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Takashi Hirata, Akitoyo Hishimoto, Ikuo Otsuka, Satoshi Okazaki, Shuken Boku, Atsushi Kimura, Tadasu Horai, Ichiro Sora Department of Psychiatry, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Kobe, Japan Background: Life expectancy is 10–20 years lower in patients with schizophrenia than in the general population. In addition, men with schizophrenia have an earlier age at onset, more pronounced deficit symptoms, poorer course, and poorer response to antipsychotic medications than women. Recent studies have indicated that loss of chromosome Y (LOY) in peripheral blood is associated with an increased risk of all-cause mortality. In order to elucidate the pathophysiology of male-specific features, we investigated the association between LOY and schizophrenia. Materials and methods: The present study included 360 Japanese men (146 patients with schizophrenia vs 214 controls). The relative amount of Y chromosome was defined as the ratio of chromosome Y to chromosome X (Y/X ratio) based on the fluorescent signal of co-amplified short sequences from the Y-X homologous amelogenin genes (AMELY and AMELX). Results: There was no significant difference in the frequency of LOY between the schizophrenia and control groups. However, longer duration of illness was associated with LOY after controlling for age and smoking status in the schizophrenia group (P=0.007, OR =1.11 [95% CI =1.03–1.19]). Conclusion: According to our results, schizophrenia may not have a remarkable effect on blood LOY; however, LOY may be associated with disease course in patients with schizophrenia. Keywords: loss of chromosome Y, schizophrenia, disease duration

Tadasu Horai,1 Akitoyo Hishimoto,1 Ikuo Otsuka,1 Tatsuhiro So,2 Kentaro Mouri,1 Naofumi Shimmyo,1 Shuken Boku,1 Noriaki Okishio,3 Ichiro Sora1 1Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan; 2So Mental Clinic, Kobe, Japan; 3Hyogo Mental Health Center, Kobe, Japan Background: Alcohol dependence induces low bone mineral density (BMD), predicting osteoporosis, while low and moderate alcohol consumption may even increase BMD. In recent years, undercarboxylated osteocalcin (ucOC) and tartrate-resistant acid phosphatase-5b (TRACP-5b), bone turnover markers, have gained special interest as useful indicators of low BMD. However, it remains unclear whether other alcohol-related variables (eg, duration of abstinence and continuous drinking) are linked to aberrant BMD. In addition, no previous study has investigated whether ucOC or TRACP-5b is clinically useful to predict low BMD not only in the general population, but also in alcohol-dependent subjects.Patients and methods: We recruited 275 male alcohol-dependent subjects and collected information about their drinking habits, comorbid diseases, smoking history and walking exercise behavior. BMD in each subject was determined by ultrasonography. Serum liver enzymes (AST, ALT, ALP, ChE, γ-GTP and LDH), ucOC and TRACP-5b were measured in all subjects. T-scores were calculated according to BMD for all subjects.Results: The mean T-scores of our subjects were negatively shifted compared to the general population (-0.75±1.36 SD). We divided our subjects into a normal BMD group (n=137) and a low BMD group (n=138) according to their T-scores (T-score ≥-1 SD, normal BMD; T-score

Naofumi Shimmyo,1 Akitoyo Hishimoto,1 Ikuo Otsuka,1 Satoshi Okazaki,1 Shuken Boku,1 Kentaro Mouri,1 Tadasu Horai,1 Motonori Takahashi,2 Yasuhiro Ueno,2 Osamu Shirakawa,3 Ichiro Sora1 1Department of Psychiatry, 2Division of Legal Medicine, Department of Community Medicine and Social Health Science, Kobe University Graduate School of Medicine, Kobe, 3Department of Neuropsychiatry, Kindai University Faculty of Medicine, Osaka, Japan Background: Numerous studies suggest that inflammation plays a key role in suicidal behavior. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has received increasing attention in depression research. However, no study has investigated whether MIF has genetic involvement in completed suicide. In this study, we sought to explore the relationship between two functional polymorphisms on the MIF gene promoter (MIF-794CATT5–8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) and completed suicide by using one of the largest samples of suicide completers ever reported.Methods: The subjects comprised 602 suicide completers and 728 healthy controls. We genotyped MIF-794CATT5–8 microsatellite by polymerase chain reaction–based size discrimination assay and MIF-173G/C SNP by TaqMan® SNP genotyping assay. The allele-, genotype-, or haplotype-based association analyses between the suicide completers and the controls were carried out with the χ2 test, the Cochran–Armitage trend test, or Fisher’s exact test.Results: Analyses of allele or genotype frequency distributions of the polymorphisms studied here did not reveal any significant differences between the suicide completers and the controls. Haplotype analysis also revealed no association with completed suicide.Conclusion: To our knowledge, this is the first study that has examined the genetic association between MIF and completed suicide. Our results suggest that the effects of MIF-794CATT5–8 microsatellite and MIF-173G/C SNP on the MIF gene promoter might not contribute to the genetic risk of completed suicide in the Japanese population. Keywords: MIF, suicide, microsatellite, SNP, haplotype, promoter region

