Safety of immune checkpoint inhibitors in patients aged over 80 years: a retrospective cohort study.

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.

Varying impact of lenvatinib or sorafenib therapy on skeletal muscle loss in patients with hepatocellular carcinoma.

BACKGROUND: Lenvatinib and sorafenib are key therapeutic agents for hepatocellular carcinoma. However, there are no useful biomarkers for selecting molecular-targeted agents (MTAs). Skeletal muscle volume is associated with the clinical outcomes in these patients. We investigated the effects of lenvatinib and sorafenib on the skeletal muscles of patients with HCC. METHODS: We evaluated the impact of skeletal muscle changes over a 3-month period for each MTA (n = 117; lenvatinib/sorafenib, 45/72). The skeletal muscle mass index (SMI) was measured at the third lumbar vertebra. Furthermore, we evaluated the direct effect of each MTA on primary human skeletal muscle cells by estimating muscle protein synthesis using western blot analysis. RESULTS: The median change in SMI was -0.7% (p = 0.959) and -5.9% (p <0.001) for the lenvatinib and sorafenib groups, respectively. Sorafenib had a greater effect on skeletal muscle loss than lenvatinib (p < 0.001). Additionally, SMI significantly decreased in the sorafenib group regardless of initial skeletal muscle volume (p < 0.001), whereas no significant differences were observed in the lenvatinib group. Sorafenib therapy (odds ratio [OR], 2.98; p = 0.023) and non-muscle depletion (OR, 3.31; p = 0.009) were associated with a decreased SMI. In vitro analysis showed that sorafenib negatively affected muscle synthesis compared to lenvatinib. CONCLUSIONS: Sorafenib may have a more negative effect on skeletal muscle than lenvatinib.

[The Science of Drug Addiction].

Several causes of drug addiction in people remain unknown. It is known that only a small percentage of those who use potent dependent drugs, such as methamphetamine and heroin, develop addiction. In addition, some studies suggest that the choice of preferred drugs among drug addicts is made proactively according to criteria other than the strength of pharmacological dependence. Therefore, this paper discusses the pathogenesis of drug dependence, focusing on the "self-medication hypothesis" of Khantzian et al.

Clinical characteristics of over-the-counter (OTC) drug abusers in psychiatric practice in Japan: Comparison of single and multiple OTC product abusers.

OBJECTIVE: To examine the clinical characteristics of over-the-counter (OTC) drug abusers in psychiatric practice in Japan. METHOD: We examined the attributes, ICD-10 subcategory, and comorbid mental disorders of patients who mainly abuse OTC products and compared the clinical characteristics of single product and multiple products abusers, using the database of the "2022 Nationwide Mental Hospital Survey of Drug-related Disorders." RESULTS: Among the 2468 subjects included in this survey, 273 (11.1%) used OTC products as main drugs. Of these, 209 (78.3%) and 58 (21.7%) were classified into the single product group and the multiple products group, respectively. Six were excluded for unknown ingredients. By comparing these groups, we found that many of the multiple products group consisted of young women who were recently treated for drug problems. Many subjects in the group also had a short treatment period. No differences were observed between the groups regarding the ICD-10 F1 subcategory, but many subjects in the multiple products group fulfilled the criteria of F6 "disorders of adult personality and behavior." CONCLUSION: OTC products are easily accessible drugs of abuse for young women in Japan. The results of this study indicate the necessity to reconsider the educational approach for preventing drug abuse, which has focused on illicit drugs. The study also indicates that some OTC products, which contain ingredients banned overseas due to their harmful effects, are still sold in Japan and that abusers for those products exist. Measures by the government are considered urgently needed.

Psychosocial characteristics of the general population who habitually use hypnotics: Results from a national survey on drug use among the Japanese.

