooth muscle actin protein, and collagen 1A1 mRNA expression was significantly suppressed. Furthermore, liver steatosis area was significantly lower, the 8-hydroxy-2'-deoxyguanosine-positive cells were significantly fewer, and superoxide dismutase 2 protein expression of the liver was significantly increased. In conclusion, our data confirmed the efficacy of trans-portal hepatic infusion of BMSCs in a steatohepatitis murine model.

Objectives There is no standard chemotherapy for advanced pancreatic cancer (APC) after gemcitabine plus nab-paclitaxel (GP) failure. The aim of this study was to evaluate the efficacy and safety of FOLFIRINOX (5-Fluorouracil, leucovorin, irinotecan, and oxaliplatin) (5-Fluorouracil, leucovorin, irinotecan, and oxaliplatin) (FFX) and modified FFX (mFFX) for APC patients after GP failure. Methods We retrospectively evaluated the efficacy and safety of FFX in APC patients who were refractory or intolerant of GP. Results Between July 2014 and October 2018, 23 patients received FFX after failure of GP. The overall response rate (RR) was 23%, and the disease control rate (DCR) was 68%. The median progression-free survival (PFS) was 5.3 months (95% confidence interval, 2.5-8.9), and the median overall survival (OS) was 12.1 months (95% confidence interval, 4.0-14.2). Twelve patients received FFX, and 11 patients received mFFX. In the FFX group, the RR was 9%, the DCR was 73%, the PFS was 5.3 months, and the OS was 6.9 months. In the mFFX group, the RR was 23%, the DCR was 64%, the PFS was 4.3 months, and the OS was 12.8 months. There was no significant difference between the groups. Conclusions FOLFIRINOX has potential activity for patients with APC in whom GP failed.

Background Internet-based intervention could help drug users recover from drug dependence. This study evaluated the effectiveness of a newly developed web-based relapse prevention program (e-SMARPP) for people with a drug problem, including the use of methamphetamine, in Japan. Methods The study was a pilot randomized controlled trial comprised of 48 psychiatric outpatients diagnosed with drug use disorder. The participants were randomly assigned to an eight-week, six-session web-based relapse prevention program (an intervention group) or only web-based self-monitoring (a control group). The primary outcome was the duration of abstinence from a primary drug during the intervention and relapse risk. Secondary outcomes included motivation to change, self-efficacy, and money spent on drugs. The outcomes, except for the duration of abstinence during the intervention, were assessed at baseline, 2-, 5-, and 8-months. Program completion rate was also assessed. Results No significant difference was observed between the intervention and the control groups for the primary and the secondary outcomes. The effect size of the duration of abstinence during the intervention was d = 0.42, which was comparable to previous studies. In the intervention group, about 26% did not complete the entire intervention. Conclusions e-SMARPP failed to demonstrate efficacy, however, is potentially helpful for enhancing abstinence. The low attrition rate may suggest the acceptance and feasibility of the program. Further improvement of the program and evaluation in a full-scale trial are needed.

Liquid biopsies are not used in practice for hepatocellular carcinoma (HCC). Epi proColon is the first commercial blood‐based test for colorectal cancer screening based on methylated DNA testing of the septin 9 gene (SEPT9). However, Epi proColon has some disadvantages, including the requirement of a large amount of blood and lack of quantitative performance. Therefore, we previously developed a novel liquid biopsy test that can quantitatively detect even a single copy of methylated SEPT9 in a small amount of DNA. In the current study, we evaluated the application potential of this assay for diagnosing HCC. Study subjects included 80 healthy volunteers, 45 patients with chronic liver disease (CLD) without HCC, and 136 patients with HCC (stage 0, 12; stage A, 50; stage B, 31; stage C, 41; and stage D, 2), according to the Barcelona Clinic Liver Cancer staging system. For the assay, DNA was treated with methylation‐sensitive restriction enzymes in two steps, followed by multiplex droplet digital polymerase chain reaction. The median copy number of methylated SEPT9 was 0.0, 2.0, and 6.4 in the healthy control, CLD, and HCC groups, respectively, with significant differences among the groups (HCC vs. healthy control, P

BackgroundSubstance use disorder (SUD) is a leading contributor to the global burden of disease. In Indonesia, the availability of formal treatment for SUD falls short of the targeted coverage. A standardised therapeutic option for SUD with potential for widespread implementation is required, yet evidence-based data in the country are scarce. In this study, we developed a cognitive behavioural therapy (CBT)-based group telemedicine model and will investigate effectiveness and implementability in a multicentre randomised controlled trial.MethodsA total of 220 participants will be recruited from the social networks of eight sites in Indonesia: three hospitals, two primary healthcare centres and three rehabilitation centres. The intervention arm will participate in a relapse prevention programme called the Indonesia Drug Addiction Relapse Prevention Programme (Indo-DARPP), a newly developed 12-week module based on CBT and motivational interviewing constructed in the Indonesian context. The programme will be delivered by a healthcare provider and a peer counsellor in a group therapy setting via video-conferencing, as a supplement to participants’ usual treatments. The control arm will continue treatment as usual. The primary outcome will be the percentage increase in days of abstinence from the primarily used substance in the past 28 days. Secondary outcomes will include addiction severity, quality of life, motivation to change, psychiatric symptoms, cognitive function, coping, and internalised stigma. Assessments will be performed at baseline (week 0), post-treatment (week 13), and 3 and 12 months post-treatment completion (weeks 24 and 60). Retention, participant satisfaction, and cost-effectiveness will be assessed as the implementation outcomes.Ethics and disseminationThe study protocol was reviewed and approved by the Ethics Committees of Universitas Indonesia and Kyoto University. The results will be disseminated via academic journals and international conferences. Depending on trial outcomes, the treatment programme will be advocated for adoption as a formal healthcare-based approach for SUD.Trial registration numberUMIN000042186.

