Published papers

Aim: No effective pharmacological interventions have been developed for patients with methamphetamine use disorder. Ifenprodil is a blocker of G protein-activated inwardly rectifying potassium channels, which play a key role in the mechanism of action of addictive substances. We conducted a randomized, double‑blind, exploratory, dose-ranging, placebo-controlled trial to examine the clinical efficacy of ifenprodil for the treatment of methamphetamine use disorder. Methods: Participants were assigned to three groups: placebo, 60 mg/d ifenprodil, or 120 mg/d ifenprodil. The drug administration period was 84 days. The primary outcome was the use or nonuse of methamphetamine during the drug administration period in the placebo group vs 120 mg/d ifenprodil group. We also assessed drug use status, relapse risk based on the Stimulant Relapse Risk Scale (SRRS), drug craving, and methamphetamine in urine as secondary outcomes. We further evaluated drug use status and SRRS subscale scores in patients who were not taking addiction medications during the study. Results: Ifenprodil did not affect the primary or secondary outcomes. However, the additional analyses showed that the number of days of methamphetamine use during the follow-up period and scores on the emotionality problems subscale of the SRRS improved in the 120 mg/d ifenprodil group. The safety of ifenprodil was confirmed in patients with methamphetamine use disorder. Conclusion: The present findings did not confirm the efficacy of ifenprodil for methamphetamine use disorder treatment based on the primary or secondary outcomes, but we found evidence of its safety and efficacy in reducing emotionality problems. Clinical trial registration: The study was registered at the University Hospital Medical Information Network Clinical Trial Registry (no. UMIN000030849) and Japan Registry of Clinical Trials (no. jRCTs031180080). The main registration site is jRCT (https://jrct.niph.go.jp/).

Background: The aim of this study was to analyze the nationwide surgical outcome of a left trisectionectomy (LT) and to identify the perioperative risk factors associated with its morbidity. Methods: Cases of LT for hepato-biliary malignancies registered at the Japanese National Clinical Database between 2013 and 2019 were retrospectively reviewed. Statistical analyses were performed to identify the perioperative risk factors associated with a morbidity of Clavien–Dindo classification (CD) ≥III. Results: Left trisectionectomy was performed on 473 and 238 cases of biliary and nonbiliary cancers, respectively. Morbidity of CD ≥III and V occurred in 45% and 5% of cases with biliary cancer, respectively, compared with 26% and 2% of cases with nonbiliary cancer, respectively. In multivariable analyses, biliary cancer was significantly associated with a morbidity of CD ≥III (odds ratio, 1.87; p =.018). In subgroup analyses for biliary cancer, classification of American Society of Anesthesiologists physical status (ASA-PS) 2, portal vein resection (PVR), and intraoperative blood loss ≥30 mL/kg were significantly associated with a morbidity of CD ≥III. Conclusions: Biliary cancer induces severe morbidity after LT. The ASA-PS classification, PVR, and intraoperative blood loss indicate severe morbidity after LT for biliary cancer.

Identification of antisynthetase syndrome (ASS) could be challenging due to inaccessibility and technical difficulty of the serology test for the less common non-Jo-1 antibodies. This study aimed to describe ASS antibody-specific myopathology and evaluate the diagnostic utility of myofiber HLA-DR expression. We reviewed 212 ASS muscle biopsies and compared myopathologic features among subtypes. Additionally, we compared their HLA-DR staining pattern with 602 non-ASS myositis and 140 genetically confirmed myopathies known to have an inflammatory component. We used t-test and Fisher's exact for comparisons and used sensitivity, specificity, positive and negative predictive values to assess the utility of HLA-DR expression for ASS diagnosis. RNAseq performed from a subset of myositis cases and histologically normal muscle biopsies was used to evaluate interferon (IFN)-signaling pathway-related genes. Anti-OJ ASS showed prominent myopathology with higher scores in muscle fiber (4.6 ± 2.0 vs. 2.8 ± 1.8, p = 0.001) and inflammatory domains (6.8 ± 3.2 vs. 4.5 ± 2.9, p = 0.006) than non-OJ ASS. HLA-DR expression and IFN-γ-related genes upregulation were prominent in ASS and inclusion body myositis (IBM). When dermatomyositis and IBM were excluded, HLA-DR expression was 95.4% specific and 61.2% sensitive for ASS with a positive predictive value of 85.9% and a negative predictive value of 84.2%; perifascicular HLA-DR pattern is common in anti-Jo-1 ASS than non-Jo-1 ASS (63.1% vs. 5.1%, p < 0.0001). In the appropriate clinicopathological context, myofiber HLA-DR expression help support ASS diagnosis. The presence of HLA-DR expression suggests involvement of IFN-γ in the pathogenesis of ASS, though the detailed mechanisms have yet to be elucidated.

