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CD74 is a transmembrane protein that functions as a specialized chaperone of HLA class II and CD74 in tumor cells was suggested to be involved in cell proliferation in several kinds of malignant tumors. CD74 is also known to be expressed in macrophages, therefore, we investigated the CD74 expression in clear cell renal cell carcinoma (ccRCC). Immunohistochemistry of CD74 indicated that CD74 was expressed not only in cancer cells but also macrophages. CD74 was detected in surface membrane and cytoplasm of cancer cells in 92 of 94 cases (98%) and of 87 of 94 cases (93%). CD74 was expressed both in cancer cells and TAMs in 86 of 94 cases (91%). In vitro studies using cancer cell lines and monocyte-derived macrophages stimulated by anti-CD74 antibodies showed that CD74 signal accelerated cancer cell proliferation and macrophage activation. However, macrophage activation via CD74 signal did not influence macrophage-mediated cancer cell growth. RNA-sequence of macrophages stimulated by anti-CD74 antibodies indicated that CD74 signal was associated to inflammatory responses in macrophages. In conclusion, we examined the expression and functional significance of CD74 in ccRCC using tissue specimens and cell culture studies. The function of CD74 was suggested to be different in cancer cells and in macrophages, and further studies are necessary to clarify the functional significance of CD74 in ccRCC., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib-tamoxifen in patients with HR+/HER2- advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib-tamoxifen or placebo-tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1-32.4) with palbociclib-tamoxifen and 11.1 months (95% CI, 7.4-14.6) with placebo-tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43-0.85; P = 0.002). Palbociclib-tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44-1.21) with palbociclib-tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib-tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo-tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2- advanced breast cancer, palbociclib-tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib-tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018., (© 2024. The Author(s).)

Objective　In 2019, the Ministry of Health, Labour and Welfare emphasized the importance of promoting "Kayoi-no-ba" (or "places to go") initiatives according to the Plan-Do-Check-Action (PDCA) cycle. However, it proposed no specific promotion measures or standardized evaluation frameworks. This study is intended to propose a framework for local government officials to promote and evaluate "Kayoi-no-ba" initiatives according to the PDCA cycle.Methods　The working group (WG) conducted a narrative review of research and extracted evaluation models and indicators that could be used to create the framework. The co-researcher review committee discussed a draft framework prepared by the WG, and the WG revised it based on the discussion; this process was repeated four times. Using the completed framework, we calculated the score of the "Kayoi-no-ba" initiatives in 50 Tokyo municipalities and conducted regional correlation analyses on the relationship between the score of the "Kayoi-no-ba" initiatives in 50 Tokyo municipalities and the number of "Kayoi-no-ba" per 1,000 older persons.Results　The completed framework (named "ACT-RECIPE" by rearranging the underlined characters below) comprised the following six evaluation phases: (1) Comprehension: understanding the key lessons around disability and frailty prevention, and the necessity for "Kayoi-no-ba"; (2) Research and Planning: clarifying the current status of "Kayoi-no-ba," the strengths of the community, and the issues to be addressed through a community assessment, and developing a plan to resolve the issues; (3) Team Building and Collaboration: building a team by collaborating with organizations to solve problems; (4) Implementation: implementing the initiatives necessary to solve problems; (5) Evaluation: verifying changes in output and outcome indicators from the initiatives; and (6) Adjustment and Improvement: re-examining plans, teams, content, and goals based on the evaluation results. In these six phases, we designated 10 core items and accompanying subitems. The median score rate of the ACT-RECIPE framework in 50 municipalities was 75% for "Comprehension," 61% for "Research and Planning," 69% for "Team Building and Collaboration," 64% for "Implementation," 31% for "Evaluation," and 56% for "Adjustment and Improvement," and the mean ACT-RECIPE score rate was 57%. A significant positive correlation (r s =0.43, P=0.002) was observed between the ACT-RECIPE mean score rate and the number of "Kayoi-no-ba" per 1,000 older persons.Conclusion　We proposed the ACT-RECIPE as a framework for promoting and evaluating "Kayoi-no-ba" initiatives according to the PDCA cycle. We hope that this framework will lead to further progress in "Kayoi-no-ba" initiatives and facilitate evaluation of their effectiveness according to the PDCA cycle.

In July 2023 the Japan Gastroenterological Association published the first version of its clinical guidelines for chronic constipation 2023. Based on the latest evidence, these guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic constipation. They include flowcharts for both diagnosis and treatment of chronic constipation. In the treatment of chronic constipation, the first step involves differentiating between secondary forms, such as organic disease-associated constipation, systemic disease-associated constipation, and drug-induced constipation. The next step is to determine whether the chronic constipation stems from a motility disorder, a form of primary chronic constipation. For functional constipation and constipation-predominant irritable bowel syndrome, treatment should be initiated after evaluating symptoms like reduced frequency of bowel movement frequency type or defecation difficulty type. The first line of treatment includes improvement of lifestyle habits and diet therapy. The first drugs to consider for oral treatment are osmotic laxatives. If these are ineffective, secretagogues and ileal bile acid transporter inhibitors are candidates. However, stimulant laxatives are exclusively designated for as-needed use. Probiotics, bulk-forming laxatives, prokinetics, and Kampo medicine, for which there is insufficient evidence, are considered alternative or complementary therapy. Providing the best clinical strategies for chronic constipation therapy in Japan, these clinical guidelines for chronic constipation 2023 should prove useful for its treatment worldwide., (The Author(s). Published by S. Karger AG, Basel.)

Background/aims: Treatment using tumor necrosis factor-α (TNF-α) inhibitors is one of the risk factors for active tuberculosis (TB) in patients with Crohn's disease (CD). Biologics, such as ustekinumab (UST) and vedolizumab (VDZ), are less likely to cause opportunistic infections. However, large-scale studies for active TB and biologics other than TNF-α inhibitors are limited. We aimed to investigate the association between biologics and active TB utilizing a Japanese medical claims database., Methods: We analyzed retrospectively the association of the risk of active TB development with treatment using TNF-α inhibitors and other biologics (UST and VDZ) in patients with CD using the Japanese Medical Data Vision (MDV) database between April 2008 and June 2022. The durations of each biologic and biologic-free treatment were calculated for each patient. Univariate and multivariate analyses were performed using the Cox proportional hazards model, with the utilization of biologics considered as time-dependent covariates., Results: We included 28,811 patients with CD in MDV database. Finally, 17,169 patients were analyzed. In total, 7,064 patients were categorized as biologic-naïve, while 10,105 were classified as biologic-experienced. Seventeen patients developed active TB, including 7 on infliximab, 5 on adalimumab, and 5 on no biologics. None of the patients treated with UST and VDZ developed active TB. Multivariate analysis suggested that TNF-α inhibitors were the risk factors for active TB (hazard ratio, 3.66; P= 0.020)., Conclusions: TNF-α inhibitors, but not UST or VDZ, are risk factors for active TB in Japanese patients with CD.

Background: Tumor-promoting inflammation and inflammatory cytokines are linked to immune checkpoint blockade (ICB) resistance. Methods: We assessed the associations between pre-treatment Interleukin-6 (IL-6), Interleukin-8 (IL-8) levels and on-treatment changes in IL-6, IL-8 and C-reactive protein (CRP) with ICB trial end points. Results: 27 studies representing 6,719 patients were included. Low pre-treatment IL-6 levels were associated with improved objective response rate (ORR) (odds ratio (OR) = 0.31 [0.18-0.55]) and better progression-free survival (PFS) (hazard ratio (HR) = 0.59 [0.48-0.72]) and overall survival (OS) [95% confidence interval (CI)] (HR = 0.42 [0.35-0.50]). Low pre-treatment IL-8 levels were associated with improved ORR (OR = 0.47 [0.36-0.61]) and better PFS (HR = 0.65 [0.58-0.74]) and OS (HR = 0.44 [0.39-0.51]). On-treatment decline in CRP was associated with improved ORR (OR = 0.18 [0.11-0.20]), PFS (HR = 0.40 [0.31-0.91]) and OS (HR = 0.48 [0.40-0.58]). Conclusion: Peripheral blood cytokines warrant further evaluation as enrichment and pharmacodynamic biomarkers for strategies targeting tumor-promoting inflammation.