Aim: The aim of this study was to examine the characteristics of habitual hypnotic users in Japan. Methods: This nationwide, cross-sectional survey used self-administered questionnaires. Data were collected from four national surveys conducted every 2 years between 2015 and 2021. The participants were Japanese individuals who had taken prescription hypnotics in the past year or had never taken them. We divided 13,396 participants into three groups to compare the social background and status of taking medication and controlled drugs, drinking, and smoking among the three groups: people who use hypnotics habitually daily (habitual hypnotic users [HUs]), people who use them only occasionally (occasional hypnotic users [OUs]), and people who do not use them (hypnotic non-users [NUs]). We compared the perception of using hypnotics between the HU and OU groups. Results: HUs were more likely to be older, unemployed, and to habitually use anxiolytics and analgesics than NUs. The main reasons for taking anxiolytics in HUs were alleviating insomnia and reducing anxiety, whereas the main reason for taking analgesics was improving joint pain. Additionally, the HU group had a higher proportion of habitual smokers than the OU group. There was no difference in drinking status or taking of controlled drugs among the three groups. HUs were more likely to use hypnotics and to have concerns about their side-effects than OUs. Conclusion: HUs were more likely to be unemployed, habitually use anxiolytics and analgesics, smoke heavily, and take hypnotic drugs with concerns regarding side-effects. These results may help encourage the appropriate use of hypnotics.

Situational factors affecting abstinence from drugs: Panel data analysis of patients with drug use disorders in residential drug use treatment.

Aim: To identify situational factors that can predict drug abstention in patients with drug use disorders undergoing residential drug use treatment. Methods: Patients with drug use disorders admitted to drug addiction rehabilitation centers (DARCs) in 2016 were involved in this study. Longitudinal panel data were used, with eight follow-up surveys over 6 years, approximately every 6 months. Of the 2752 samples from the eight follow-up surveys, 2293 were analyzed as the complete panel data set. The primary outcome was drug abstention for approximately 6 months. The influences of situational factors during this period on the primary outcome were also assessed using a generalized linear mixed model in which inter-individual differences were controlled as variable effects. Results: The use of residential DARCs positively influenced the primary outcome (adjusted odds ratio [AOR] 3.33, 95% confidence interval [CI] 1.79-6.21) when compared to no DARC usage. The cessation of drinking also positively affected the primary outcome (AOR 3.10, 95% CI 1.79-4.62), while employment status (AOR 2.22, 95% CI 1.12-4.41) and the cessation of drinking (AOR 4.92, 95% CI 2.77-8.72) positively impacted the primary outcomes of patients not using DARCs. Conclusion: The use of residential DARCs and the cessation of drinking positively affected drug abstention rates. Employment and the cessation of drinking for patients who were not using the DARCs also had a positive effect. This information will aid in the development of social recovery strategies for people with drug use disorders.

Comparison of patients with benzodiazepine receptor agonist-related psychiatric disorders and over-the-counter drug-related psychiatric disorders before and after the COVID-19 pandemic: Changes in psychosocial characteristics and types of abused drugs.

AIM: To investigate changes in the clinical characteristics of patients who abused benzodiazepine receptor agonists (BZRA) or over-the-counter (OTC) drugs before and after COVID-19 based on the 2018 and 2022 data of the "Nationwide Psychiatric Hospital (NPH) Survey on Drug-related Psychiatric Disorders." METHOD: A total of 446 and 155 cases, and 435 and 273 cases, who mainly abused BZRAs or OTC drugs, respectively, were extracted from the database of the two NPH Surveys. Demographic variables, education, employment, criminal record, drug use during the previous year, psychiatric diagnosis, and types of abused drugs were compared between 2018 and 2022. RESULT: A comparison of BZRA abusers revealed a decreased number of users during the previous year and an increase in the comorbidity rate of other disorders (F3 and F4 in ICD-10) in 2022. Etizolam, flunitrazepam, triazolam, and zolpidem were used most in both years, with an increase in zolpidem and a decrease in triazolam in 2022. A comparison of OTC drug abusers revealed a higher proportion of women and young patients in 2022. An increase in the comorbidity rate of F3 and F9 and a significant increase in the use of dextromethorphan products were observed in 2022, although codeine products were in the majority in both years. CONCLUSION: By comparing NPH Surveys before and after the COVID-19 pandemic, both BZRA abusers and OTC drug abusers present complex pathologies, requiring tailor-made treatment. The younger OTC drug abusers were particularly evident among women, and the abuse of dextromethorphan-containing OTC drugs has increased alarmingly.

