Search

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.

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: Although serum carbohydrate antigen 19-9 (CA19-9) is widely used as a useful biomarker of pancreatic cancer for monitoring the response to therapy, it is not recommended for screening of early pancreatic cancer because of its limited sensitivity for small tumors. Thus, it is critical to discover novel serum biomarkers to complement CA19-9 in order to improve sensitivity. Although methylated runt-related transcription factor 3 (RUNX3) is a biomarker of pancreatic cancer, its detection by conventional bisulfite-based methylation assays from a small serum sample amount is very difficult. Therefore, we developed a new methylation assay, the combined restriction digital PCR (CORD) assay, that enables counting of even one copy of a methylated gene in a small DNA sample amount without DNA bisulfite treatment. Objectives: We evaluated the sensitivity and specificity of serum DNA testing of methylated RUNX3 by the CORD assay in combination with and without CA19-9 for the detection of pancreatic cancer in 55 patients with pancreatic cancer, 12 patients with benign pancreatic disease, and 80 healthy individuals. Results: The CORD assay of methylated RUNX3 had a sensitivity of 50.9% (28/55) and specificity of 93.5% (86/92). Combination of the CORD assay of methylated RUNX3 and CA19-9 resulted in a sensitivity of 85.5% (47/55) and specificity of 93.5% (86/92) for all stages of pancreatic cancer and a sensitivity of 77.8% (7/9) for stage I pancreatic cancer. Conclusions: ombination of the CORD assay and CA19-9 may provide an alternative screening strategy for detecting early-stage pancreatic cancer.

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.

Background: The term “addiction” encompasses both substance dependence and behavioral addiction and is associated with major societal problems. Measures to combat addiction are currently insufficient in Japan, and further research on addiction is necessary. Methods: Science Council of Japan (SCJ) has three subcommittees – the Addiction Subcommittee, Brain and Mind Subcommittee, and Neuroscience Subcommittee among others. Those three subcommittees are dealing directly or indirectly with addiction problems in Japan. Thus, all authors of this review, members of those subcommittees, collectively recommended what research activities are required in Japan for continuing effort in overcoming addiction problems in Japan. Results: We proposed the following measures. Proposal 1: Understand diversity in addiction and promote related research and education; Proposal 2: Promote personalized measures for patients with addiction disorders; Proposal 3: Foster addiction research personnel; Proposal 4: Develop new guidelines for the rehabilitation of patients with drug dependence; Proposal 5: Establish an institute specializing in addiction research and comprehensively handling information collection, research, countermeasures, treatment, and public relation related to addiction. Conclusion: The opinions of the review are based on the recommendations that were published in 2020 in Japanese by the Addiction Subcommittee, Brain and Mind Subcommittee, and Neuroscience Subcommittee of the SCJ. The authors here are sharing colleagues of Taiwanese Society of Psychiatry with these proposed research activities required to overcome addiction problems in Japan.

Liver transplantation is the only radical treatment for decompensated cirrhosis, but its use is limited owing to a shortage of donors; hence, there is an urgent need for new treatments. Previously, we developed a liver-regeneration therapy using autologous bone marrow-derived mesenchymal stem cells (BMSCs), which is under clinical investigation. Cell-cell interactions between BMSCs and macrophages (Mφs) participate in the improvement of liver function and alleviation of liver fibrosis, although the associated mechanisms have not been elucidated. Therefore, in this study, we investigated phenotypic changes in Mφs caused by interactions with BMSCs, as well as the underlying mechanisms. Co-culturing lipopolysaccharide (LPS)-stimulated murine bone marrow-derived Mφs (BMDMs) with BMSCs substantially upregulated matrix metalloproteinase 9 (

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.