Background: The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor., Methods: This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing., Findings: Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group., Interpretation: The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival., Funding: The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development., Competing Interests: Declaration of interests YoS has received grants from Chugai Pharmaceutical; and personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Taiho Pharmaceutical, and Kyowa Kirin, all outside of the submitted work. ShN has received grants from AstraZeneca, Chugai Pharmaceutical, and MSD; consulting fees from Asahi Kasei Pharma; and personal fees from AstraZeneca, Bayer, Chugai Pharmaceutical, Asahi Kasei Pharma, Kyowa Hakko Bio, and MSD, all outside of the submitted work. SS has received grants from AnHeart Therapeutics, AstraZeneca, Chugai Pharmaceutical, MSD, Daiichi Sankyo, Bristol Myers Squibb, Nippon Boehringer Ingelheim, Ono Pharmaceutical, AbbVie, Amgen, Taiho Pharmaceutical, Takeda, Accerise, and Parexel International; and personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly, Novartis, Kyowa Kirin, Takeda, Nippon Kayaku, Merck, Amgen, AbbVie, Otsuka, Thermo Fisher Scientific, Towa Pharmaceutical, Sysmex, and Eisai, all outside of the submitted work. HidehH has received research fundings from MSD, AbbVie, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Janssen, Chugai Pharmaceutical, and Roche; personal fees from AstraZeneca, MSD, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Roche, Amgen, and Abbvie; and personal fees from AstraZeneca, Chugai Pharmaceutical, Roche, Ono Pharmaceutical, Bristol Myers Squibb, and AbbVie (served on the advisory board), all outside of the submitted work. YaY has received personal fees from Taiho Pharmaceutical and Takeda, all outside of the submitted work. HidetH has received grants from IQVIA Services Japan, Eisai, Syneos Health Clinical, EP-CRSU, EPS, Shionogi, Nippon Kayaku, Otsuka Pharmaceutical, Takeda, GSK, MSD, Sanofi, Amgen, Chugai Pharmaceutical, Taiho Pharmaceutical, Nippon Boehringer Ingelheim, Bristol Myers Squibb, SRL Medisearch, Janssen Pharmaceutical, PRA Health Sciences, CMIC, Astellas Pharma, Pfizer R&D Japan, Ascent Development Services, Labcorp Development Japan, Eisai, Kobayashi Pharmaceutical, Bayer, and Pfizer Japan; royalties or licenses from Sysmex; personal fees from Ono Pharmaceutical, Merck, Daiichi Sankyo, 3H Clinical Trial, AstraZeneca, Novartis Pharma, Chugai Pharmaceutical, Bristol Myers Squibb, Eli Lilly Japan, Amgen, MSD, Sysmex, Pfizer Japan, Takeda, Nippon Boehringer Ingelheim; and personal fees for serving on an advisory board from Daiichi Sankyo, Nippon Boehringer Ingelheim, AstraZeneca, Amgen, Chugai Pharmaceutical, Novocure, Eli Lilly Japan, Gilead Science, and Blueprint Medicine, all outside of the submitted work. KA has received lecture fees from AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, MSD, Bristol Myers Squibb, and Takeda, all outside of the submitted work. SN has received grants from GSK, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Teijin, Kyowa Kirin, Shionogi, Boehringer Ingelheim, Daiichi Sankyo, Kyorin, and Nippon Kayaku; personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, MSD, Ono Pharmaceutical, Eisai, Kyorin, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Novartis, Amgen, Merck, Nippon Kayaku, and Kyowa Kirin; and personal fees for serving on advisory boards from AstraZeneca and Daiichi Sankyo, all outside of the submitted work. RM has received personal fees from Daiichi Sankyo, Chugai Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Eli Lilly Japan, MSD, Amgen, and Merck; and personal fees for serving on an advisory board from Daiichi Sankyo, all outside of the submitted work. MY has received grants from Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Kayaku, Taiho Pharmaceutical, and Takeda; and personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Johnson & Johnson, MSD, Nippon Kayaku, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical, all outside of the submitted work. TY has received grants from MSD, Chugai Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim Japan, Takeda, Delta-Fly Pharma, Janssen, AbbVie, Daiichi Sankyo, and Parexel International; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Pfizer Japan, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Nippon Kayaku, MSD, Novartis, and Merck, all outside of the submitted work. KY has received grants from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Lilly, MSD, Pfizer, Taiho Pharmaceutical, and Takeda; and personal fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Janssen, Kyowa Kirin, Lilly, Merck Serono, Novartis, Ono Pharmaceutical, Otsuka, Taiho Pharmaceutical, and Takeda, all outside of the submitted work. TakayK has received grants from AstraZeneca, Amgen, MSD, Janssen, Takeda, and Daiichi Sankyo; and personal fees from AstraZeneca, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, MSD, Pfizer, and Nippon Kayaku, all outside of the submitted work. HO has received grants from Bristol Myers Squibb, MSD, and Taiho Pharmaceutical, all outside of the submitted work. TakasK has received personal fees from MSD, AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol Myers Squibb, all outside of the submitted work. KK has received personal fees from AstraZeneca, MSD, Chugai Pharmaceutical, Eli Lilly Japan, and Taiho Pharmaceutical; payment for expert testimony from Eli Lilly Japan; and personal fees for serving on advisory boards from Eli Lilly Japan and AstraZeneca, all outside of the submitted work. YF has received personal fees from AstraZeneca, Amgen, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical; payment for expert testimony from Chiome Bioscience, Otsuka Pharmaceutical, and Ono Pharmaceutical; and personal fees for serving on advisory boards from AstraZeneca, Daiichi Sankyo, Micron, and Ono Pharmaceutical, all outside of the submitted work. SM has received grants from AstraZeneca, Takeda, Chugai Pharmaceutical, Sanofi, MSD, Daiichi Sankyo, Ono Pharmaceutical, and Janssen; and personal fees from AstraZeneca, Chugai Pharmaceutical, Takeda, Eli Lilly, MSD, Pfizer, Novartis, and Taiho Pharmaceutical, all outside of the submitted work. SK has received personal fees from Boehringer Ingelheim Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, MSD, Ono Pharmaceutical, and Guardant Health Japan, all outside of the submitted work. HA reports grants from Amgen and Chugai Pharmaceutical; personal fees from Amgen, AstraZeneca, Boehringer Ingelheim Japan, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical; personal fees for serving on advisory boards from Amgen, MSD, Janssen, and Sandoz; and a role on the WCLC Patient Advocacy Committee, all outside of the submitted work. HK has received grants from Eli Lilly; and personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Novartis, Eli Lilly Japan, Ono Pharmaceutical, and Takeda, all outside of the submitted work. ToshiK has received grants from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Kyowa Hakko Kirin, Merck, Daiichi Sankyo, Amgen, AbbVie, Sanofi, Eisai, Labcorp Development Japan, IQVIA Services Japan, Gilead Sciences, Pfizer, and Bayer; consulting fees from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Pfizer Japan, Daiichi Sankyo, Bayer, and AbbVie; and personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Pfizer Japan, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Merck, Nippon Kayaku, Novartis, Daiichi Sankyo, Takeda, Bayer, Sawai, Amgen, and Eisai, all outside of the submitted work. HF has received grants from the National Cancer Center Research and Development Fund; and lecture fees from Kyowa Kirin, Chugai Pharmaceutical, and CMIC, all outside of the submitted work. YO reports grants from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, LOXO, Kirin, Sumitomo, Pfizer, Taiho Pharmaceutical, Novartis, Takeda, Kissei, Daiichi Sankyo, and Janssen; personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Hakko Kirin, Eisai, and Daiichi Sankyo; payment for expert testimony from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics, and PharmaMar; personal fees for serving on an advisory board from Haihe Biopharma; and roles in the Japanese Society of Medical Oncology, Japan Lung Cancer Society, and Japan Clinical Oncology Group, all outside of the submitted work. IO has received grants from the National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development during the conduct of the study; grants from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Astellas, Bristol Myers Squibb, Novartis, Chugai Pharmaceutical, Pfizer, and AbbVie; consulting fees from AstraZeneca, Bristol Myers Squibb, and AbbVie; and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Bristol Myers Squibb, Novartis, Chugai Pharmaceutical, and Pfizer, all outside of the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Endoscopic submucosal dissection (ESD) is a specific procedure that uses an electrosurgical knife for en-bloc resectioning large tumors. However, no study has examined the effect of ESD on the defecation function of patients with rectal tumors. We aimed to investigate the potential effects caused by ESD by analyzing changes in the morphology and movement of the anorectum pre- and post-ESD., Methods: This prospective observational study included 11 patients with anorectal tumors who underwent ESD between April 2020 and February 2022. Pre-ESD assessments included anorectal manometry and defecography. Post-ESD assessments were conducted 2 months later, including anorectal manometry, defecography, and proctoscopy for ulcer and stenosis evaluation., Results: The median patient age was 73 years, including seven males and four females. Eight patients (73%) had a tumor in the lower rectum, and the extent of resection was less than 50% of the rectal lumen. Resection reached the dentate line in six cases (55%). In the patients with post-ESD mucosal defects involving the dentate line, the median of functional anal canal length significantly decreased from (3.4 cm pre-ESD to 2.8 cm post-ESD, p  = 0.04). Defecography revealed one case with incomplete evacuation (<50%) and incontinence post-ESD. Interestingly, patients with pre-existing rectoceles noted resolution of lesions post-ESD. None of the patients reported daily constipation or fecal incontinence., Conclusions: While rectal ESD is unlikely to cause significant real-world defecation difficulties, alterations in rectal and anal canal morphology and function may occur if the dentate line is involved in the resection range.