Among lifestyle-related diseases, fatty liver is the most common liver disease. To date, mammalian models have been used to develop methods for inhibiting fatty liver progression, however, new, more efficient models are expected. This study investigated the creation of a new model to produce fatty liver more efficiently than the high-fat diet medaka model that has been used to date. We compared the GAN (Gubra-Amylin nonalcoholic steatohepatitis) diet, which has been used in recent years to induce fatty liver in mice, and the high-fat diet (HFD). Following administration of the diets for three months, enlarged livers and pronounced fat accumulation was noted. The GAN group had large fat vacuoles and lesions, including ballooning, compared to the HFD group. The GAN group had a higher incidence of lesions. When fenofibrate was administered to the fatty liver model created via GAN administration and liver steatosis was assessed, a reduction in liver fat deposition was observed, and this model was shown to be useful in drug evaluations involving fatty liver. The medaka fatty liver model administered with GAN will be useful in future fatty liver research.

Objectives Liver transplantation remains the only curative therapy for decompensated liver cirrhosis. However, it has several limitations, and not all patients can receive liver transplants. Therefore, liver regenerative therapy without liver transplantation is considered necessary. In this study, we attempted minimally invasive liver regenerative therapy by peripheral vein infusion of bone marrow-derived mesenchymal stem cells (BMSCs) cultured from a small amount of autologous bone marrow fluid and evaluated the effects of BMSCs on hepatocarcinogenesis in a mouse model. Methods C57BL/6 male mice were injected intraperitoneally with N-nitrosodiethylamine once at 2 weeks of age, followed by carbon tetrachloride twice a week from 6 weeks of age onwards, to create a mouse model of highly oncogenic liver cirrhosis. From 10 weeks of age, mouse isogenic green fluorescent protein–positive BMSCs (1.0 × 106/body weight) were infused once every 2 weeks, for a total of 5 times, and the effects of frequent BMSC infusion on hepatocarcinogenesis were evaluated. Results In the histologic evaluation, no significant differences were observed between the controls and BMSC-administered mice in terms of incidence rate, number, or average size of foci and tumors. However, significant suppression of fibrosis and liver injury was confirmed in the group that received BMSC infusions. Discussion Considering that BMSC infusion did not promote carcinogenesis, even in the state of highly oncogenic liver cirrhosis, autologous BMSC infusion might be a safe and effective therapy for human decompensated liver cirrhosis.

Recent success of systemic therapeutic agents, including combination immunotherapy, could promote a change in the treatment strategy in patients with advanced hepatocellular carcinoma (HCC). Although hepatic arterial infusion chemotherapy (HAIC) is a treatment option for advanced HCC in Japan, it is not recommended by other guidelines. We discuss the clinical benefits of HAIC compared to sorafenib. The clinical benefits of HAIC are as follows: (1) even a patient with Child–Pugh B HCC (7 or 8 points) is a candidate for HAIC (2) Child–Pugh scores barely decline with the use of HAIC compared with sorafenib (3) HAIC is highly effective in patients with vascular invasion compared with sorafenib; and (4) survival in patients receiving HAIC may not be associated with skeletal muscle volume. In contrast, the disadvantages are problems related with the reservoir system. HAIC has clinical benefits in a subpopulation of patients without extrahepatic metastasis with Child–Pugh A HCC and vascular invasion (especially primary branch invasion or main portal vein invasion) or with Child–Pugh B HCC.

Background Alcohol problems in parents have been revealed to affect adolescent alcohol misuse. However, few studies examine the effects of parental drinking on adolescent risky drinking (including binge drinking) in the general population. In particular, previous study findings are inconsistent regarding the influence of parental drinking according to parental composition. In this study, we aimed to examine the relationship between parental drinking, according to parental composition, and binge drinking among high school students in Japan. Methods We performed a secondary analysis of the Nationwide High School Survey on Drug Use and Lifestyle 2018, Japan. A total of 46,848 valid surveys from high school students of 78 schools were included for analysis. Logistic regression analysis with a generalized linear mixed model was conducted with binge drinking as the dependent variable and “parental drinking according to parental composition” (e.g., father’s drinking, mother’s drinking, father’s absence, mother’s absence, both parents drinking, and neither parent at home) as the independent variable, after adjusting with covariates. Binge drinking was defined as five or more alcoholic drinks for male adolescents or four or more alcoholic drinks for females on the same occasion within two hours. Results In the fully adjusted models, adolescents whose mothers drink (adjusted odds ratio (AOR): 1.50, 95% confidence interval (CI): 1.06–2.12) were significantly associated with adolescent binge drinking. This risk was significantly higher among students with neither parent living at home (AOR: 4.35, 95% CI: 2.10–9.02). Conclusion Parental drinking and absence do affect adolescent binge drinking; our findings show that adolescents are more likely to engage in binge drinking if their mothers drink or if they are not living with either parent. Therefore, it is important to engage parents and non-parental family members in future programs and interventions to prevent adolescent binge drinking.