Hiroyuki Toda,1 Takeshi Inoue,2,3 Tomoya Tsunoda,1 Yukiei Nakai,2 Masaaki Tanichi,1 Teppei Tanaka,1 Naoki Hashimoto,2 Yasuya Nakato,2 Shin Nakagawa,2 Yuji Kitaichi,2 Nobuyuki Mitsui,2 Shuken Boku,4 Hajime Tanabe,5 Masashi Nibuya,1 Aihide Yoshino,1 Ichiro Kusumi2 1Department of Psychiatry, National Defense Medical College, Tokorozawa, Saitama, Japan; 2Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan; 3Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 4Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan; 5Department of Clinical Human Sciences, Graduate School of Humanities and Social Sciences, Shizuoka University, Shizuoka, Japan Background: Previous studies have shown the interaction between heredity and childhood stress or life events on the pathogenesis of a major depressive disorder (MDD). In this study, we tested our hypothesis that childhood abuse, affective temperaments, and adult stressful life events interact and influence the diagnosis of MDD. Patients and methods: A total of 170 healthy controls and 98 MDD patients were studied using the following self-administered questionnaire surveys: the Patient Health Questionnaire-9 (PHQ-9), the Life Experiences Survey, the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire, and the Child Abuse and Trauma Scale (CATS). The data were analyzed with univariate analysis, multivariable analysis, and structural equation modeling. Results: The neglect scores of the CATS indirectly predicted the diagnosis of MDD through cyclothymic and anxious temperament scores of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire in the structural equation modeling. Two temperaments – cyclothymic and anxious – directly predicted the diagnosis of MDD. The validity of this result was supported by the results of the stepwise multivariate logistic regression analysis as follows: three factors – neglect, cyclothymic, and anxious temperaments – were significant predictors of MDD. Neglect and the total CATS scores were also predictors of remission vs treatment-resistance in MDD patients independently of depressive symptoms. Limitations: The sample size was small for the comparison between the remission and treatment-resistant groups in MDD patients in multivariable analysis. Conclusion: This study suggests that childhood abuse, especially neglect, indirectly predicted the diagnosis of MDD through increased affective temperaments. The important role as a mediator of affective temperaments in the effect of childhood abuse on MDD was suggested. Keywords: neglect, major depressive disorder, affective temperament, mediator

Ikuo Otsuka,1 Yuichiro Watanabe,2 Akitoyo Hishimoto,1 Shuken Boku,1 Kentaro Mouri,1 Kyoichi Shiroiwa,1 Satoshi Okazaki,1 Ayako Nunokawa,2 Osamu Shirakawa,3 Toshiyuki Someya,2 Ichiro Sora1 1Department of Psychiatry, Graduate School of Medicine, Kobe University, Kobe, 2Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, 3Department of Neuropsychiatry, School of Medicine, Kinki University, Osaka, Japan Background: Cadherin13 (CDH13) is a glycosylphosphatidylinositol-anchored cell adhesion molecule that plays a crucial role in morphogenesis and the maintenance of neuronal circuitry. CDH13 has been implicated in the susceptibility to a variety of psychiatric diseases. A recent genome-wide association study using Danish samples showed, for the first time, the involvement of a single nucleotide polymorphism (SNP) of CDH13 (intronic SNP rs8057927) in schizophrenia. Here, we investigated the association between other SNPs of CDH13 and schizophrenia and tried to replicate the association for the SNP of rs8057927, in the Japanese population.Methods: Using TaqMan® SNP genotyping assays, five tag SNPs (rs12925602, rs7193788, rs736719, rs6565051, and rs7204454) in the promoter region of CDH13 were examined for their association with schizophrenia in two independent samples. The first sample comprised 665 patients and 760 controls, and the second sample comprised 677 patients and 667 controls. One tag SNP for rs8057927 was also examined for the association with schizophrenia in the first sample set.Results: A GACAG haplotype of the five SNPs in the promoter region of CDH13 was significantly associated with schizophrenia in the first sample set (P=0.016 and corrected P=0.098). A combined analysis of the GACAG haplotype with the second sample set enhanced the significance (P=0.0026 and corrected P=0.021). We found no association between rs8057927 and schizophrenia in the first sample set.Conclusion: Our results suggest that CDH13 may contribute to the genetic risk of schizophrenia. Further replication on the association of CDH13 with schizophrenia and functional studies are required to confirm the current findings. Keywords: CDH13, promoter region, haplotype, SNP