Background: HER2-low populations constitute a heterogeneous group, and the cytotoxic anticancer agent efficacy based on HER2 status remains unclear. This study evaluated the clinicopathological features and outcomes of patients with advanced breast cancer showing HER2-low expression treated with eribulin or capecitabine, two treatment options after anthracycline and taxane treatment., Methods: We retrospectively evaluated patients who were treated with eribulin or capecitabine between 2011 and 2015. HER2 status was evaluated according to the ASCO/CAP guidelines., Results: No significant difference was observed in overall survival (OS; eribulin: hazard ratio [HR], 0.66; 95% CI 0.40-1.10; capecitabine: HR, 0.76; 95% CI 0.45-1.30) or progression-free survival (PFS; eribulin: HR, 1.13; 95% CI 0.72-1.78; capecitabine: HR, 0.90; 95% CI 0.56-1.44) between patients receiving eribulin (HER2-null: 35, HER2-low: 44) and those receiving capecitabine (HER2-null: 41, HER2-low: 33). Subgroup analysis revealed no significant differences in OS between the two groups in the hormone-positive and -negative populations for eribulin and capecitabine. HER2-null and HER2-low patients showed objective response rates (ORRs) of 22.5% and 9.1% (p = 0.09) overall, and 32.0% and 10.5% (p = 0.03), respectively, in hormone-positive cases among eribulin-treated patients. No response was observed in hormone-negative patients. Capecitabine treatment in HER2-null and HER2-low patients had overall ORRs of 26.8% and 15.2% (p = 0.23), respectively, with 27.3% and 16.1% (p = 0.28) for hormone-positive cases; and 25.0% and 0% (p = 1.0), respectively, for hormone-negative cases., Conclusions: Eribulin and capecitabine sensitivity may vary based on HER2 expression in patients with HER2-low and HER2-null breast cancer. Prognosis was similar between the HER2-low and the HER2-null groups., (© 2024. The Author(s).)

Background: Although a preference for solitude (PS) may mitigate the negative effects of social isolation (SI) owing to the enjoyment of time alone, its impact on mental health and its underlying factors remain unclear., Methods: An Internet survey was conducted with 9000 individuals aged 20-79 years in August 2023 and the analyses were performed across three generations. SI was defined as contact with non-cohabitating family members or relatives and friends/neighbors less than once a week. The PS scale, which was used to assess whether a person preferred spending time alone, stratified respondents into three PS-level groups. Mental health status was evaluated using the WHO-5 (well-being), the K6 (distress symptoms), and the UCLA Loneliness Score (severity of loneliness) as the main outcomes. The mediation analyses assessed whether troublesomeness in socializing, a potential negative aspect of PS, could explain the association between PS and mental health status., Results: A mixed-design two-way analysis of covariance showed that both SI and PS had significant main effects on all outcomes without interactions across generations, indicating that SI and higher PS were associated with poor mental health status. The association between higher PS and poor mental status was mediated by socializing troublesomeness across generations., Limitations: The cross-sectional design prevented making causal inferences from the results. Additionally, sampling bias from Internet surveys may limit the generalizability of the results., Conclusions: The results confirmed that there is no protective effect of PS on social isolation-related poor mental health. The hassle of socializing may partly explain why people with a higher PS experience poor mental status, including greater loneliness., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research., (Copyright © 2024. Published by Elsevier B.V.)

Aim: The Japanese Society for Respiratory Care and Rehabilitation, Japanese Association on Sarcopenia and Frailty, Japanese Society of Respiratory Physical Therapy, and Japanese Association of Rehabilitation Nutrition proposed the definition and diagnosis of respiratory sarcopenia using low respiratory muscle strength and appendicular skeletal muscle mass (ASM; ASM/height 2 ) instead of respiratory muscle mass; however, these parameters have not been validated. This study aimed to confirm the validity of the respiratory sarcopenia definition proposed by these four professional organizations., Methods: Participants of our cohort study in 2015 of 468 community-dwelling older people who were evaluated for sarcopenia and underwent spirometry were included in this analysis. We determined two respiratory sarcopenia models based on low skeletal muscle mass and respiratory muscle strength. Low skeletal muscle mass was defined by low ASM/height 2 , and low respiratory muscle strength was defined by peak expiratory flow rate (PEFR) or percentage of predicted PEFR (%PEFR). Survival status was assessed 5 years after baseline assessment (in 2020). To evaluate the validity of the cut-off values for PEFR and %PEFR, we determined different respiratory sarcopenia models by sequentially varying the cut-off values for each parameter, including ASM/height 2 , from high to low. We subsequently calculated the hazard ratio (HR) for mortality for each respiratory sarcopenia model using the Cox proportional hazards model. Additionally, we plotted the HR for each combination of cut-off values for ASM/height 2 and PEFR or %PEFR on a three-dimensional chart to observe the relationship between the different cut-off values and HR., Results: A total of 31 people died during the 5-year observation period. With ASM/height 2 cut-off values of approximately 7.0 kg/m 2 for men and 5.7 kg/m 2 for women and %PEFR cut-off values of 66-75%, respiratory sarcopenia was associated with mortality risk (HR, 2.36-3.27, point estimation range)., Conclusions: The definition of respiratory sarcopenia by the four professional organizations is related to future health outcomes, and this definition is valid. Geriatr Gerontol Int 2024; ••: ••-••., (© 2024 Japan Geriatrics Society.)

Background: To date simple assessment tool to evaluate early low nutrition risk in general older population has not been available. This study aimed to create such tool and examined its reliability and criterion-related validity., Methods: 1,192 community elderly with a mean age of 74.7(5.8) years responded to a questionnaire consisting of 48 (Hatoyama) or 34 items (Kusatsu), which have been reported to be associated with nutritional state in older people. Item analysis was conducted on the 34 common items, and items were selected based on the following criteria: adequate pass rates and discriminative power, no gender and regional differences, and a certain level of commonality based on factor analysis. Next, the factor structure of the candidate items was examined through exploratory factor analysis, and confirmatory factor analysis was conducted as the final scale structure. Furthermore, Spearman's partial rank correlation coefficients (sex- and age-adjusted) between the created index and important health indicators were examined to determine the criterion-related validity., Results: Finally, we obtained a semantic coherence of 4 factors (named health beliefs, dietary status, physical activity, and food-related quality of life) totaling 13 items; confirmatory factor analysis of the 4-factor solution yielded good model fit values, χ 2 (59) =275.4 (p<0.001), CFI=0.930, and RMSEA=0.056. The factor loadings for each factor ranged from 0.43 to 0.82, indicating adequate loadings. The reliability of the index was shown to be high by Good-Poor analysis and Cronbach's α. The index showed statistically significant correlations with all health indicators., Conclusions: We have developed a simple assessment tool to evaluate early low nutrition risk in general older population.