Lessons Learned A biweekly TAS-102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS-102 plus BEV combination. Biweekly TAS-102 plus BEV combination could reduce unnecessary dose reduction of TAS-102, maintain higher doses, and possibly be effective even in cases without chemotherapy-induced neutropenia (CIN). The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS-102 plus BEV. Background TAS-102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS-102 (70 mg/m2/day on days 1–5 and 8–12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS-102 plus BEV combination. Methods Patients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS-102 (twice daily on days 1–5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression-free survival rate at 16 weeks (16-w PFS rate). Results From October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS-102 (70 mg/m2/day). Of the 44 eligible patients, the 16-w PFS rate was 40.9% (95% confidence interval, 26.3%–56.8%), and the null hypothesis was rejected (p < .0001). Median progression-free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%). Conclusion Biweekly TAS-102 plus BEV showed promising antitumor activity with safety.

There are limited reports regarding early predictors of objective response (OR) in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. This retrospective study including 70 patients aimed to investigate the efficacy of hepatic biochemical markers. Changes in tumor marker (alpha-fetoprotein (AFP)/des-gamma-carboxy prothrombin (DCP)) levels and albumin&ndash, bilirubin (ALBI) score between the baseline value and that estimated one month after treatment were evaluated. We identified several predictors of OR, including changes in tumor marker levels. The OR rate calculated using modified Response Evaluation Criteria in Solid Tumor (mRECIST) was 41.4%. Response was defined as a reduction in AFP and DCP levels of &ge, 40% from baseline. OR was significantly associated with AFP response, but not with DCP. Predictors of OR were evaluated in two groups (high-AFP group: baseline AFP &ge, 10 ng/mL, low-AFP group: remaining patients). A multivariate analysis identified AFP response (odds ratio, 51.389, p = 0.001) and ALBI score (odds ratio, 6.866, p = 0.039) as independent predictors of OR in the high-AFP and low-AFP groups, respectively. Changes in the ALBI score indicated deterioration in both responders and non-responders, with a significant difference in non-responders (p = 0.003). AFP response, baseline ALBI score, and change in the ALBI score were early predictors of OR in patients with HCC undergoing lenvatinib treatment.

Aims This study aimed to investigate the influence of tightened regulations on new psychoactive substances in patients with disorders related to these drugs in Japan. Methods We used a biennial nationwide survey on drug‐related psychiatric disorders to examine why individuals who had previously used new psychoactive substances as their primary drug (the drug that had the greatest impact on their psychiatric symptoms) had switched to other drugs, how they had used drugs in the last 12 months and what type of drugs they were now using. We compared the clinical features of these individuals with patients who mainly used new psychoactive substances and had used these drugs at least once in the last 12 months. Results A total of 2262 people were included, and 399 had used new psychoactive substances. Of those, 71 people had switched to another drug as primary drug, mostly stimulant drugs (35.2%), hypnotics and anxiolytics (15.5%), and cannabis (14.1%) and used these drugs during the previous 12 months. The majority, 53.3%, had switched “because new psychoactive substances were no longer available.” In total, 25 people mainly used new psychoactive substances. The group that had changed drugs had more experience of using methamphetamine and were more likely to have abused other drugs before using new psychoactive substances. They had often switched to illegal or prescription drugs after regulations had been tightened. Conclusion The number of patients abusing new psychoactive substances decreased after drug regulations were tightened, but new psychoactive substances‐related problems still exist. It is therefore not enough to tighten regulations. Drug dependence treatment and recovery support are also needed., We investigate the influence of tightened regulations on new psychoactive substances in patients with disorders related to these drugs in Japan. Tightening regulations were not enough. Drug dependence treatment and recovery support are also needed.

Sorafenib is used worldwide as a first-line standard systemic agent for advanced hepatocellular carcinoma (HCC) on the basis of the results of two large-scale Phase III trials. Conversely, hepatic arterial infusion chemotherapy (HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC, several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib, whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization, good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally, sorafenib is generally used to treat patients with Child-Pugh A, while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings, we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A, while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non-responders with Child-Pugh B through future clinical trials.

Primary malignant melanoma of the esophagus (PMME) is a rare, aggressive, therapy-resistant malignant tumor arising from esophageal mucosal melanocytes. It has been reported that fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) has a clinical impact on PMME diagnosis; however, it remains unclear whether postoperative surveillance using FDG-PET/CT is useful for PMME patients. In this case study, FDG-PET/CT detected the recurrent tumors in their early stage after a curative resection of PMME. We report on a case of a 67-year-old Japanese male admitted to our hospital for the evaluation of polypoid tumors of the esophagogastric junction, which were diagnosed as PMME. He was treated with a curative resection by esophagectomy and 6 cycles of adjuvant chemotherapy of DAV (dacarbazine, nimustine, and vincristine). However, the PMME recurred 26 months after the surgery when surveillance FDG-PET/CT detected the recurrent tumors in their early stage. FDG-PET/CT may be useful to detect recurrence in the postoperative surveillance phase for PMME patients.