Background Iron is required for cellular metabolism, and rapidly proliferating cancer cells require more of this essential nutrient. Therefore, iron regulation may well represent a new avenue for cancer therapy. We have reported, through in vitro and in vivo research involving pancreatic cancer cell lines, that the internal-use, next-generation iron chelator deferasirox (DFX) exhibits concentration-dependent tumour-suppressive effects, among other effects. After performing a microarray analysis on the tumour grafts used in that research, we found that DFX may be able to suppress the cellular movement pathways of pancreatic cancer cells. In this study, we conducted in vitro analyses to evaluate the effects of DFX on the invasive and migratory abilities of pancreatic cancer cells. Methods We used pancreatic cancer cell lines (BxPC-3, Panc-1, and HPAF II) to examine the efficacy of DFX in preventing invasion in vitro, evaluated using scratch assays and Boyden chamber assays. In an effort to understand the mechanism of action whereby DFX suppresses tumour invasion and migration, we performed G-LISA to examine the activation of Cdc42 and Rac1 which are known for their involvement in cellular movement pathways. Results In our scratch assays, we observed that DFX-treated cells had significantly reduced invasive ability compared with that of control cells. Similarly, in our Boyden chamber assays, we observed that DFX-treated cells had significantly reduced migratory ability. After analysis of the Rho family of proteins, we observed a significant reduction in the activation of Cdc42 and Rac1 in DFX-treated cells. Conclusions: DFX can suppress the motility of cancer cells by reducing Cdc42 and Rac1 activation. Pancreatic cancers often have metastatic lesions, which means that use of DFX will suppress not only tumour proliferation but also tumour invasion, and we expect that this will lead to improved prognoses.

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

Mesenchymal stem cells, which have the potential to be used in regenerative medicine, require improvements in quality for patient use. To maintain stemness of cultured bone marrow-derived mesenchymal stem cells, we focused on the bone marrow microenvironment, generated a conditioned medium of whole bone marrow cells (BMC-CM), and assessed its effects on bone marrow-derived mesenchymal stem cells. BMC-CM suppressed morphological deterioration and proliferative decline in cultured bone marrow-derived mesenchymal stem cells, suppressed mitochondrial oxidative phosphorylation activity, a stemness indicator, and upregulated suppressors of oxidative phosphorylation such as hypoxia-inducible factor-1 alpha, Sirtuin 3, 4, and 5. Furthermore, BMC-CM upregulated TNF-stimulated gene 6 and ameliorated the therapeutic effects of cells on liver injury in carbon tetrachloride-administered rats. Since the elimination of 20-220-nm particles attenuated the effects of BMC-CM, we further analyzed exosomal microRNAs produced by whole bone marrow cells. Among the 49 microRNAs observed to be upregulated during the preparation of BMC-CM, several were identified that were associated with suppression of oxidative phosphorylation, upregulation of TNF-stimulated gene 6, and the pathogenesis of liver diseases. Thus, bone marrow-derived humoral factors including exosomal microRNAs may help to improve the therapeutic quality of bone marrow-derived mesenchymal stem cells for liver regenerative therapy.

Introduction: Altered dopaminergic neurotransmission, especially in the functioning of dopamine D2-type receptors, is considered central to the etiology of a variety of neuropsychiatric disorders. In particular, individuals with substance use disorders have been consistently observed to exhibit lower D2-type receptor availability (quantified as binding potential; BPND) using positron emission tomography (PET). Upregulation of D2-type receptor density thus may therefore provide a therapeutic effect for substance use disorders. Importantly, in vitro studies reveal that D2 receptors coexist with adenosine 2A (A2A) receptors to form the highest density of heteromers in the whole striatum, and there is a functional interaction between these two receptors. As such, blockade of A2A receptor’s function may prevent D2 receptor downregulation, yet no study has currently examined this hypothesis in humans.Methods and Analysis: This double-blind, randomized controlled trial aims to evaluate the effect of the A2A receptor antagonist istradefylline (compared to placebo) on both dopamine D2-type receptor availability in the human brain and on neuropsychological measurements of impulsivity. It is hypothesized that istradefylline will both increase striatal D2-type BPND and improve control of impulsivity more than placebo. Forty healthy participants, aged 20–65 with no history of psychiatric or neurological disorders, will be recruited and randomized into two groups and will undergo [11C]raclopride PET, once before and once after administration of either 40 mg/day istradefylline or placebo for 2 weeks. Neuropsychological measurements will be administered on the same days of the PET scans.Ethics and Dissemination: The study protocol was approved by the Certified Review Boards (CRB) of National Center of Neurology and Psychiatry (CR18-011) and prospectively registered with the Japan Registry of Clinical Trials (jRCTs031180131; https://jrct.niph.go.jp/latest-detail/jRCTs031180131). The findings of this study will be disseminated through peer reviewed scientific journals and conferences.Clinical Trial Registration:www.ClinicalTrials.gov, identifier jRCTs031180131.

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.