Objective: Trophoblast Cell Surface Antigen 2 (Trop-2) is a transmembrane glycoprotein that is overexpressed in various cancers, with immunological significance as a target for tumor-reactive T-cells. We aimed to investigate the association between the expression of Trop-2 and the tumor immune microenvironment in cervical cancer., Methods: The study included 123 patients with cervical cancer who underwent primary surgery between 2000 and 2020 in our hospital. Trop-2 expression was evaluated using anti-Trop-2 monoclonal antibody clone MAB650. Immune biomarkers, including PD-L1 (22C3), CD3 (PS1), and CD8 (4B11), were also evaluated. Trop-2 and PD-L1 positivity were defined by an H-score ≥ 10 and a combined positive score (CPS) ≥1, respectively. Tumor-infiltrating lymphocytes (TILs) were assessed in the five selected independent areas. The correlation between Trop-2 expression and immune biomarkers was analyzed., Results: The cohort comprised patients with squamous cell carcinoma (SCC) (54.5%) and non-SCC (45.5%). Trop-2 was positive in 84.6% of samples and more commonly expressed in SCC (SCC vs. non-SCC; 97.0% vs. 69.6%, p < 0.001). Intratumoral CD3+ and CD8 + TILs were significantly more common in Trop-2-positive cases (CD3, Mann-Whitney U = 383, p < 0.0001; CD8, U = 442, p < 0.0001). Additionally, significant positive correlations were found between the Trop-2 H-score and immune markers (CD3 + TILs, r = 0.295, p < 0.001; CD8 + TILs, r = 0.267, p = 0.001; PD-L1 CPS, r = 0.178, p = 0.025). No significant associations were detected between TILs and other clinicopathological features, including prognosis., Conclusion: Expression of Trop-2 in cervical cancer is associated with increased levels of intratumoral TILs, indicating the potential of Trop-2 targeted therapy alone or in combination with immune checkpoint inhibitors., Competing Interests: Declaration of competing interest Yohei Chiba, Yuki Kojima, Shu Yazaki, Hiroshi Yoshida, Shigemasa Takamizawa, Rui Kitadai, Ayumi Saito, Hitomi Sumiyoshi-Okuma, Tatsunori Shimoi, Kazuki Sudo, Masaya Uno, Mitsuya Ishikawa, and Tomoyasu Kato have nothing to disclose. Tadaaki Nishikawa reports personal fees from Takeda Pharmaceutical Company, Eisai, and AstraZeneca outside of the submitted work. Emi Noguchi reports personal fees from Pfizer, Taiho, Eli Lilly, AstraZeneca, Chugai, and Eisai outside the submitted work. Yasuhiro Fujiwara reports personal fees from AstraZeneca, Chugai, Daiichi Sankyo, Bristol-Myers, SRL, and Santen outside the submitted work. Kan Yonemori reports personal fees from Pfizer, AstraZeneca, Eisai, Takeda Pharmaceutical Company, Chugai, Ono Pharmaceutical Company, Novartis, and Daiichi Sankyo outside the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Emergency surgery for a hiatal hernia (HH) is uncommon. However, mediastinal gastric perforation may occasionally present as the initial symptom of HH and demonstrate high mortality rates. Managing mediastinal gastric perforation in HH has no established standard surgical technique, and the selection of surgical techniques may be challenging. A 78-year-old female patient was referred to our department because of an upper gastrointestinal perforation in HH based on computed tomography (CT) results. Determining the possibility of esophageal perforation and intrathoracic penetration was difficult according to CT results alone, and whether a transthoracic or transabdominal approach was preferable. We diagnosed the patient with a mediastinal gastric perforation in HH without intrathoracic penetration based on an additional gastrointestinal contrast study and a right thoracentesis. We treated the patient with laparotomy, involving the perforation site and esophageal hiatus closure and gastropexy. Postoperatively, the patient experienced complications associated with delayed gastric emptying and aspiration pneumonia. Fortunately, no severe infections, such as residual abscess formation or empyema, were observed, and the recovery progressed favorably. Mediastinal gastric perforation should be considered a differential diagnosis for elderly patients with sudden-onset chest pain and dyspnea, and the threshold for imaging should be lowered. Identifying the perforation site and the presence of intrathoracic penetration based on preoperative results is useful for determining the appropriate surgical technique. Postoperative quality of life to the extent feasible needs to be considered, as the selection of surgical technique may cause subsequent recurrence or reflux symptoms., Competing Interests: The authors declare no conflicts of interest., (©2024 Tottori University Medical Press.)

Objective　In this study, we clarified the characteristics of tasks performed by older assistant care workers at geriatric health services facilities, by individual characteristics and work status. Additionally, we examined the relationship between the tasks and benefits of working for older assistant care workers.Methods　A self-administered questionnaire survey was provided to 2,571 elderly care facilities employing assistant care workers aged ≥60.　A total of 1,606 responses were obtained, and personal characteristics, working conditions, tasks, and benefits of working for older care assistants were surveyed. Thirteen work tasks were established and categorized into four broad categories; user transfer assistance, facility maintenance, meal-related assistance, and managing and talking to users. Seven benefits of working as care assistants were "contribution to society," "social connection," "purpose of life," "income," "learning from caregiving," "health maintenance and promotion," and "time utilization."Results　Most of the respondents were women and relatively young workers. Among tasks, men, younger workers, and those working >5 days weekly represented a high proportion of those performing user transfer assistance tasks. Tasks on managing and talking to users were not correlated with sex, age, and number of days worked, but those with more flexible work patterns were more likely to be engaged in such tasks. Logistic regression analysis showed that user transfer assistance was correlated with benefits of working, such as "contribution to society," "social connection," and "learning from caregiving." Moreover, facility maintenance was associated with "income," "health maintenance and promotion," and "time utilization" and meal-related assistance was associated with "learning from caregiving." Managing and talking to users was associated with "contribution of society," "social connection," "purpose of life," and "learning from caregiving."Conclusion　The tasks of the workers were associated with individual characteristics and work status. The perception of benefits between the working tasks that involved frequent contact with users and those that did not were considerably different.

Aim: The pathophysiological mechanisms of postoperative delirium (POD) are still unclear, and there is no reliable biomarker to distinguish between those with and without POD. Our aim was to discover DNAm markers associated with POD in blood collected from patients before and after gastrointestinal surgery., Method: We collected blood samples from 16 patients including 7 POD patients at three timepoints; before surgery (pre), the first and third postoperative days (day1 and day3). We measured differences in DNA methylation between POD and control groups between pre and day1 as well as between pre and day3 using the Illumina EPIC array method. Besides, enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also performed after excluding influence of common factors related to surgery and anesthesia., Result: The results showed that pre and day1 comparisons showed that immune and inflammatory signals such as 'T-cell activation' were significantly different, consistent with our previous studies with non-Hispanic White subjects. In contrast, we found that these signals were not significant any more when pre was compared with day3., Conclusion: These results provide strong evidence for the involvement of inflammatory and immune-related epigenetic signals in the pathogenesis of delirium, including POD, regardless of ethnic background. These findings also suggest that DNAm, which is involved in inflammation and immunity, is dynamically altered in patients with POD. In summary, the present results indicate that these signals may serve as a new diagnostic tool for POD., Competing Interests: Declaration of competing interest Gen Shinozaki has pending patents “Epigenetic Biomarker of Delirium Risk” in the PCT Application No. PCT/US19/51276, in the PCT Application No. PCT/US21/63166, and in U.S. Provisional Patent No. 62/731599. All other authors have declared that no conflict of interest exists., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Targeted therapy is now the standard of care in driver-oncogene-positive non-small cell lung cancer (NSCLC). Its initial clinical effects are remarkable. However, almost all patients experience treatment resistance to targeted therapy. Hence, chemotherapy is considered a subsequent treatment option. In patients with driver-oncogene-negative NSCLC, combined immune checkpoint inhibitors (ICIs) and chemotherapy as the first-line therapy has been found to be beneficial. However, the efficacy of ICI plus chemotherapy against driver-oncogene-positive NSCLC other than epidermal growth factor receptor mutation and anaplastic lymphoma kinase fusion is unclear., Methods: Using the hospital medical records, we retrospectively reviewed advanced or recurrent NSCLC patients who were treated with chemotherapy with or without ICIs at Aichi Cancer Center Hospital between January 2014 and January 2023. Patients with druggable rare mutations such as KRAS-G12C, MET exon 14 skipping, HER2 20 insertion, BRAF-V600E mutations, and ROS1 and RET rearrangements were analyzed., Results: In total, 61 patients were included in this analysis. ICI plus chemotherapy was administered in 36 patients (the ICI-chemo group) and chemotherapy in 25 patients (the chemo group). The median progression-free survival (PFS) rates were 14.0 months in the ICI-chemo group and 4.8 months in the chemo group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.28-1.01). The median overall survival rates were 31.3 and 21.7 months in the ICI-chemo and chemo groups, respectively (HR = 0.70, 95% CI = 0.33-1.50). Multivariate Cox regression analysis of PFS revealed that HER2 exon 20 insertion mutation was significantly associated with a poorer PFS (HR: 2.39, 95% CI: 1.19-4.77, P = 0.014). Further, ICI-chemo treatment was significantly associated with a better PFS (HR: 0.48, 95% CI: 0.25-0.91, P = 0.025)., Conclusion: ICI plus chemotherapy improves treatment efficacy in rare driver-oncogene-positive NSCLC., (© 2024. The Author(s).)

The placenta secretes a prolactin (PRL)-like hormone PRL3B1 (placental lactogen II), a luteotropic hormone essential for maintaining pregnancy until labor in mice. A report from 1984 examined the secretion pattern of PRL3B1 in prepartum mice. In the current study, we found contradictory findings in the secretion pattern that invalidate the previous report. By measuring maternal plasma PRL3B1 and PRL every 4 hrs from gestational day 17 (G17), we newly discovered that maternal plasma PRL3B1 levels decrease rapidly in prepartum C57BL/6 mice. Interestingly, the onset of this decline coincided with the PRL surge at G18, demonstrating a plasma prolactin axis shift from placental to pituitary origin. We also found that maternal plasma progesterone regression precedes the onset of the PRL shift. The level of Prl3b1 mRNA was determined by RT-qPCR in the placenta and remained stable until parturition, implying that PRL3B1 peptide production or secretion was suppressed. We hypothesized that production of the PRL family, the 25 paralogous PRL proteins exclusively expressed in mice placenta, would decrease alongside PRL3B1 during this period. To investigate this hypothesis and to seek proteomic changes, we performed a shotgun proteome analysis of the placental tissue using data-independent acquisition mass spectrometry (DIA-MS). Up to 5,891 proteins were identified, including 17 PRL family members. Relative quantitative analysis between embryonic day 17 (E17) and E18 placentas showed no significant difference in the expression of PRL3B1 and most PRL family members except PRL7C1. These results suggest that PRL3B1 secretion from the placenta is suppressed at G18 (E18).