Takotsubo cardiomyopathy (TCM) is also known as stress-induced cardiomyopathy. The occurrence of TCM due to infusion reaction is extremely rare. A 65-year-old man began receiving trastuzumab monotherapy for gastric cancer. However, he developed an infusion reaction after administration. Electrocardiography revealed negative T waves, ST segment elevation, and apical akinesis and hypokinesis of the left ventricle with apical ballooning in the systole and diastole. Furthermore, troponin I and creatinine kinase (CK) levels and CK-myocardial band were elevated. Based on these findings, he was diagnosed with TCM. This is the first report of TCM due to an infusion reaction.

Transcatheter arterial chemoembolization (TACE) is used as a palliative treatment for unresectable hepatocellular carcinoma (HCC) worldwide. Recently, a novel drug delivery-embolic agent, the drug-eluting bead (DEB), was introduced for TACE. There are a few reports of tumor hemorrhage after TACE using DEB (DEB-TACE) for HCC. However, there have not been any reports of hemobilia immediately after DEB-TACE for HCC with intrahepatic bile duct invasion. Here, the first such case is reported. A 71-year-old woman was admitted to our hospital to undergo DEB-TACE for multiple HCCs with worsening left intrahepatic bile duct dilatation. She was diagnosed with HCC that extensively invaded the left hepatic duct. After DEB-TACE through the left hepatic artery, a hepatic arteriogram showed extra flow of the contrast agent to the left hepatic and common bile ducts. Therefore, transcatheter arterial embolization (TAE) of the responsible vessel was carried out using coils, and no extra flow of the contrast agent was identified. The patient was discharged 14 days after TAE without deterioration of liver function. Although hemobilia immediately after DEB-TACE is rare, there may be increased potential for hemobilia when DEB-TACE is carried out for HCC with extensive bile duct invasion. We suggest that DEB-TACE may be contraindicated for such cases.

Summary Background In patients with heavily treated metastatic colorectal cancer, TAS-102—a combination of trifluridine and tipiracil—has shown a significant overall survival benefit compared with placebo. In preclinical models, TAS-102 plus bevacizumab has shown enhanced activity against colorectal cancer xenografts compared with that for either drug alone. In this phase 1/2 study, we assessed the activity and safety of TAS-102 plus bevacizumab. Methods We did this investigator-initiated, open-label, single-arm, multicentre, phase 1/2 trial of TAS-102 plus bevacizumab in four cancer centres in Japan. Eligible patients were aged 20 years or older; had histologically confirmed unresectable, metastatic colorectal adenocarcinoma; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumours with wild-type KRAS ); and had no previous treatment with regorafenib. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Using a dose de-escalation design in phase 1, the recommended phase 2 dose (RP2D) was determined for TAS-102 (35 mg/m 2 given orally twice daily on days 1–5 and 8–12 in a 28-day cycle for level 1) plus bevacizumab (5 mg/kg, administered by intravenous infusion for 30 min every 2 weeks). In phase 2, patients received the RP2D. The primary endpoint was centrally assessed progression-free survival at 16 weeks, analysed in the first 21 patients to be enrolled and treated with the RP2D who had at least one imaging assessment. This study is completed and registered with the University Hospital Medical Information Network, number UMIN000012883. Findings Between Feb 25, 2014, and July 23, 2014, we enrolled 25 patients with metastatic colorectal cancer: six patients in phase 1 and 19 patients in phase 2. The six patients who received TAS-102 at level 1 experienced no dose-limiting toxicities and this was deemed the RP2D. Nine of 21 patients who received the RP2D did not have a centrally assessed progression event; 16-week progression-free survival was 42·9% (80% CI 27·8–59·0). The most common grade 3 or worse adverse events as assessed in all 25 patients were neutropenia (18 [72%] patients), leucopenia (11 [44%]), anaemia (four [16%]), febrile neutropenia (four [16%]), and thrombocytopenia (three [12%]). Treatment-related serious adverse events were reported in three (12%) patients. No treatment-related deaths occurred. Interpretation TAS-102 plus bevacizumab has promising activity with manageable safety, suggesting that this combination might become a potential treatment option for patients with metastatic colorectal cancer in a refractory setting. Funding Taiho Pharmaceutical.

Liver cirrhosis can disturb circadian rhythms, decreasing patient quality of life. Changes in metabolic products in cirrhosis are poorly understood. We evaluated changes in liver metabolism products using a thioacetamide-induced mouse model of liver cirrhosis exhibiting circadian rhythm disturbance. Principal component analysis indicated that the circular progression found in the control group was disrupted in the thioacetamide group, and Jonckheere-Terpstra-Kendall analysis showed an imbalanced pattern of oscillating metabolic products. In addition to changes in serotonin and other vitamin A-related metabolites, differences in metabolic products associated with energetics, redox homeostasis, bile acid production, inflammation, and other processes were identified. Carbohydrate metabolism showed a reduction in metabolic products associated with the tricarboxylic acid cycle, suggesting up-regulation of glycolysis and reduced mitochondrial activity. Lipid metabolism showed an increase in ω-oxidation products, suggesting decreased β-oxidation. Conclusion: These data will be useful for chronotherapy and modulation of circadian rhythms in patients with liver damage. (Hepatology Communications 2017;1:704-718).