Yuji Kitaichi, Takeshi Inoue, Shin Nakagawa, Shuken Boku, Akiko Kato, Ichiro Kusumi, Tsukasa KoyamaDepartment of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, JapanBackground: Up to 30% of depressed patients are partially or totally resistant to antidepressant therapy. The administration of triiodothyronine (T3) to antidepressant nonresponders can be an effective augmentation strategy, although the mechanism is not fully understood.Methods: In vivo microdialysis was used to examine the effect of T3 augmentation of the antidepressant, milnacipran. Basal extracellular serotonin, norepinephrine, and dopamine levels were measured before and after acute milnacipran administration in the medial prefrontal cortex and amygdala of rats which had received subchronic (7 days) T3 treatment or control saline.Results: Subchronic administration of T3 at 0.1 mg/kg significantly increased basal extracellular levels of serotonin in the medial prefrontal cortex, but not in the amygdala. In contrast, subchronic administration of T3 at 0.2 mg/kg did not alter basal extracellular serotonin levels in the medial prefrontal cortex. Basal extracellular levels of norepinephrine and dopamine were not modified by either dose of T3 in either region. Acute administration of milnacipran, a serotonin-norepinephrine reuptake inhibitor, to control animals resulted in a significant increase of extracellular levels of serotonin, norepinephrine, and dopamine. When administered to animals treated subchronically with T3 at 0.1 mg/kg, milnacipran produced an additional increase in extracellular serotonin levels but not in levels of norepinephrine or dopamine in the medial prefrontal cortex of rats.Conclusion: These results suggest that the mechanism of the augmentation effect of milnacipran by T3 administration occurs via enhancement of serotonergic neurotransmission, but not through noradrenergic or dopaminergic neurotransmission.Keywords: depression, in vivo microdialysis, milnacipran, monoamines, triiodothyronine

The purpose of this article is to discuss the inter-urban linkage between the non-capital cities in Korea and Japan, focusing on the relationships between Fukuoka and Busan, as part of an empirical research on the internationalization of non-capital cities in East Asia. We attempt to subdivide international trade activities of firms and analyze foreign destinations based on cities. The linkage between Busan and Fukuoka mainly sits at the apex of the international urban system, from the perspective of the gateway of 'Physical Distribution' and 'Business Trip'; however, links to Tokyo and Osaka mostly act as 'Transaction' and functional cores such as sales channels. Fukuoka airport and Shimonoseki port have been utilized as a gateway. Fukuoka Airport has a promising evaluation concerning accessibility and convenience. Shimonoseki port has certain advantages due to the short time required for customs formalities, brevity of the shipping time and convenient daily shipping schedules.

Abstract Background The Patient Health Questionnaire-9 (PHQ-9), despite its excellent reliability and validity in primary care, has not been examined for administration to psychiatric patients. This study assesses the accuracy of PHQ-9 in screening for major depressive episode and in diagnosing major depressive episode in patients of a psychiatric specialty clinic. Methods We compared operational characteristics of PHQ-9 as a screening and diagnostic instrument to DSM-IV-TR diagnosis by a trained psychiatrist as a reference standard. The reference criteria were “current major depressive episode” or “current major depressive episode with major depressive disorder”. PHQ-9 was used with two thresholds: diagnostic algorithm and summary scores (PHQ-9 ≥ 10). The optimal cut-off points of PHQ-9 summary scores were analyzed using a receiver operational characteristics (ROC) curve. Results For “current major depressive episode”, PHQ-9 showed high sensitivity and high negative predictive value at both thresholds, but its specificity and positive predictive value were low. For “current major depressive episode with major depressive disorder”, PHQ-9 also showed high sensitivity and high negative predictive value at both thresholds, but the positive predictive value decreased more than that for “current major depressive episode”. The ROC analysis showed the optimal cut-off score of 13/14 for “current major depressive episode”. Conclusions PHQ-9 is useful for screening, but not for diagnosis of “current major depressive episode” in a psychiatric specialty clinic.