Background: Living alone has been associated with cognitive impairment; however, findings have been inconsistent. Social isolation among older adults who live alone may contribute to cognitive impairment. This study was carried out to examine the association of social isolation and living alone with cognitive impairment in community-dwelling older adults., Methods: In this cross-sectional study, data from the Integrated Research Initiative for Living Well with Dementia Cohort Study, which comprises pooled data from five community-based geriatric cohorts, was used. Social isolation was defined as infrequent interactions with others. Participants were categorized into four groups based on their social isolation and living alone statuses. Cognitive function was assessed using the Mini-Mental State Examination, with a score <24 indicating cognitive impairment. The association between social isolation combined with living alone and cognitive impairment was analyzed using logistic regression., Results: Of the 4362 participants included in the analysis (mean age 75.6 years, 44.3 % male), 11 % had cognitive impairment. Regardless of living alone, social isolation was associated with cognitive impairment (no social isolation x not living alone: reference, social isolation x not living alone; odds ratio (OR): 1.74, 95 % confidence interval (CI): 1.29-2.33, social isolation x living alone; OR: 2.10, 95 % CI: 1.46-3.01)., Conclusions: Social isolation is associated with cognitive impairment; however, living alone is not intrinsically associated with cognitive impairment in older adults. Healthcare providers must focus on social interactions to prevent cognitive impairment in older adults rather than simply focusing on living arrangements., Competing Interests: Declaration of competing interest The authors 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 Elsevier B.V. All rights reserved.)

Introduction: Social isolation is associated with increased mortality risk. On the other hand, some older adults prefer to be alone. Additionally, predictors of isolation are mostly unchanged across interventions. Therefore, knowledge of how to prevent negative health outcomes in isolation would be beneficial. One of the factors that reduces the risk of mortality is regular exercise. However, to date, no studies to our knowledge have examined whether regular exercise reduces mortality among socially isolated individuals. This study aimed to determine the effects of the combination of social isolation and regular exercise on mortality among community-dwelling older adults., Methods: This prospective cohort study was part of the larger Otassha Study of community-dwelling older adults living in Itabashi Ward, Tokyo, Japan. In October 2012, 835 individuals (males = 350, females = 485; mean age 73.1 years) completed a comprehensive baseline health survey. Individuals were considered socially isolated if their frequency of interactions with others averaged less than once per week. Regular exercise was defined as exercise performed at least twice a week. The participants were assigned to one of the following four groups: (1) not isolated with regular exercise, (2) not isolated without regular exercise, (3) isolated with regular exercise, and (4) isolated without regular exercise. All-cause mortality information was obtained from the ward office database. Follow-ups were conducted until 1 November 2020. A Cox proportional regression analysis was performed., Results: A final analysis was performed on a complete dataset of 735 participants (males = 303, females = 432; mean age 72.9 years). A total of 132 (18.0%), 426 (58.0%), 27 (3.7%), and 150 (20.4%) participants were assigned to groups 1, 2, 3, and 4, respectively. The mortality rates in groups 1, 2, 3, and 4 were 6.1%, 9.2%, 7.4%, and 19.3%, respectively. Compared with group 1, isolated individuals who did not perform regular exercise had a significantly higher mortality rate [adjusted hazard ratio (aHR), 2.48; 95% confidence interval (CI), 1.12-5.52]. However, no significant association was noted in isolated individuals who performed regular exercise (aHR, 1.25; 95% CI, 0.26-5.91)., Conclusion: Regular exercise was associated with a decrease in mortality risk, regardless of social isolation status. Thus, our results indicate that encouraging isolated older adults to exercise regularly may reduce their negative health outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ejiri, Kawai, Imamura, Fujiwara, Ihara, Hirano and Obuchi.)

Background: With the aging of the population, more and more patients ≥90 years old are undergoing surgery. We retrospectively examined factors affecting morbidity and in-hospital mortality among patients ≥90 years old who underwent emergency abdominal operations., Materials and Methods: Forty-six cases of emergency abdominal surgery for patients ≥90 years old who underwent surgery at our hospital between 2011 and 2022 were included in this study. Factors affecting morbidity and in-hospital mortality were analyzed statistically. Physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM)-predicted morbidity and Portsmouth-POSSUM (P-POSSUM)-predicted mortality were calculated., Results: Postoperative complications occurred in 30 patients (65.2 %) and 5 patients (10.8 %) died in the hospital. Factors affecting morbidity included American Society of Anesthesiologists physical status score, operative time and blood loss, and operative severity score. Multivariate analysis identified male sex, operative severity score, and length of hospital stay as factors affecting morbidity. Eastern Cooperative Oncology Group performance status and physiological score were identified as factors influencing mortality in hospital, and only physiological score was identified in the multivariate analysis. Area under the receiver operating characteristic (ROC) curve for POSSUM-predicted morbidity was 0.796 and area under the ROC curve for P-POSSUM-predicted mortality was 0.805, both of which were moderately accurate., Conclusion: Risk of emergency abdominal surgery in patients ≥90 years old may be predictable to some extent, and we are able to provide convincing explanations to patients and families based on these data., Competing Interests: The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article., (© 2024 The Authors.)

Background/aim: Hypomagnesemia is a common side effect of anti-epidermal growth factor receptor (EGFR) antibodies, which may lead to arrhythmia. However, there are no evidence-based guidelines for magnesium (Mg) supplementation in the management of hypomagnesemia in patients with anti-EGFR antibodies. Therefore, we performed a systematic review to address clinical questions regarding these cancer patients., Materials and Methods: Three electronic databases were searched for articles published until June 18, 2021. The main outcomes used were "anti-EGFR antibody" and "hypomagnesemia"., Results: After screening 78 references in PubMed, Cochrane Library, and ICHUSHI-web databases, three studies were included in the review. One study revealed the effectiveness of Mg supplementation in the management of hypomagnesemia in patients receiving cetuximab. However, no studies have investigated whether correcting hypomagnesemia can lead to the suppression of arrhythmias as a clinical outcome., Conclusion: Weak evidence suggests that Mg supplementation, as a preventive measure when developing hypomagnesemia following the initiation of anti-EGFR antibody therapy, may prevent the worsening of hypomagnesemia, and subsequently prevent associated arrhythmia occurrence., Competing Interests: The Authors declare no potential conflicts of interest in relation to this study., (Copyright 2024, International Institute of Anticancer Research.)

Background/aim: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β superfamily of ligands and have been shown to promote or suppress colorectal cancer (CRC) growth. Developing treatments that target BMPs is challenging due to their multiple roles, including involvement in the inflammatory response and nutritional status. The present study evaluated the prognostic value of BMP-4, which is believed to be highly expressed in CRC, and its correlation with inflammatory and nutrition statuses in patients with CRC., Materials and Methods: We analyzed BMP-4 expression in tumor tissues from 144 patients who underwent CRC surgery using immunohistochemistry and evaluated the relationship between BMP-4 levels and clinical outcomes., Results: Kaplan-Meier analysis revealed that patients with high expression levels of BMP-4 exhibited a shorter overall survival rate than those with low levels of expression. Multivariate analysis revealed that BMP-4 expression was an independent prognostic factor for overall survival and death from other diseases in CRC patients. Furthermore, high BMP-4 expression was significantly correlated with high C-reactive protein/Albumin ratio, sarcopenia, and osteopenia., Conclusion: BMP-4 is a significant prognostic factor in CRC, particularly in predicting death from other diseases, while also showing associations with inflammatory and nutritional statuses., Competing Interests: The Authors declare that they have no conflicts of interest in relation to this study., (Copyright 2024, International Institute of Anticancer Research.)

Chemosynthesis-based ecosystems such as hydrothermal vents and hydrocarbon seeps harbour various endemic species, each uniquely adapted to the extreme conditions. While some species rely on obligatory relationships with bacterial symbionts for nutrient uptake, scavengers and predators also play important roles in food web dynamics in these ecosystems. Acoels, members of the phylum Xenacoelomorpha, are simple, worm-like invertebrates found in marine environments worldwide but are scarcely understood taxa. This study presents a novel genus and species of acoel from a deep-sea hydrocarbon seep off Hatsushima, Japan, Hoftherma hatsushimaensis gen. et sp. nov. Our multi-locus phylogenetic analysis revealed that the acoels are nested within Hofsteniidae, a family previously known exclusively from shallow waters. This finding suggests that at least two independent colonization events occurred in the chemosynthesis-based environments from the phylum Xenoacoelomorpha, represented by hofsteniid acoels and Xenoturbella . Previous reports of hofsteniid species from low-oxygen and sulfide-rich environments, including intertidal habitats with decomposing leaves, in addition to H. hatsushimaensis gen. et sp. nov. from a deep-sea hydrocarbon seep, imply a common ancestral adaptation to sulfide-rich ecosystems within Hofsteniidae. Moreover, the sister relationship between solenofilomorphid acoels predominating in sulfide-rich habitats indicates common ancestral adaptation to sulfide-rich ecosystems between these two families.