We have been developing a therapy for liver cirrhosis using cultured autologous bone marrow–derived mesenchymal stem cells (BMSCs). Before human clinical trials can be considered, the safety and efficacy of BMSC infusion in medium to large animals must be confirmed; thus, we developed a canine liver fibrosis model. A small amount of bone marrow fluid was aspirated from the canine humerus to assess the characteristics of BMSCs. We implanted a venous catheter in the stomach and a subcutaneous infusion port in the back of the neck of each canine. Repeated injection of CCl4 through the catheter was performed to induce liver cirrhosis. After 10 weeks of CCl4 injection, eight canines were equally divided into two groups: no cell infusion (control group) and autologous BMSC infusion through the peripheral vein (BMSC group). A variety of assays were carried out before and 4 weeks after the infusion. The area of liver fibrosis stained with sirius red was significantly reduced in the BMSC group 4 weeks after BMSC infusion, consistent with a significantly shortened half‐life of indocyanine green and improved liver function. Conclusion: We established a useful canine liver fibrosis model and confirmed that cultured autologous BMSC infusion improved liver fibrosis without adverse effects. (Hepatology Communications 2017;1:691–703)

AIM Although the female suicide rate in Japan is one of the highest among OECD countries, little has been done to assess the psychosocial and psychiatric characteristics of Japanese female suicide completers. This study aimed to examine sex differences in psychosocial and psychiatric characteristics of suicide completers using a psychological autopsy study method, and to identify female suicide factors and intervention points to prevent female suicides. METHODS A semi-structured interview was conducted with close family members of adult suicide completers. The interview included questions regarding sociodemographic factors, suicide characteristics, previous suicidal behaviors and a family history of suicidal behaviors, financial problems, and physical/psychiatric problems. Fisher's exact test and the Student's t-test were used to explore sex differences in these survey items, and individual descriptive information of female suicide cases was also examined. RESULTS Of the 92 suicide completers, 28 were female and 64 were male. Females had a significantly higher prevalence of a history of self-harm/suicide attempts (P < 0.001). The prevalence of eating disorders was significantly higher among females than males (P < 0.01). CONCLUSION The findings of this study highlight the importance of providing psychological and social support to caregivers of those who repeatedly attempt suicide and express suicidal thoughts, and to suggest the need to improve community care systems to be aware of suicide risk factors among female suicide attempters.

Organisms living in temperate regions are sensitive to seasonal variations in the environment; they are known to accumulate energy as fat in their livers during the winter when days are shorter, temperatures are lower, and food is scarce. However, the impact of variations in photoperiod alone on hepatic lipid metabolism has not been well-studied. Therefore, in this study, we analyzed lipid metabolism in the liver of medaka,Oryzias latipes, while varying the length of days at constant temperature. Larger amounts of fatty acids accumulated in the liver after 14 days under short-day conditions than under long-day conditions. Metabolome analysis showed no accumulation of the long-chain unsaturated fatty acids required at low temperatures, but showed a significant accumulation of long-chain saturated fatty acids. Short-day conditions induced decreased levels of succinate, fumarate, and malate in the tricarboxylic acid cycle, decreased expression of PPARα, and decreased accumulation of acylcarnitine, which suggested inhibition of lipolysis. In addition, when a high-fat diet was administered to transparent medaka under short-day conditions, larger amounts of fat accumulated and medaka with fatty liver were efficiently produced. Detailed analysis of the relationship between seasonal changes and hepatic steatosis will be important in the future as hepatic diseases become more prevalent in modern society; the findings obtained in our study will be useful for research studies pertaining to the relationship between photoperiod and disorders such as hepatic steatosis and non-alcoholic steatohepatitis.

Liver cirrhosis is the end stage of chronic liver disease and causes serious complications such as ascites, encephalopathy, and portal hypertension. The only radical treatment currently available is liver transplantation, but issues such as a shortage of donors, long-term immunosuppression, and high lifelong medical costs limit the feasibility of liver transplantation. To overcome these limits to the feasibility of liver transplantation, liver regeneration therapy through cell and stem cell transplantation, bioartificial liver systems, and organ bioengineering are advancing. This chapter will describe the current status and perspective of liver regeneration therapy for liver cirrhosis.

Advancements in antiviral drugs have enabled control of viral hepatitis; yet, many patients with liver cirrhosis (LC) are awaiting liver transplants. Liver transplantation yields dramatic therapeutic effects, but problems such as shortage of donors, surgical invasiveness, immunological rejection and costs, limit the number of transplantations. Advances in liver regeneration therapy through cell transplantation as a non-invasive treatment for cirrhosis will supplement these restrictions to the number of liver transplants. Clinical trials for LC have included hematopoietic stem cell mobilization by administration of granulocyte colony-stimulating factor, infusion of autologous bone marrow cells, and administration of autologous mesenchymal stem cells derived from bone marrow or umbilical cord. Several recently reported randomized controlled studies have shown the effectiveness of these approaches. However, to promote implementation of new liver regeneration therapies, it is important to develop a system whereby cell therapies with ensured safety can be approved quickly.