Risk and protective factors for early dropout from telephone monitoring for individuals with drug convictions in community mental health centers in Japan.

INTRODUCTION: Individuals involved with the criminal justice system face challenges in receiving and maintaining substance use disorder (SUD) treatment and support. Although telephone monitoring (TM) could reduce these barriers, data on TM for community-dwelling individuals involved with the criminal justice system and research on individuals who drop out of TM are scarce. We examined the factors associated with dropping out early from the Voice Bridges Project, which provides TM for individuals on probation for drug-related convictions through community mental health centers in Japan. METHODS: Participants (n = 546) were individuals aged ≥20 years with methamphetamine-related convictions who were on probation. Univariate analyses examine the associations between one-year follow-up status and baseline variables, and multivariate Cox proportional hazards regression analyses identify the risk and protective factors associated with dropping out. Stratified analyses report results based on sex and halfway-house residency. RESULTS: The one-year dropout rate was 43.6 % (n = 238). Multivariate analysis identified two risk factors for dropping out-halfway-house residency and suicide attempts in the past year, and two protective factors-higher education and the current use of SUD services. Sex-stratified analyses showed that halfway-house residency was a risk factor for both men and women. Attempted suicide was a risk factor for women. Conversely, higher education and current use of SUD services were protective factors for men. CONCLUSIONS: Our results identify unique risk factors for women, such as a recent history of suicide attempts, and distinctive protective factors for men, including higher education and current use of SUD services, emphasizing the importance of sex-specific approaches. Furthermore, the study reveals that irrespective of sex, vulnerable individuals, such as halfway-house residents, are at a higher risk of dropping out from TM.

Prospective multicenter study of the epidemiological features of emergency patients with overdose of over-the-counter drugs in Japan.

Aim: To investigate the epidemiological characteristics of patients presenting to the emergency department with an overdose of over-the-counter (OTC) drugs. Methods: A questionnaire survey was conducted to examine the sociodemographic characteristics of patients with OTC drugs overdoses visiting emergency departments at eight sites across the country. The patients were divided into "habitual" and "nonhabitual" groups according to their history of OTC drugs overdose. Student's t-test or Welch's t-test was performed for numerical variables, and Pearson's χ 2 test was performed for dichotomous and nominal variables between the two groups. Results: Of the 124 patients included in this study, 79% were women. The habitual (26.6%) and the nonhabitual (73.4%) groups showed no differences in sex, occupation, cohabitants, history of mental illness, or history of alcohol consumption or smoking; however, those in the habitual group were significantly younger. The proportion of OTC drugs obtained from physical stores was higher in the habitual group, whereas the nonhabitual group used more household medicines. Suicide and self-harm were more common reasons for overdose in the nonhabitual group. Antipyretic analgesics were significantly more common in the nonhabitual group, whereas antitussive expectorants and antihistamines were significantly more common in the habitual group. Conclusion: This is the first multicenter study to determine the status of OTC drugs overdose patients treated at emergency departments of medical facilities in Japan. To prevent new overdoses of OTC drugs, continued detailed epidemiologic studies of patient backgrounds and drug acquisition routes, and investigation of the components of OTC drugs that cause dependency are necessary.

Relapse Prevention Group Therapy in Indonesia Involving Peers via Videoconferencing for Substance Use Disorder: Development and Feasibility Study.