Repro57 mice, induced with N-ethyl-N-nitrosourea and harboring a mutation in the Rnf212 gene, exhibit infertility in both homozygous mutant males and females. Rnf212 plays a crucial role in recombination and crossover designation. In male repro57 homozygous mutants, spermatocytes often degenerate during late prophase, and mature spermatozoa are absent in the seminiferous epithelium, indicating arrested spermatogenesis as the cause of infertility. Despite reports of infertility in Rnf212 knockout female mice, the specific mechanisms underlying infertility in female repro57 homozygous mutants remain elusive. This study investigates the chromosomal and kinetochore patterns of mature oocytes and their developmental potential following in vitro fertilization in female repro57 homozygous mutant mice. While all wild-type oocytes progress to metaphase II and exhibit euploidy, all repro57 homozygous mutant mouse oocytes display aneuploidy. Additionally, kinetochore distances in repro57 homozygous mutant oocytes exceed those observed in wild-type counterparts. Although no significant differences are noted in fertilization and early embryo development rates between wild-type and repro57 homozygous mutant mice, embryos derived from repro57 homozygous mutants exhibit significantly lower morula and blastocyst rates, accompanied by frequent cytokinesis failure and vacuole formation. These findings suggest that premature segregation of sister chromatids in repro57 homozygous mutant mice adversely impacts later stages of embryo development.

TK-ALCL1, a novel anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK + ALCL) cell line, was established from the primary tumor site of a 59-year-old Japanese male patient. The immune profile of TK-ALCL1 corresponds to that seen typically in primary ALCL cells, i.e., positive for ALK, CD30, EMA, and CD4, but negative for CD2, CD3, CD5, CD8a, and EBV-related antigens. The rearrangement of the T cell receptor-gamma locus shows that TK-ALCL1 is clonally derived from T-lineage lymphoid cells. FISH and RT-PCR analysis revealed that TK-ALCL1 has the nucleophosmin (NPM)-ALK fusion transcript, which is typical for ALK + ALCL cell lines. When TK-ALCL1 was subcutaneously inoculated into 6-week-old BALB/c Rag2 -/- /Jak3 -/- (BRJ) mice, it formed tumor masses within 4-6 weeks. Morphological, immunohistochemical, and molecular genetic investigations confirmed that the xenograft and the original ALCL tumor were identical. The ALK inhibitors Alectinib and Lorlatinib suppressed proliferation in a dose-dependent manner. Thus, TK-ALCL1 provides a useful in vitro and in vivo model for investigation of the biology of ALK + ALCL and of novel therapeutic approaches targeting ALK., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Upadacitinib, a recently approved Janus kinase (JAK) inhibitor specific for JAK1, may be a promising candidate in patients with ulcerative colitis (UC) who present no response or intolerance to first-line JAK inhibitors. We assessed the therapeutic impact of upadacitinib on six UC patients who demonstrated an inadequate response or intolerance to tofacitinib or filgotinib. After 2 months of treatment, 5 patients (83.3%) achieved clinical remission, and all patients experienced decreased levels of C-reactive protein. One patient had coronavirus disease 2019 pneumonia and showed a mild increase in transaminase levels. This case series highlights the potential utility of a rotation strategy among JAK inhibitors.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Purpose: Multiparametric arterial spin labeling (MP-ASL) can quantify cerebral blood flow (CBF) and arterial cerebral blood volume (CBV a ). However, its accuracy is compromised owing to its intrinsically low SNR, necessitating complex and time-consuming parameter estimation. Deep neural networks (DNNs) offer a solution to these limitations. Therefore, we aimed to develop simulation-based DNNs for MP-ASL and compared the performance of a supervised DNN (DNN Sup ), physics-informed unsupervised DNN (DNN Uns ), and the conventional lookup table method (LUT) using simulation and in vivo data., Methods: MP-ASL was performed twice during resting state and once during the breath-holding task. First, the accuracy and noise immunity were evaluated in the first resting state. Second, CBF and CBV a values were statistically compared between the first resting state and the breath-holding task using the Wilcoxon signed-rank test and Cliff's delta. Finally, reproducibility of the two resting states was assessed., Results: Simulation and first resting-state analyses demonstrated that DNN Sup had higher accuracy, noise immunity, and a six-fold faster computation time than LUT. Furthermore, all methods detected task-induced CBF and CBV a elevations, with the effect size being larger with the DNN Sup (CBF, p = 0.055, Δ = 0.286; CBV a , p = 0.008, Δ = 0.964) and DNN Uns (CBF, p = 0.039, Δ = 0.286; CBV a , p = 0.008, Δ = 1.000) than that with LUT (CBF, p = 0.109, Δ = 0.214; CBV a , p = 0.008, Δ = 0.929). Moreover, all the methods exhibited comparable and satisfactory reproducibility., Conclusion: DNN Sup outperforms DNN Uns and LUT with respect to estimation performance and computation time., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Vitronectin (VN) is an extracellular matrix protein with a crucial role in regulating bone remodeling. In this study, we aimed to investigate the effect of VN deficiency in a mouse model of osteoporosis induced by ovariectomy (OVX). The findings revealed that the absence of VN led to an increase in the activity of tartrate-resistant acid phosphatase (TRAP), a marker for osteoclasts, in the plasma of OVX-operated mice. TRAP staining further demonstrated that VN deficiency resulted in a higher number of osteoclasts within the femurs of OVX-operated mice. X-ray micro-computed tomography analysis of the femurs in OVX-operated mice indicated that VN deficiency significantly suppressed the OVX-induced increase of marrow area and total volume of bone. Additionally, we assessed structural model index (SMI) and degree of anisotropy (DA) as indices of osteoporosis. The results showed that VN deficiency effectively attenuated the OVX-induced increase in SMI and DA among OVX-operated mice. In summary, our study demonstrates the vital role of VN in regulating osteoclastogenesis and bone remodeling in the mouse model of osteoporosis.

Retinoic acid (RA) plays a critical role in cell growth and tissue development. RA is synthesized from retinoids through oxidation processes by the retinaldehyde dehydrogenase (Raldh) family. However, the expression of Raldhs during pituitary development and the identification of Raldh -expressing cells in the adult pituitary have not been fully elucidated. Here, we performed in situ hybridization to localize the three Raldh isoforms ( Raldh1-3 ) in fetal and adult mouse pituitary glands. The results showed that Raldh2 expression was observed in Rathke's pouch from embryonic day 13.5 (E13.5), and this expression was sustained in the anterior lobe of the pituitary primordium from E15.5 to E17.5. In contrast, Raldh1 and Raldh3 were rarely detectable. Real-time PCR analysis revealed that Raldh2 was the predominant isoform expressed in the adult pituitary, although Raldh1 was also expressed to a lesser extent. In the adult pituitary, Raldh1 -expressing cells were primarily observed in the posterior lobe. Raldh2 -expressing cells were found in the marginal cell layer and parenchyma of the anterior lobe and were immunopositive for aldolase C (folliculostellate cells), but not for anterior pituitary hormones. These results suggest that RA is an important regulatory factor in the functions of the pituitary throughout its development in mice., Competing Interests: VThe authors declare that there are no conflicts of interest., (2024 The Japan Society of Histochemistry and Cytochemistry.)

There are numerous macrophages and dendritic cells in lymph nodes (LNs). Recent studies have highlighted that sinus macrophages (SMs) in LNs possess antigen-presenting capabilities and are related to anti-cancer immune responses. In this study, we assessed the distribution of SMs in mesenteric LNs removed during surgery for colorectal cancer. A marked reduction of SMs was noted in elderly patients, particularly those over 80 years old. We observed a disappearance of CD169-positive cells in LNs where SMs were reduced. In silico analysis of publicly available single-cell RNA sequencing data from LNs revealed that CD169-positive macrophages express numerous genes associated with antigen presentation and lymphocyte proliferation, similar to dendritic cells' functions. In conclusion, our study demonstrates that SMs, potentially crucial for immune activation, diminish in the LNs of elderly patients. This reduction of SMs may contribute to the immune dysfunction observed in the elderly.