Previous studies have reported prognostic factors for hepatocellular carcinoma (HCC) patients receiving lenvatinib, however, no studies have evaluated the effects of both handgrip strength and skeletal muscle mass on the clinical outcomes. Therefore, this retrospective study investigated the individual effect of handgrip strength, skeletal muscle mass, and sarcopenia on clinical outcomes of 53 HCC patients treated with lenvatinib. Before receiving lenvatinib, handgrip strength and skeletal muscle index (SMI) were measured. Low handgrip strength and muscle depletion were defined as &lt, 26 and &lt, 18 kg and SMI &lt, 42 and SMI &lt, 38 cm2/m2 in men and women, respectively. Sarcopenia was defined as having low handgrip strength and muscle depletion. Multivariate analysis identified modified albumin&ndash, bilirubin grade 1&ndash, 2a (p = 0.010), Barcelona Clinic Liver Cancer stage A&ndash, B (p = 0.011), and absence of low handgrip strength (p = 0.015) as favorable prognostic factors for survival. Furthermore, sarcopenia was an independent significant prognostic factor for survival. Time to treatment failure was associated with handgrip strength and sarcopenia. Our findings suggest that handgrip strength may be a useful marker of clinical outcomes in HCC patients treated with lenvatinib.

Introduction We have reported previously that fecal DNA testing of TWIST1 methylation in combination with the fecal immunochemical test for hemoglobin (FIT) (combination test) is useful for colorectal neoplasia screening. In this study, using larger sample sizes, we studied the clinical performance of the combination test for the detection of colorectal neoplasia and, especially, advanced colorectal adenoma. Methods We performed a prospective study in which FIT, fecal DNA testing of TWIST1 methylation, and colonoscopy were performed on 372 patients with colorectal neoplasia and 71 subjects without colorectal neoplasia. We assessed the individual clinical performance of each of FIT and fecal DNA testing of TWIST1 methylation and of the combination test for the detection of colorectal neoplasia including advanced adenoma based on morphologic subtypes. Results The FIT alone had a sensitivity of 7.5% (3/40) for nonadvanced adenoma, 32.3% (41/127) for advanced adenoma, and 93.7% (192/205) for colorectal cancer and a specificity of 87.3% (62/71). The combination test had a sensitivity of 35.0% (14/40) for nonadvanced adenoma, 68.5% (87/127) for advanced adenoma, and 95.6% (196/205) for colorectal cancer and a specificity of 80.3% (57/71). For morphological subtypes of advanced adenoma, the sensitivity of FIT was only 28.2% (20/71) for polypoid type and 16.1% (5/31) for nonpolypoid type, whereas the combination test increased the sensitivities to 64.8% (46/71) and 71.0% (22/31), respectively. Discussion The combination of the fecal DNA test with FIT seemed to be useful to detect colorectal neoplasia and, especially, advanced adenoma of the nonpolypoid type.

377 Background: Nivolumab has demonstrated a survival benefit for advanced gastric cancer (AGC). However, hyperprogressive disease (HPD) has been reported in various cancers. Methods: The subjects of this retrospective study were AGC patients with measurable disease who received nivolumab, and their tumors were assessed at least 3 times (during prior therapy, before and after nivolumab) in 24 institutions. Tumor growth rates (TGR) during nivolumab were compared to those during prior therapy as reported (Champiat S, 2017). HPD was defined as an increase in TGR > 2-fold. Results: 218 patients were identified as the subjects. While 33 (15.1%) partial response (PR) were achieved, 130 patients (59.6%) showed progression disease (PD), 38 of whom were classified as HPD (17.4%) and 2 patients showed pseudo progression (1.0%). The median progression-free survival (PFS) was 1.9 months (95% CI: 1.9–2.4) and the median overall survival (OS) was 8.5 months (95% CI: 7.1–9.6) in all patients. While patients with PD showed shorter prognosis compared with non-PD patients (median PFS: 1.5 months vs 6.4 months, hazard ratio; 6.0 [95% CI: 4.3–8.4]; p < 0.0001; median OS: 4.7 months vs not reached, hazard ratio; 4.1 [95% CI: 2.8–6.3]; p < 0.0001), there were no differences either in PFS or OS between patients with HPD and those with PD other than HPD (median PFS: 1.5 months vs 1.6 months, hazard ratio; 1.3 [95% CI: 0.9–2.0]; p = 0.1194; median OS: 5.0 months vs 4.6 months, hazard ratio; 1.0 [95% CI: 0.6–1.5]; p = 0.8695). Histological type, liver metastases, carbohydrate antigen 19-9 (CA19-9) level were associated with HPD. Conclusions: HPD was observed 17.4% in AGC patients treated with nivolumab. There were no differences either in PFS or OS between patients with HPD and those with PD other than HPD. Clinicopathological characteristics might be a predict factor for HPD.