Abstract Background Causative role of encephalitis in major psychotic features, dyskinesias (particularly orofacial), seizures, and autonomic and respiratory changes has been recently emphasized. These symptoms often occur in young females with ovarian teratomas and are frequently associated with serum and CSF autoantibodies to the NMDA receptor (NMDAR). Methods The study included a total of 61 patients from age 15 to 61 and was carried out between January 1, 2005, and Dec 31, 2010. The patients were divided into the following three clinical groups for comparison. Group A; Patients with typical clinical characteristics of anti-NMDAR encephalitis. Group B; Patients with narcolepsy with severe psychosis. Group C; Patients with schizophrenia or schizo-affective disorders. Results Ten out of 61 cases were anti-NMDAR antibody positive in typical encephalitis cases (group A: 3 of 5 cases) and cases in a broader range of psychiatric disorders including narcolepsy (group B: 3 of 5 cases) and schizophrenia (group C: 4 of 51 cases). Conclusion In addition to 3 typical cases, we found 7 cases with anti-NMDAR antibody associated with various psychotic and sleep symptoms, which lack any noticeable clinical signs of encephalitis (seizures and autonomic symptoms) throughout the course of the disease episodes; this result suggest that further discussion on the nosology and pathophysiology of autoimmune-mediated atypical psychosis and sleep disorders is required.