The tumor suppressor TP53 gene, the most frequently mutated gene in human cancers, produces the product tumor protein p53, which plays an essential role in DNA damage. p53 protein mutations may contribute to tumorigenesis by loss of tumor suppressive functions and malignancy of cancer cells via gain-of-oncogenic functions. We previously reported that mutant p53 proteins form aggregates and that cytoplasmic p53 aggregates were associated with poor prognosis in human ovarian cancer. However, the prognostic impact of p53 aggregation in other tumors including lung squamous cell carcinoma (SCC) is poorly understood. Here, we demonstrated that lung SCC cases with cytoplasmic p53 aggregates had a significantly poor clinical prognosis. Analysis via patient-derived tumor organoids (PDOs) established from lung SCC patients and possessing cytoplasmic p53 aggregates showed that eliminating cytoplasmic p53 aggregates suppressed cell proliferation. RNA sequencing and transcriptome analysis of p53 aggregate-harboring PDOs indicated multiple candidate pathways involved in p53 aggregate oncogenic functions. With lung SCC-derived cell lines, we found that cytoplasmic p53 aggregates contributed to cisplatin resistance. This study thus shows that p53 aggregates are a predictor of poor prognosis in lung SCC and suggests that detecting p53 aggregates via p53 conventional immunohistochemical analysis may aid patient selection for platinum-based therapy., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Maintaining higher-level functional capacity is important for independent living in older age. The aging trajectory of the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) has three patterns; however, the subscale patterns are unclear., Aims: This study aimed to clarify the aging trajectory patterns of the TMIG-IC subscales among community-dwelling older Japanese., Methods: Participants were 3,169 community-dwelling older Japanese who participated in the 2012-2022 mail survey of the Otassha study. The aging trajectory patterns of the TMIG-IC total and subscale scores for those aged 65-90 years were identified using group-based trajectory modeling. Further, the combination frequency of the subscale trajectory patterns was determined., Results: Three patterns were identified: early-onset decreasing, late-onset decreasing, and high-stable., Discussion: The instrumental activities of daily living (IADL) trajectory was maintained until approximately 80 years of age; however, chronic disease prevailed the most in the early-onset decreasing pattern. The early-onset decreasing pattern of intellectual activity (IA) was present in 25% of participants, showing impaired IA from 65 years of age. The late-onset decreasing pattern of social roles (SR) was present in 30% of participants, showing a sharp decline compared to other subscales. For many people, the patterns of decrease in SR and IA overlapped., Conclusions: To maintain higher-level functional capacity, interventions that include disease management and prevention of decline in IADL and increase the awareness of the social support provided throughout old age and interventions for people with an early decline in IA should be implemented., (© 2024. The Author(s).)

X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP) are uncommon diseases caused by loss-of-function and gain-of-function mutations, respectively, in the erythroid form of 5-aminolevulinic acid synthetase, ALAS2, which encodes the first enzyme in heme biosynthesis. A related sideroblastic anemia is due to mutations in SLC25A38, which supplies mitochondrial glycine for ALAS2 (SLC25A38-CSA). The lack of viable animal models has limited studies on the pathophysiology and development of therapies for these conditions. Here, using CRISPR-CAS9 gene editing technology, we have generated knock-in mouse models that recapitulate the main features of XLSA and XLPP, and, using conventional conditional gene targeting in embryonic stem cells, we also developed a faithful model of the SLC25A38-CSA. In addition to examining the phenotypes and natural history of each disease, we determine the effect of restriction or supplementation of dietary pyridoxine (vitamin B6), the essential cofactor of ALAS2, on the anemia and porphyria. In addition to the well-documented response of XLSA mutations to pyridoxine supplementation, we also demonstrate the relative insensitivity of the XLPP porphyria, severe sensitivity of the XLSA models, and an extreme hypersensitivity of the SLC25A38-CSA model to pyridoxine deficiency, a phenotype that is not shared with another mouse hereditary anemia model, Hbbth3/+ -thalassemia intermedia. Thus, in addition to generating animal models useful for examining the pathophysiology and treatment of these diseases, we have uncovered an unsuspected conditional synthetic lethality between the heme synthesis-related CSAs and pyridoxine deficiency. These findings have the potential to inform novel therapeutic paradigms for the treatment of these diseases., (Copyright © 2024 American Society of Hematology.)

Background: As gastric cancer patients aged ≥ 85 years have a short life expectancy and often die from other diseases such as pneumonia, indications for surgery are controversial. In this study, we retrospectively analyzed the prognostic factors of elderly patients with gastric cancer who are candidates for curative gastrectomy., Methods: Among 114 patients aged ≥ 85 years with gastric cancer at our hospital between 2010 and 2019, prognostic factors were examined using the Cox proportional hazards model in 76 patients excluding those with cStage IVB or endoscopic submucosal dissection. We also analyzed the factors of pneumonia death., Results: cStage was I/IIA/IIB/III/IVA in 37/6/14/14/5 patients, respectively. Treatment included distal gastrectomy in 28 patients, total gastrectomy in 6, local resection in 9, others in 3, and no surgery in 30. In univariate analyses of overall survival, Eastern Cooperative Oncology Group Performance Status, physiological score of Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM), Onodera's prognostic nutritional index, cStage, and treatment were prognostic factors. In a multivariate analysis, POSSUM physiological score, cStage, treatment method {no surgery vs. distal gastrectomy: hazard ratio (HR) 5.78, 95% confidence interval (CI) 2.33-14.3}, (total gastrectomy vs. distal gastrectomy: HR 4.26, 95% CI 1.22-14.9) were independent prognostic factors. In univariate analyses of pneumonia-specific survival, treatment (total gastrectomy vs. distal gastrectomy: HR 6.98, 95% CI 1.18-41.3) was the only prognostic factor., Conclusions: The prognosis of distal gastrectomy was better than that of non-surgery even in patients aged ≥ 85 years. However, total gastrectomy was considered to be avoidable due to the high rate of postoperative pneumonia death., (© 2024. The Author(s).)

Aim: Acute pancreatitis is a complication of acute liver failure (ALF). This study aimed to investigate the prevalence of and clinical features associated with acute pancreatitis in patients with ALF., Methods: We retrospectively analyzed a cohort of ALF patients without hepatic encephalopathy diagnosed during a period 2011-2018, and compared clinical features between patients with acute pancreatitis and those without. Acute pancreatitis was diagnosed according to the Acute Pancreatitis Clinical Practice Guidelines 2021. A multivariate analysis was carried out to identify factors associated with acute pancreatitis., Results: There were 83 ALF patients without hepatic encephalopathy (34 men; 11 deaths; 6 liver transplants; median age, 63 years). Acute pancreatitis occurred in nine patients (10.8%). The median time duration from ALF to the onset of acute pancreatitis was 8 days. The survival rate was lower in patients with than those without acute pancreatitis (22% vs. 86%). The model for end-stage liver disease score (hazard ratio 1.10, 95% confidence interval 1.03-1.18) was found to be a significant factor associated with acute pancreatitis, whereas triglyceride, age, and sex were not., Conclusions: A high model for end-stage liver disease score may be a marker to stratify patients with ALF at a risk of acute pancreatitis., (© 2024 Japan Society of Hepatology.)

Folate receptor α (FRα) is a cell-surface protein and an attractive target for cancer treatment. We investigated the association between FRα expression and the tumor immune microenvironment in patients with cervical cancer. We examined whole tumor sections of 123 patients with cervical cancer: 67 and 56 sections of squamous cell carcinoma (SCC) and non-SCC, respectively. FRα expression was assessed using immunohistochemical staining with the anti-FRα monoclonal antibody clone 26B3. Programmed death-ligand 1 (PD-L1) expression was assessed using a combined positive score (CPS). The intratumoral CD3 and CD8 cell densities were calculated as the average number of positive cells in five independent areas. FRα-positivity was identified in 72.4% of the patients, and it differed by histology (SCC vs. non-SCC; 55.2% vs. 92.9%, P<0.001). PD-L1 status was positive (CPS ≥1) in 75.6% and was more commonly expressed in patients with SCC (SCC vs. non-SCC; 83.5% vs. 66.1%, P=0.02). FRα expression had a weak correlation with PD-L1 expression (r=-0.22, P<0.001) and CD8-positive cells (r=-0.19, P=0.03). FRα-positivity was more frequently observed in the PD-L1 CPS <10 group than in the PD-L1 CPS ≥10 group (81% vs. 64%, P=0.03). FRα-high was significantly associated with poor prognosis, especially in the PD-L1 CPS ≥10 groups (hazard ratio: 4.10, 95% confidence interval: 1.39-12.06, P=0.01). In conclusion, FRα expression was higher in patients with cervical cancer and PD-L1 CPS <10 than in those with CPS ≥10. Targeting FRα expression may be a potential therapeutic strategy for cervical cancer patients with low or negative PD-L1 expression., Competing Interests: T.N. reports personal fees from Takeda Pharmaceutical Company, Eisai, and AstraZeneca outside of the submitted work. E.N. reports personal fees from Pfizer, Taiho, Eli Lilly, AstraZeneca, Chugai, and Eisai outside of the submitted work. K.Y. reports receiving grants from Merck Sharp & Dohme, Daiichi Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe and report personal fees from Pfizer, Eisai, Astrazeneca, Eli Lilly, Takeda, Chugai, MSD, FujiFilm Pharma, Bayer, Asteras, Boeringer Ingelheim, Daiichi Sankyo, PDR pharma, Sanofi outside of the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