121 Background: We have conducted the multicenter, phase Ib/II study to assess the activity and safety of biweekly Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) combination for pts with metastatic colorectal cancer (mCRC) who were refractory or intolerant to standard therapies, and the primary endpoint of investigator assessed progression-free survival rate at 16 weeks (16w-PFS) was met [Kotaka M, ASCO-GI 2018]. We show longer follow-up data from this prospective study. Methods: Patients with unresectable mCRC; refractory or intolerant to standard chemotherapies were enrolled. Phase Ib part is designed to determine the recommended phase II dose (RP2D), and the treatment was determined as biweekly FTD/TPI (70mg/m2/day on day 1-5, every 2 weeks) with BEV (5mg/kg, every 2 weeks). The primary endpoint in phase II part was a 16w-PFS with a hypothesis of 15% considered unacceptable and 38.7% deemed promising. Given a one-sided α of 0.025 and statistical power of 90%, a minimum of 40 pts were required for phase II part. This trial registered in University Hospital Medical Information Network, number UMIN000029198. Results: From October 2017 to January 2018, totally 46 pts were enrolled. Nine patients (20.5 %) received regorafenib before enrollment. Of the 44 eligible pts, 16w-PFS rate was 40.9 %. With a median follow up of 15.36 months (range, 2.79-16.93), median PFS was 4.29 months (95% CI: 2.54 to 5.83), median TTF was 4.16 months (95% CI: 2.39 to 5.82), and median OS was 10.86 months (95% CI:8.32 to 13.68), respectively. Disease control rate was 59.1 % (95%CI: 43.3 to 73.7 %). Patients received the study treatment for a median of 6.5 cycles (range, 1 to 24). The median relative dose intensity of FTD/TPI and BEV was 80.9% (range: 44.0 to 100%), 81.5% (range: 50.0 to 100%), respectively. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (11.4 %) and leucopenia (11.4 %). Conclusions: An update analysis confirmed that biweekly FTD/TPI plus BEV showed promising anti-tumor effect with acceptable less toxicities, and might be one of the treatment options for patients with heavily treated mCRC. Clinical trial information: UMIN000029198.

391 Background: Nivolumab has changed the treatment of advanced gastric cancer (AGC). Nivolumab shows better outcome compared to best supportive care in AGC patients who received at least two prior regimen. Although there is not reliable date of poor performance status(PS) AGC patients who received nivolumab. We investigated efficacy and safety of nivolumab for AGC patients with poor PS. Methods: We retrospectively collected clinicopathologic data from patients with AGC who received nivolumab monotherapy in Himeji Red Cross Hospital from October 2017 to June 2019. Results: 49 AGC patients who received nivolumab were analyzed. 27 patients were PS 0 or 1(Good Group), and 22 patients were PS 2 or 3(Poor Group). Median progression free survival and overall survival was 61 days and 180 days in Good Group and 36 days and 85 days in Poor Group. Overall survival (OS) was significantly shorter in Poor group(180 days vs 85 days, p = 0.0255). Disease control rate was 23% in Good group and 9% in Poor group. 33% patients were experienced immune related adverse event (iRAE) in Good Group, and 18% in Poor Group. We investigated prognostic factor of OS in Poor Group such as Royal Marsden Hospital Score(RMH score), modified Glasgow prognostic score(mGPS), and Japan Clinical Oncology Group (JCOG) prognostic index. RMH score and JCOG prognostic index good or moderate group was significantly longer overall survival than poor group (93 days vs 35 days (p = 0.0214)). JCOG prognostic index was most correlated with OS among these tools. Conclusions: This study suggested that nivolumab has a modest effect and is feasible as third line or later line for AGC patients. JCOG prognostic index was suggested to be effective in predicting prognosis in AGC patients who received nivolumab.

134 Background: FOLFOXIRI-Bmab has been recognized as one of the standard first-line treatments for mCRC. We conducted a single arm, multicenter, phase II study to assess the efficacy and safety of FOLFOXIRI-Bmab in pts with untreated mCRC harboring UGT1A1(*6 and *28) wild or single hetero genotype. Methods: Pts received FOLFOXIRI-Bmab (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, l-leucovorin 200mg/m2, fluorouracil 3200 mg/m2 and Bmab 5mg/kg repeated biweekly) up to a maximum of 12 cycles, followed by the sequential therapy which consisted of the remaining drugs if any of the individual drugs were discontinued at the investigator’s discretion. Protocol therapy was continued until progressive disease, an unacceptable adverse event, tumor resection or consent withdrawal. The primary endpoint was ORR evaluated by central reviewers. Secondary endpoints include TTF, PFS, OS, R0 resection rate, relative dose intensity (RDI) and safety. The exploratory objectives were early tumor shrinkage (ETS), depth of response (DoR). Results: 47 pts were enrolled from 16 centers between April 2015 and May 2017, of whom 1 was excluded for not meeting the inclusion criteria. The full analysis set consisted of 44 pts because 2 had no target lesions that were considered measurable lesion by central reviewers. 46 pts had the following characteristics: median age 58 (29-68), 57% male, 76% PS0, 22% right-sided tumors and 52% UGT1A1 wild. RAS status was 37% wild, 52% mutant, 11% unknown. Primary endpoint was met. The ORR was 63.6% (95% CI, 47.8-77.6). ETS and DoR was 70.5%, 43.9%, respectively. R0 resection rate was 23%. Median PFS was 15.5mo (95% CI, 11.5-23.4). Median TTF was 8.1mo (95% CI, 5.3-10.1). Median OS was 34.4mo (95% CI, 26.4-not reached). The mean RDI of fluorouracil, irinotecan and oxaliplatin were 71%, 67%, and 64%, respectively. Grade 3 or higher adverse events (≥10%) were neutropenia (65.2%), febrile neutropenia (FN) (26.1%), anorexia (10.9%), nausea (10.9%), and diarrhea (10.9%). No treatment-related deaths were observed. Conclusions: Our results of FOLFOXIRI-Bmab in Japanese pts showed to be beneficial and manageable although caution to FN is required. Clinical trial information: NCT02497157.