The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multiomics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% have participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% CI, 13.4-16.3) for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83). Significance: Our nationwide molecular profiling initiative played pivotal roles in facilitating the enrollment of patients with advanced solid tumors into matched clinical trials and highlighted the substantial survival benefits of patients treated with matched therapy. We aim to facilitate an industry-academia data-sharing infrastructure ecosystem, fostering new drug discovery paradigms and precision medicine., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: To investigate an association between the gut microbiome and efficacy of poly(ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer., Methods: This study conducted fecal microbiome analysis (16S rRNA gene sequencing) and circulating tumor DNA (ctDNA) profiling for ovarian cancer patients who underwent PARPi maintenance therapy. Fecal and blood samples were collected at the baseline and the progressive disease (PD) or last follow-up. The relative abundance of gut microbes and progression-free survival (PFS) were analyzed using linear discriminant analysis of effect size and the Cox proportional hazard model according to BRCA1 / 2 mutation ( BRCA1 / 2 mut) status detected by ctDNA sequencing., Results: Baseline samples were available from 23 BRCA1 / 2 mut-positive patients and 33 BRCA1/2 mut-negative patients. The microbes enriched in the baseline samples with long PFS were Bifidobacterium , Roseburia , Dialister , Butyricicoccus , and Bilophila for BRCA1/2 mut-positive patients and Phascolarctobacterium for BRCA1/2 mut-negative patients. In multivariate analyses dividing patients by the median values of relative abundances, no bacteria were associated with PFS in BRCA1/2 mut-positive patients, whereas high Phascolarctobacterium abundances (≥1.11%) was significantly associated with longer PFS in BRCA1/2 mut-negative patients (median 14.0 vs. 5.9 months, hazard ratio=0.28; 95% confidence interval=0.11-0.69; p=0.014). In the last samples, the relative abundances of Phascolarctobacterium were significantly higher in patients without PD (n=5) than those with PD (n=15) (median 1.25% vs. 0.06%; p=0.016)., Conclusion: High fecal composition of Phascolarctobacterium was associated with prolonged PFS in patients with BRCA1/2 mut-negative ovarian cancer receiving PARPi therapy. Our results would provide new insights for future research., Competing Interests: Mika Okazawa-Sakai declares no competing interests. Shunsuke A. Sakai declares no competing interests. Ichinosuke Hyodo reports advisory roles for Asahi-Kasei, Ono, Taiho, Chugai, and Eisai Pharmaceutical Companies. Satoshi Horasawa declares no competing interests. Kentaro Sawada declares no competing interests. Takao Fujisawa reports honoraria from Amelieff Co. Ltd. Yasuko Yamamoto declares no competing interests. Shogen Boku reports honoraria from Nippon Kayaku Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bristol-Myers Squibb Japan, and MSD. Yoh Hayasaki declares no competing interests. Masanori Isobe declares no competing interests. Daisuke Shintani declares no competing interests. Kosei Hasegawa reports honoraria from AstraZeneca, GSK, MSD, and Takeda; advisory role for GSK, MSD, and Takeda; research grants from MSD. Tomomi Egawa-Takata declares no competing interests. Kimihiko Ito reports honoraria from AstraZeneca. Kei Ihira declares no competing interests. Hidemichi Watari reports honoraria from AstraZeneca, Takeda, MSD, and Chugai. Kazuhiro Takehara reports honoraria from AstraZeneca, Takeda, MSD, Chugai, Eisai, and Sanofi. Hiroshi Yagi declares no competing interests. Kiyoko Kato declares no competing interests. Tatsuyuki Chiyoda reports research grants from Takeda Pharmaceutical Company. Kenichi Harano reports honoraria from AstraZeneca, Chugai, Eizai, MSD, Taiho and Takeda, and advisory roles for AstraZeneca, Chugai, Eizai, Taiho and Takeda. Yoshiaki Nakamura declares advisory role from Guardant Health Pte Ltd., Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Exact Sciences Corporation, Gilead Sciences, Inc.; speakers' bureau from Guardant Health Pte Ltd., MSD K.K., Eisai Co., Ltd., Zeria Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., CareNet, Inc., Hisamitsu Pharmaceutical Co., Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Becton, Dickinson and Company, Guardant Health Japan Corp; research funding from Seagen, Inc., Genomedia Inc., Guardant Health AMEA, Inc., Guardant Health, Inc., Tempus Labs, Inc., Roche Diagnostics K.K., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd. Riu Yamashita declares no competing interests. Takayuki Yoshino reports honoraria from Chugai Pharma, Takeda Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical and MSD K. K.; consulting fees from Sumitomo Corp.; and research grants from Amgen, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia Inc., Medical & Biological Laboratories, Merus N.V., Molecular Health, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer, Roche Diagnostics, Sanofi, Sysmex, Taiho and Takeda. Daisuke Aoki reports honoraria from AstraZeneca, Takeda, MSD, Chugai, and Myriad Genetics., (© 2025. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Purpose: HER2-targeted therapies in ERBB2-amplified metastatic colorectal cancer (mCRC) are effective; however, a notable portion of patients do not respond to treatment, and secondary resistance occurs in most patients receiving these treatments. The purpose of this study was to investigate determinants of treatment efficacy and resistance in patients with ERBB2-amplified mCRC who received HER2-targeted therapy by analyzing multiomics data., Experimental Design: We investigated genomic data from a nationwide large cancer genomic screening project, the SCRUM-Japan project. We analyzed paired genome and transcriptome data of tissue and genomic data of ctDNA collected pre- and postprogression in patients enrolled in the related trial, TRIUMPH, in ERBB2-amplified mCRC., Results: In 155 patients with ERBB2-amplified solid tumors who received HER2-targeted therapy based on the SCRUM-Japan project, the objective response rate was 50%, 51%, and 35% in ERBB2 wild-type, variant of unknown significance, and pathogenic variant groups, respectively. In the paired genome and transcriptome data analyses in TRIUMPH, we identified the novel splicing-associated variant c.644-66_-2del in one of the 11 patients with paired whole-exome sequencing and whole-transcriptome sequencing data sets, which lacks the binding domain of pertuzumab, in progressed metastatic tumor as a variant with potential pathogenicity. The time-course ctDNA analysis detected c.644-66_-2del as an acquired variant., Conclusions: This study highlighted the importance of ERBB2 genomic status when evaluating the efficacy of HER2-targeted therapies in ERBB2-amplified mCRC. The identification of a novel splicing-associated variant may provide insights into potential mechanisms of treatment resistance. Furthermore, we demonstrated the utility of ctDNA to follow the acquired genomic status of mCRC tumors., (©2024 The Authors; Published by the American Association for Cancer Research.)