Objective To identify the characteristic pathologic features of dermatomyositis (DM) associated with anti-Mi-2 autoantibodies (anti-Mi-2 DM).MethodsWe reviewed 188 muscle biopsies from patients (1) pathologically diagnosed with DM through the sarcoplasmic expression for the myxovirus-resistant protein A and (2) serologically positive for 1 of 5 DM-specific autoantibodies (DMSAs) (anti-Mi-2, n = 30; other DMSAs, n = 152) or negative for all 5 DMSAs (n = 6). We then compared the histopathologic and immunohistochemical features of patients with anti-Mi-2 DM to those with non-Mi-2 DM and patients with anti-synthetase syndrome (ASS) (n = 212) using the t test, Fisher exact test, and a logistic regression model.ResultsPatients with anti-Mi-2 DM showed significantly higher severity scores in muscle fiber and inflammatory domains than non-Mi-2 DM patients. The presence of perifascicular necrosis, increased perimysial alkaline phosphatase activity, and sarcolemmal membrane attack complex deposition was more frequent in patients with anti-Mi-2 DM (p < 0.01). After Bonferroni correction, there were no significant differences in the percentages of the features mentioned above between the patients with anti-Mi-2 DM and those with ASS (p > 0.01).ConclusionPerifascicular necrosis and perimysial pathology, features previously reported in ASS, are common in patients with anti-Mi-2 DM. Our findings not only assist in differentiating anti-Mi-2 DM from other DM subtypes but also suggest the possibility of an overlapping mechanism between anti-Mi-2 DM and ASS.Classification of EvidenceThis study provides Class II evidence that the muscle biopsies of DM patients with anti-Mi-2 autoantibodies are more likely to demonstrate higher severity scores in muscle fiber and inflammatory domains.

Aim: The existing predictive risk models for the surgical outcome of acute diffused peritonitis (ADP) need renovation by adding relevant variables such as ADP's definition or causative etiology to pursue outstanding data collection reflecting the real world. We aimed to revise the risk models predicting mortality and morbidities of ADP using the latest Japanese Nationwide Clinical Database (NCD) variable set. Methods: Clinical dataset of ADP patients who underwent surgery, and registered in the NCD between 2016 and 2019, were used to develop a risk model for surgical outcomes. The primary outcome was perioperative mortality. Results: After data cleanup, 45 379 surgical cases for ADP were derived for analysis. The perioperative and 30-day mortality were 10.6% and 7.2%, respectively. The prediction models have been created for the mortality and 10 morbidities associated with the mortality. The top five relevant predictors for perioperative mortality were age >80, advanced cancer with multiple metastases, platelet count of <50 000/mL, serum albumin of <2.0 g/dL, and unknown ADP site. The C-indices of perioperative and 30-day mortality were 0.859 and 0.857, respectively. The predicted value calculated with the risk models for mortality was highly fitted with the actual probability from the lower to the higher risk groups. Conclusions: Risk models for postoperative mortality and morbidities with good predictive performance and reliability were revised and validated using the recent real-world clinical dataset. These models help to predict ADP surgical outcomes accurately and are available for clinical settings.

Aim: We evaluated the morbidity and mortality associated with liver surgery in Japan and developed a risk model for liver resection using information from a national database. Methods: We retrospectively reviewed 73 861 Japanese patients who underwent hepatectomy between 2014 and 2019, using information from the National Clinical Database (NCD) registrations. The primary endpoints were 30 days and in-hospital mortality, and the secondary endpoints were postoperative complications. Logistic regression risk models for postoperative morbidity and mortality after hepatectomy were constructed based on preoperative clinical parameters and types of liver resection, and validated using a bootstrapping method. Results: The 30-day and in-hospital mortality rates were 0.9% and 1.7%, respectively. Trisectionectomy, hepatectomy for gallbladder cancer, hepatectomy for perihilar cholangiocarcinoma, and poor activities of daily living were statistically significant risk factors with high odds ratios for both postoperative morbidity and mortality. Internal validations indicated that the c-indices for 30-day and in-hospital mortality were 0.824 and 0.839, respectively. Conclusions: We developed a risk model for liver resection by using a national surgical database that can predict morbidity and mortality based on preoperative factors.