Aims Pharmacotherapy for methamphetamine dependence has not yet been developed in Japan or elsewhere in the world. Ifenprodil is a blocker of G protein‐activated inwardly rectifying potassium channels that play a key role in the mechanism of action of addictive substances. Our aim is to examine the safety, efficacy, and outcomes of ifenprodil for the treatment of methamphetamine dependence in a randomized, double‐blind, placebo‐controlled trial. Methods The recruitment of outpatients with methamphetamine dependence began in January 2018. The patients will be randomized into three arms: placebo, 60 mg/d ifenprodil, or 120 mg/d ifenprodil. Placebo or ifenprodil will be taken for 84 days. We will use Cerocral fine granule 4%® (ifenprodil tartrate). Follow‐up assessments will be conducted for 84 d after the drug administration period. All of the patients will be assessed by self‐administered questionnaires and urine tests. The primary outcome will be the presence or absence of methamphetamine use during the 84‐day administration period in the 120 mg/d ifenprodil and placebo groups. Secondary outcomes will include the number of days and percentage of days of abstinence from methamphetamine use, positive urine for methamphetamine, relapse risk, and drug craving. Discussion This study is the first clinical trial of ifenprodil treatment for methamphetamine dependence and is designed as an intervention test with off‐label drug use. The present study is expected to provide evidence of the effects of ifenprodil treatment on methamphetamine dependence. Trial registry This trial was registered in the UMIN clinical trial registry (UMIN000030849; date of registration: January 17, 2018)., This study is the first clinical trial of ifenprodil treatment for methamphetamine dependence and is designed as an intervention test with off‐label drug use. The present study is expected to provide evidence of the effects of ifenprodil treatment on methamphetamine dependence.

Aims The use of new psychoactive substances (NPS) has become increasingly widespread over the last decade, in Japan and internationally. NPS are associated with a range of increasingly serious clinical, public, and social issues. Political measures to ameliorate the effects of NPS in Japan have focused on tightening regulation rather than establishing treatment methods. The current study sought to compare the neuropsychiatric symptoms of patients with NPS‐related disorders across several years. We examined patients who attended specialized hospitals for treating addiction, to elucidate the impacts of legal measures to control NPS. Methods Subjects (n = 864) were patients with NPS‐related disorders who received medical treatment at eight specialized hospitals for treating addiction in Japan between April 2012 and March 2015. Clinical information was collected retrospectively from medical records. Results Among psychiatric symptoms, the ratio of hallucinations/delusions decreased over time across 3 years of study (first year vs second year vs third year: 40.1% vs 30.9% vs 31.7%, P = 0.037). Among neurological symptoms, the ratio of coma/syncope increased over the 3‐year period (7.8% vs 11.0% vs 17.0%, P = 0.002), as did the ratio of convulsions (2.8% vs 4.3% vs 9.7%, P = 0.001). Conclusion The symptoms associated with NPS were primarily psychiatric in the first year, while the prevalence of neurological symptoms increased each year. The risk of death and the severity of symptoms were greater in the third year compared with the first year, as regulation of NPS increased., We collected information retrospectively based on medical records and compared with psychiatric and neurological symptoms of NPS users observed in the fiscal year of their first medical examination. We found that adverse health effects resulting from the use of NPS were changed from mainly psychiatric symptoms to neurological symptoms. These findings suggest the possibility that contained more dangerous and toxic compounds after drug‐related regulations had been tightened.

Fatty liver, which has been continuously becoming more common in a number of patients, is the most common liver disease. For detailed analysis, a useful model for fatty liver is needed and fish are considered as a potential candidate. We assessed through direct observation of the liver, which is the most conventional method for non-invasive analysis of progression in fatty liver. By using transparent medaka (Oryzias latipes), we were able to observe changes in fat deposition in the liver. An analysis of the progression of fatty liver using ultrasound showed a significant increase in echo intensity, which indicates that this is a useful examination method. In addition, we clarified a metabolite profile in the medaka liver fed a high-fat diet (HFD), which had not previously been shown in detail. This medaka model, allowing non-invasive and repetitive assessment, is a useful model for the analysis of diseases that cause fatty liver in which changes in detailed metabolites are identified., Summary: Our medaka model allows for non-invasive and repetitive assessment and is useful in the analysis of fatty liver in which changes in detailed metabolites are identified.