The prognosis of HER2-positive breast cancer (BC) has improved with the development of anti-HER2 therapies; however, the problem remains that there are still cases where anti-HER2 therapies do not respond well. We found that the expression of SREBF2, a master transcriptional factor in the mevalonate pathway, was correlated with ERBB2 (HER2) expression and a poor prognosis in HER2-positive BC. The target gene expressions of SREBF2 were associated with higher expression of ERBB2 in HER2-positive BC cells. Statins, anti-hypercholesterolemia drugs that inhibit the mevalonate pathway, enhanced the efficacy of HER2-targeting agents with inducing apoptosis in a geranylgeranylation-dependent manner. Mechanistically, statins specifically inhibited membrane localization of Rac1, a target protein of geranylgeranylation, and suppressed the activation of HER2 downstreams AKT and ERK pathways. Consistently, retrospective analysis showed a longer recurrence-free survival in Rac1-high/HER2-positive BC patients treated with HER2-targeting agents with statins than without statins. Our findings thus suggest that Rac1 expression could be used as a biomarker to stratify HER2-positive BC patients that could benefit from dual blockade, i.e., targeting HER2 with inhibition of geranylgeranylation of Rac1 using statins, thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive BC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Isao Yokota reports a relationship with KAKENHI that includes: funding grants. Isao Yokota reports a relationship with Japan Agency for Medical Research and Development (AMED) that includes: funding grants. Isao Yokota reports a relationship with Government of Japan Ministry of Health Labour and Welfare Policy Research Grants that includes: funding grants. Isao Yokota reports a relationship with Nihon Medi-Physics Co., Ltd. that includes: funding grants. Isao Yokota reports a relationship with Chugai Pharmaceutical Co., Ltd. that includes: speaking and lecture fees. Isao Yokota reports a relationship with AstraZeneca K.K. that includes: speaking and lecture fees. Isao Yokota reports a relationship with Pfizer K.K. that includes: speaking and lecture fees. Shogen Boku reports a relationship with Amgen Inc. that includes: funding grants. Shogen Boku reports a relationship with Ono Pharmaceutical Co., Ltd. that includes: funding grants. Shogen Boku reports a relationship with Taiho Pharmaceutical Co., Ltd. that includes: funding grants and speaking and lecture fees. Shogen Boku reports a relationship with AstraZeneca K.K. that includes: funding grants. Shogen Boku reports a relationship with Kyo-diagnostics Co., Ltd. that includes: funding grants. Shogen Boku reports a relationship with Nippon Kayaku Co., Ltd. that includes: speaking and lecture fees. Shogen Boku reports a relationship with MSD K.K. that includes: speaking and lecture fees. Shogen Boku reports a relationship with BMS K.K. that includes: speaking and lecture fees. Shogen Boku reports a relationship with Eisai Co., Ltd. that includes: speaking and lecture fees. Shogen Boku reports a relationship with Chugai Pharmaceutical Co., Ltd. that includes: speaking and lecture fees. Yasuto Naoi reports a relationship with Sysmex Corp that includes: speaking and lecture fees. Yasuto Naoi reports a relationship with Ono Pharmaceutical Co., Ltd. that includes: funding grants and speaking and lecture fees. Yasuto Naoi reports a relationship with Daiichi Sankyo Co., Ltd. that includes: funding grants and speaking and lecture fees. Yasuto Naoi reports a relationship with AstraZeneca K.K. that includes: funding grants and speaking and lecture fees. Yasuto Naoi reports a relationship with Pfizer K.K. that includes: speaking and lecture fees. Yasuto Naoi reports a relationship with Eli Lilly K.K. that includes: speaking and lecture fees. Yasuto Naoi reports a relationship with Chugai Pharmaceutical Co., Ltd. that includes: speaking and lecture fees. Yasuto Naoi has patent #Curebest™ 95GC Breast (JP.5725274.B2) licensed to Sysmex Corp. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aimed to evaluate the clinical impact of preoperative endoscopic ultrasound-guided tissue acquisition (EUS-TA) on the prognosis and incidence of positive peritoneal lavage cytology (PLC) during laparotomy or staging laparoscopy in patients with resectable (R) or borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC)., Methods: We retrospectively collected data from patients diagnosed with body and tail PDAC with/without EUS-TA at our hospital from January 2006 to December 2021., Results: To examine the effect of EUS-TA on prognosis, 153 patients (122 in the EUS-TA group, 31 in the non-EUS-TA group) were analyzed. There was no significant difference in overall survival between the EUS-TA and non-EUS-TA groups after PDAC resection (P = 0.777). In univariate and multivariate analysis, preoperative EUS-TA was not identified as an independent factor related to overall survival after pancreatectomy [hazard ratio 0.96, 95 % confidence interval (CI) 0.54-1.70, P = 0.897]. Next, to examine the direct influence of EUS-TA on the results of PLC, 114 patients (83 in the EUS-TA group and 31 in the non-EUS-TA group) were analyzed. Preoperative EUS-TA was not statistically associated with positive PLC (odds ratio 0.73, 95 % CI 0.25-2.20, P = 0.583). After propensity score matching, overall survival and positive PLC were the same in both groups., Conclusions: EUS-TA had no negative impact on postoperative survival and PLC-positive rates in R/BR PDAC., Competing Interests: Declaration of competing interest All authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2024. Published by Elsevier B.V.)