The number of cancer cases diagnosed during the coronavirus disease 2019 (COVID-19) pandemic has decreased. This study investigated the impact of the pandemic on the clinical practice of hepatocellular carcinoma (HCC) using a novel nationwide REgistry for Advanced Liver diseases (REAL) in Japan. We retrieved data of patients initially diagnosed with HCC between January 2018 and December 2021. We adopted tumor size as the primary outcome measure and compared it between the pre-COVID-19 (2018 and 2019) and COVID-19 eras (2020 and 2021). We analyzed 13,777 patients initially diagnosed with HCC (8074 in the pre-COVID-19 era and 5703 in the COVID-19 era). The size of the maximal intrahepatic tumor did not change between the two periods (mean [SD] = 4.3 [3.6] cm and 4.4 [3.6] cm), whereas the proportion of patients with a single tumor increased slightly from 72.0 to 74.3%. HCC was diagnosed at a similar Barcelona Clinic Liver Cancer stage. However, the proportion of patients treated with systemic therapy has increased from 5.4 to 8.9%. The proportion of patients with a non-viral etiology significantly increased from 55.3 to 60.4%. Although the tumor size was significantly different among the etiologies, the subgroup analysis showed that the tumor size did not change after stratification by etiology. In conclusion, the characteristics of initially diagnosed HCC remained unchanged during the COVID-19 pandemic in Japan, regardless of differences in etiology. A robust surveillance system should be established particularly for non-B, non-C etiology to detect HCC in earlier stages.

Introduction: We previously developed risk models for mortality and morbidity after low anterior resection using a nationwide Japanese database. However, the milieu of low anterior resection in Japan has undergone drastic changes since then. This study aimed to construct risk models for 6 short-term postoperative outcomes after low anterior resection, i.e., in-hospital mortality, 30-day mortality, anastomotic leakage, surgical site infection except for anastomotic leakage, overall postoperative complication rate, and 30-day reoperation rate. Methods: This study enrolled 120,912 patients registered with the National Clinical Database, who underwent low anterior resection between 2014 and 2019. Multiple logistic regression analyses were performed to generate predictive models of mortality and morbidity using preoperative information, including the TNM stage. Results: We developed new risk prediction models for the overall postoperative complication and 30-day reoperation rates for low anterior resection, which were absent from the previous version. The concordance indices for each endpoint were 0.82 for in-hospital mortality, 0.79 for 30-day mortality, 0.64 for anastomotic leakage, 0.62 for surgical site infection besides anastomotic leakage, 0.63 for complications, and 0.62 for reoperation. The concordance indices of all four models included in the previous version showed improvement. Conclusion: This study successfully updated the risk calculators for predicting mortality and morbidity after low anterior resection using a model based on vast nationwide Japanese data.

Background: Centralization of complex surgeries has made little progress when it only considers the minimum number of surgical procedures. We aim to assess the impact of certification system of Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) on centralization and surgical quality of advanced hepato-pancreatic-biliary (HPB) surgery. Methods: The National Clinical Database was used to review 20 111 patients who underwent pancreatoduodenectomy (PD) and 9666 who underwent advanced hepatectomy defined as hepatectomy of more than one section during 2019 and 2020. JSHPBS certifies hospitals based on the annual number of advanced HPB surgeries and the surgical quality. Minimum numbers of surgeries for board-certified A and B institutions are 50 and 30, respectively. Short-term outcomes were compared among institutions. Results: In 2020, 69.4% (7007/10090) and 72.9% (3433/4710) of patients underwent PD and advanced hepatectomy at board-certified institutions. In-hospital mortality rates after PD was 0.9% at certified A institutions, 1.4% at B institutions, and 2.7% at non-certified institutions (p <.001). The odds ratio (OR) of risk-adjusted mortality after PD compared with non-certified institutions was 0.39 (confidence interval [CI]: 0.30–0.50, p <.001) at certified A institutions, and 0.54 at certified B institutions (CI: 0.40–0.73, p <.001). In-hospital mortality rates after advanced hepatectomy was 1.7% at certified A institutions, 2.3% at B institutions, and 3.2% at non-certified institutions (p <.001). The OR of risk-adjusted mortality after advanced hepatectomy compared with non-certified institutions was 0.57 at certified A institutions (CI: 0.41–0.78, p <.001). Conclusion: The volume- and quality-controlled certification system of JSHBPS reduces surgical mortality after advanced HPB surgeries.