Differences in the culturing conditions of mesenchymal stem cells used in regenerative medicine may affect their differentiation ability, genome instability, and therapeutic effects. In particular, bone marrow-derived mesenchymal stem cells cultured under hypoxia are known to proliferate while maintaining an undifferentiated state and the use of deferoxamine, a hypoxia mimetic reagent, has proven to be a suitable strategy to maintain the cells under hypoxic metabolic state. Here, the deferoxamine effects were investigated in mesenchymal stem cells to gain insights into the mechanisms regulating stem cell survival. A 12-h deferoxamine treatment reduced proliferation, oxygen consumption, mitochondrial activity, and ATP production. Microarray analysis revealed that deferoxamine enhanced the transcription of genes involved in glycolysis and the HIF1α pathway. Among the earliest changes, transcriptional variations were observed in HIF1α, NUPR1, and EGLN, in line with previous reports showing that short deferoxamine treatments induce substantial changes in mesenchymal stem cells glycolysis pathway. NUPR1, which is induced by stress and involved in autophagy-mediated survival, was upregulated by deferoxamine in a concentration-dependent manner. Consistently, NUPR1 knockdown was found to reduce cell proliferation and increase the proapoptotic effect of staurosporine, suggesting that deferoxamine-induced NUPR1 promotes mesenchymal stem cell survival and cytoprotective autophagy. Our findings may substantially contribute to improve the effectiveness of mesenchymal stem cell-based regenerative medicine.

This study aimed to examine the relationship between methamphetamine (MA) use and high-risk sexual behavior among newly incarcerated prisoners in Japan. We conducted a secondary analysis using cross-sectional survey data, which constituted a nationwide prison sample surveyed between July and November 2017. In total, 699 participants (462 male and 237 female prisoners), who completed the self-administered questionnaire during imprisonment were recruited for the study. The prevalence of high-risk sexual behaviors was as follows: inconsistent condom use (78.4% male, 81.7% female), multiple sexual partners (61.3% male, 41.3% female), history of sexually transmitted diseases (14.1% male, 23.6% female), and trading sex for drugs (15.6% male, 17.7% female). A logistic regression analysis showed that MA use during sex increased the likelihood of high-risk sexual behavior in both male (adjusted odds ratio [AOR] = 5.86; 95% confidence interval [CI] = 3.41-10.07) and female prisoners (AOR = 2.58; 95% CI = 1.33-5.00). Additionally, in female prisoners, a history of sharing MA injection (AOR = 1.60; 95% CI = 1.06-2.42) increased high-risk sexual behavior. Our results indicate that harm reduction programs tailored according to the specific necessities of each gender to reduce high-risk sexual behaviors among MA users should be included in Japanese drug policies.

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.

In human hair follicles, the hair‐forming cells express 16 hair keratin genes depending on the differentiation stages. K85 and K35 are the first hair keratins expressed in cortical cells at the early stage of the differentiation. Two types of mutations in the gene encoding K85 are associated with ectodermal dysplasia of hair and nail type. Here, we transfected cultured SW‐13 cells with human K85 and K35 genes and characterized filament formation. The K85–K35 pair formed short filaments in the cytoplasm, which gradually elongated and became thicker and entangled around the nucleus, indicating that K85–K35 promotes lateral association of short intermediate filaments (IFs) into bundles but cannot form IF networks in the cytoplasm. Of the K85 mutations related to ectodermal dysplasia of hair and nail type, a two‐nucleotide (C1448T1449) deletion (delCT) in the protein tail domain of K85 interfered with the K85–K35 filament formation and gave only aggregates, whereas a missense mutation (233A>G) that replaces Arg78 with His (R78H) in the head domain of K85 did not interfere with the filament formation. Transfection of cultured MCF‐7 cells with all the hair keratin gene combinations, K85–K35, K85(R78H)–K35 and K85(delCT)–K35, as well as the individual hair keratin genes, formed well‐developed cytoplasmic IF networks, probably by incorporating into the endogenous cytokeratin IF networks. Thus, the unique de novo assembly properties of the K85–K35 pair might play a key role in the early stage of hair formation., We transfected SW‐13 cells with human hair keratin K85 and K35 genes. This pair formed short filaments in the cytoplasm, which gradually elongated, became thicker and entangled around the nucleus, indicating that K85–K35 promotes lateral association of short intermediate filaments into bundles but cannot form filament networks in the cytoplasm. Two K85 mutants related to ectodermal dysplasia were also tested.

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.

AIM This was an exploratory study to examine the factors influencing nursing home placement (NHP) in Japan. METHODS For this analysis, 633 patients were selected. The data were collected from the clinical records of each patient. A log-rank test was performed. The time from the patient's first visit to the clinic until the nursing home placement was the independent variable. Age (

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.