Although phase III randomized controlled trials (RCTs) represent the most robust statistical approach for answering clinical questions, they require massive expenditures in terms of time, labor, and funding. Ancillary and supplementary analyses using RCTs are sometimes conducted as alternative approaches to answering clinical questions, but the available integrated databases of RCTs are limited. In this background, the Colorectal Cancer Study Group (CCSG) of the Japan Clinical Oncology Group (JCOG) established a database of ancillary studies integrating four phase III RCTs (JCOG0212, JCOG0404, JCOG0910 and JCOG1006) conducted by the CCSG to investigate specific clinicopathological factors in pStage II/III colorectal cancer (JCOG2310A). This database will be updated by adding another clinical trial data and accelerating several analyses that are clinically relevant in the management of localized colorectal cancer. This study describes the details of this database and planned and ongoing analyses as an initiative of JCOG cOlorectal Young investigators (JOY)., Competing Interests: Declaration of competing interest None declared., (© 2024 Published by Elsevier Ltd.)

Background: Immuno-oncology (IO) drugs are essential for treating various cancer types; however, safety concerns persist in older patients. Although the incidence of immune-related adverse events (irAEs) is similar among age groups, higher rates of hospitalization or discontinuation of IO therapy have been reported in older patients. Limited research exists on IO drug safety and risk factors in older adults. Our investigation aimed to assess the incidence of irAEs and identify the potential risk factors associated with their development., Methods: This retrospective analysis reviewed the clinical data extracted from the medical records of patients aged > 80 years who underwent IO treatment at our institution. Univariate and multivariate analyses were performed to assess the incidence of irAEs., Results: Our study included 181 patients (median age: 82 years, range: 80-94), mostly men (73%), with a performance status of 0-1 in 87% of the cases; 64% received IO monotherapy. irAEs occurred in 35% of patients, contributing to IO therapy discontinuation in 19%. Our analysis highlighted increased body mass index, eosinophil counts, and albumin levels in patients with irAEs. Eosinophil count emerged as a significant risk factor for any grade irAEs, particularly Grade 3 or higher, with a cutoff of 118 (/μL). The group with eosinophil counts > 118 had a higher frequency of irAEs, and Grade 3 or higher events than the group with counts ≤ 118., Conclusion: IO therapy is a safe treatment option for patients > 80 years old. Furthermore, patients with elevated eosinophil counts at treatment initiation should be cautiously managed., (© 2024. The Author(s).)

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy., Methods/design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years., Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC., Competing Interests: Conflicts of Interest KK received lecture fees from Merck, Takeda, and Eli Lilly, and research funds from Sysmex Corporation. JF is an employee of the Sysmex Inostics GmbH. MS received lecture fees from Merck, Takeda, Yakult, Ono, and Eli Lilly. JW received lecture fees from Eli Lilly and Takeda. TK received lecture fees from Daiichi Sankyo, Taiho, Bristol-Myers Squibb, Ono, and Eli Lilly. NM received lecture fees from Takeda and scholarship endowments from Yakult. KY received lecture fees from Merck, Takeda, Chugai, Taiho, Yakult, Ono, Eli Lily, MSD and Bristol. KM received lecture fees from Chugai, Ono, Daiichi Sankyo and Eli Lilly. The rest of the authors do not have any conflicts of interest., (Copyright © 2024 The Japan Society of Coloproctology.)