BACKGROUND: Substance use disorder (SUD) is a major health issue in Indonesia, where several barriers to treatment exist, including inaccessibility to treatment services, stigma, and criminalization of drug issues. Peer involvement and the use of telemedicine to deliver psychotherapy are promising approaches to overcome these barriers. OBJECTIVE: This study aims (1) to describe the development of a new group psychotherapy coprovided by a health care worker and a peer and (2) to evaluate the acceptability, practicality, and preliminary outcomes of the program delivered via videoconferencing in Indonesia. METHODS: Building upon an established relapse prevention therapy in Japan, we developed a 3-month weekly group therapy module in the Indonesian language. Adjustments were made via focus group discussions with local stakeholders in terms of substance types, understandability, inclusive language, and cultural relevance. A pilot study was conducted to test the new module provided by a peer and a psychiatrist via videoconferencing, termed tele-Indonesia Drug Addiction Relapse Prevention Program (tele-Indo-DARPP), with a pre- and postcontrolled design. We analyzed data from semistructured feedback interviews and outcome measurements, including the number of days using substances and quality of life, and compared the intervention (tele-Indo-DARPP added to treatment as usual [TAU]) and control (TAU only) arms. RESULTS: In total, 8 people diagnosed with SUD participated in the pilot study with a mean age of 37 (SD 12.8) years. All were men, and 7 (88%) used sedatives as the primary substance. Collectively, they attended 44 of the 48 tele-Indo-DARPP sessions. A total of 3 out of 4 (75%) preferred telemedicine rather than in-person therapy. Positive acceptability and practicality were shown from qualitative feedback, in which the participants who joined the tele-Indo-DARPP reported that they liked the convenience of joining from home and that they were able to open up about personal matters, received helpful advice from peers, and received support from other participants. Providers reported that they feel the module was provider-friendly, and the session was convenient to join without diminishing rapport-building. Meanwhile, troubles with the internet connection and difficulty in comprehending some terminology in the workbook were reported. The intervention arm showed better improvements in psychological health and anxiety symptoms. CONCLUSIONS: Group psychotherapy via videoconferencing coprovided by health care workers and peers was acceptable and practical for participants with SUD and service providers in this study. A large-scale study is warranted to examine the effectiveness of the newly developed module in Indonesia.

Switching from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab based on early tumor shrinkage in RAS wild-type metastatic colorectal cancer: A phase II trial (HYBRID).

BACKGROUND: Long-term anti-EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single-arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS-negative patients switched to FOLFIRI plus bevacizumab, whereas ETS-positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression-free survival. RESULTS: This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS-negative and 22 were ETS-positive. Two ETS-negative patients and 17 ETS-positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression-free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients. CONCLUSIONS: Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities.

A Phase II Study of FOLFIRI Plus Ziv-Aflibercept After Trifluridine/Tipiracil Plus Bevacizumab in Patients with Metastatic Colorectal Cancer: WJOG 11018G.

BACKGROUND: Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients. OBJECTIVE: We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses. METHODS: This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex® multiplex assay U-kit. RESULTS: Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month-not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1). CONCLUSIONS: This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment. CLINICAL TRIAL REGISTRATION: jRCTs041190100.

Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

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.

Factors influencing stigma among healthcare professionals towards people who use illicit drugs in Japan: A quantitative study.

Aim: Stigma among healthcare professionals toward people who use drugs (PWUDs) must be addressed for recovery. However, research on this topic is limited in Japan, therefore we developed a brand-new scale through coproduction with PWUDs to measure stigma and conducted a survey using the developed scale to examine what influences stigma towards PWUDs in Japanese healthcare settings. Methods: Based on interviews with PWUDs and their families, we developed a survey containing 24 questions on stigma toward PWUDs. The survey was sent to healthcare professionals working in the public sector. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted to determine the factor construct. Generalized linear mixed model (GLMM) analyses with each factor of the stigma questions set as a dependent variable were conducted to discover the specific contribution of each variable to professionals' stigma. Results: The six factors suggested by the EFA showed a good fit, as confirmed by the CFA of the stigma questions. GLMM discovered that "currently providing treatment services to PWUDs," "having PWUDs close to themselves," and "experiencing violence by the client when providing treatment services" were significantly associated with higher stigma scale scores. "Experience in receiving support," "attending self-help groups," and "using peer-based recovery support with PWUDs" were significantly associated with lower stigma scale scores. Conclusion: The scale coproduced with local PWUDs can be a reliable tool to measure the stigma PWUDs face in Japan. Further results indicate that interaction with recovered PWUDs should be promoted.