Interstitial lung disease (ILD) or pneumonitis caused by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) or immune checkpoint inhibitors (ICI) is a major concern in the treatment of non-small cell lung cancer (NSCLC). Whether the addition of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors can reduce the incidence of drug-induced ILD remains unclear. We conducted a systematic review to assess the incidence of ILD induced by EGFR-TKIs or ICIs in the presence or absence of VEGF/VEGFR inhibitors in relevant randomized trials between January 2009 and October 2023. The primary outcome was the odds ratio for the incidence of ILD in all patients worldwide and Asians. Secondary outcomes were the odds ratios (ORs) of the incidence at grade-3 or higher ILD in all patients worldwide and Asians. We identified 13 randomized studies, one sub-analysis in the EGFR-TKI group, and three randomized studies in the ICI group. In the EGFR-TKI group, the OR of ILD incidence at any grade with VEGF/VEGFR inhibitors was 0.54 (95% CI, 0.32-0.90; p = 0.02), which represented a significantly lower incidence than that without VEGF/VEGFR inhibitors. Contrarily, the OR of ILD incidence at grade ≥ 3 with VEGF/VEGFR inhibitors was 1.00 (95% CI, 0.43-2.36; p = 0.99). In all subjects in the ICI group, the OR of ILD incidence at any grade with VEGF/VEGFR inhibitors was 0.78 (95% CI, 0.51-1.21; p = 0.27). The systematic review demonstrated that the addition of VEGF/VEGFR inhibitors could reduce the incidence of drug-induced ILD at any grade caused by EGFR-TKI in patients with NSCLC but could not reduce that at grade ≥ 3. The ILD induced by ICIs remains undetermined owing to the limited number of randomized trials for which ILD data are available., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?RecordID=409534, identifier CRD42023409534., Competing Interests: YF reports receiving personal fees for honoraria for lectures from AstraZeneca, Amgen, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Merck Biopharma, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical, outside the submitted work; reports receiving personal fees for being on the advisory board from AstraZeneca, Chiome Bioscience, Daiichi-Sankyo, Micron, Otsuka Pharmaceutical, and Ono Pharmaceutical, outside the submitted work; reports receiving research grants from Abbvie, Amgen, AnHeart, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Incyte, Merck KGaA, Merck Sharp & Dohme, and Taiho Pharmaceutical, outside the submitted work. TY reports receiving personal fees for honoraria for lectures from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck Biopharma, Merck Sharp & Dohme, Ono Pharmaceutical, and Taiho Pharmaceutical, outside the submitted work; reports receiving personal fees for being on the advisory board from Daiichi-Sankyo. JS reports receiving personal fees for honoraria for lectures from AstraZeneca, Amgen, Chugai, Merck Biopharma, Merck Sharp & Dohme, Novartis, Pfizer, Taiho Pharmaceutical and Takeda Pharmaceutical, outside the submitted work. RM reports receiving personal fees for honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, Merck Sharp & Dohme, Ono Pharmaceutical, Pfizer and Taiho Pharmaceutical, outside the submitted work. KM reports receiving personal fees for honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Merck Sharp & Dohme, Pfizer and Taiho Pharmaceutical, outside the submitted work; reports receiving personal fees for consulting fees from Otsuka Pharmaceutical. YH reports receiving research grants from Eli Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fujiwara, Shimomura, Yamaguchi, Shimizu, Watanabe, Matsuzawa, Murotani and Horio.)

Pneumonia after cervical spinal cord injury (CSCI) is a common and serious complication; however, its nutrition-related etiology has not yet been elucidated. This study aimed to elucidate the effects of nutritional factors on pneumonia after CSCI. Patients with acute traumatic CSCI who were admitted within 3 days after injury and followed up for at least 3 months were retrospectively examined. Occurrence of pneumonia, nutritional status, severity of dysphagia, vital capacity, use of respirators, and motor scores for paralysis were evaluated. Of 182 patients included in this study, 33 (18%) developed pneumonia. Multiple logistic regression analysis revealed that low nutritional status, severe paralysis, and low vital capacity were significant risk factors for pneumonia. The severity of paralysis, respiratory dysfunction, and poor nutritional status can affect the occurrence of pneumonia after CSCI. In addition to respiratory management, nutritional assessment and intervention may play key roles in preventing pneumonia associated with spinal cord injury-induced immune depression. Nutritional care should be provided as soon as possible when the nutritional status of a patient worsens after an injury., (© 2024. The Author(s).)

Background: Perioperative use of immune checkpoint blockade (ICB) improves survival in patients with early-stage cancer. Treatment-related adverse events (AEs), frequently involve the endocrine system which may increase perioperative complications and affect quality of life., Objective: We conducted a meta-analysis to elucidate the impact of adding ICB to conventional neoadjuvant/adjuvant therapy on the incidence of endocrine AEs., Design: A systematic review and meta-analysis of randomize-controlled trials (RCTs)., Data Sources and Methods: A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed for RCTs comparing groups with and without the addition of ICB to conventional perioperative therapy in patients with cancer. Outcomes included all-grade and grade 3-5 thyroiditis, hyperthyroidism, hypothyroidism, adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, and hyperglycemia. The odds ratios (ORs) of all-grade and grade 3-5 endocrine were pooled using the random-effect model meta-analysis., Results: Twenty-four RCTs comprising 12,199 patients were identified for meta-analysis. The addition of ICB was associated with higher incidence of thyroiditis [all grade: OR = 3.53 (95% confidence interval (CI): 1.88-6.64)], hyperthyroidism [all-grade: 7.18 (4.30-12.01); grade 3-5: 3.93 (1.21-12.82)], hypothyroidism [all-grade: 5.39 (3.68-7.90); grade 3-5: 3.63 (1.18-11.11)], adrenal insufficiency [all-grade: 3.82 (1.88-7.79); grade 3-5: 5.91 (2.36-14.82)], hypophysitis [all-grade: 10.29 (4.97-21.3); grade 3-5: 5.80 (1.99-16.92)], and type 1 diabetes mellitus [all-grade: 2.24 (1.06-4.74); grade 3-5: 3.49 (1.21-10.08)]. The cumulative incidence of each grade 3-5 endocrine AE was low (<1.3%). No grade 5 AEs leading to death were observed., Conclusion: The addition of neoadjuvant/adjuvant ICB to conventional therapy was associated with an increased incidence of several endocrine AEs. Clinicians should be aware of the risk of endocrinopathy from the perioperative ICB use to facilitate risk-benefit discussion with patients with early-stage cancer., Trial Registration: The protocol of this research was registered in PROSPERO (CRD42022332624)., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Objectives: Frailty is a significant cause of adverse health events including long-term care and hospitalization. Although information and communication technology (ICT) has become an integral part of modern life, it remains unclear whether ICT use is associated with frailty., Design: A cross-sectional study (Integrated Longitudinal Studies on Aging in Japan, ILSA-J)., Setting and Participants: Aged 75 and older data from the ILSA-J in 2017 (n = 2893)., Methods: ICT use was measured using the technology usage sub-items of the Japan Science and Technology Agency Index of Competence. Specifically, the use of mobile phones, ATMs, DVD players, and sending e-mails were rated as "yes" (able to do) or "no" (unable to do), with the first quintile (≤1 point) defined as ICT non-users. Frailty was assessed using the Japanese version of the Cardiovascular Health Study criteria based on the phenotype model (e.g., weight loss, slowness, weakness, exhaustion, and low activity). Further, multivariate logistic regression analysis analyzed its association with ICT use. Subgroup analyses were stratified according to gender, years of education, and living arrangements., Results: Higher ICT use was not associated with frailty after adjusting for covariates (odds ratio [OR]: 0.53; 95%CI 0.39-0.73). Similar associations were found in the sub-groups of women (OR 0.45, 95%CI 0.30-0.66), <13 years of education (OR 0.48, 95%CI 0.34-0.67), living alone (OR 0.46, 95%CI 0.27-0.79), and living together (OR 0.57, 95%CI 0.38-0.85). No association existed between using ICT and frailty in the sub-groups of men and ≥13 years of education., Conclusions and Implications: Higher ICT use is associated with the absence of frailty in individuals 75 years and older. Such benefits may be particularly pronounced in women, those with lower levels of education, and older adults living alone or with others., (© 2024. The Author(s).)

Purpose: Cancer cachexia leads to poor outcomes, especially for patients with advanced stage disease. The cachexia index (CXI), a novel biomarker for cancer cachexia, has been identified as a prognostic indicator for several malignancies. The present study aimed to clarify the prognostic significance of the CXI for patients with recurrent pancreatic cancer., Methods: This retrospective study enrolled 113 patients diagnosed with recurrence following pancreatectomy for pancreatic cancer, to analyze the association between the CXI and prognostic survival., Results: The 2-year overall survival rate and median survival of all patients were 28.5% and 12.6 months, respectively. The 2-year overall survival curve in the high CXI group was significantly better than that in the low CXI group (p < 0.001). The rate of chemotherapy after recurrence was significantly lower in the low CXI group than in the high CXI group (p = 0.002). Multivariate analysis identified the CXI as an independent prognostic factor for patients with recurrent pancreatic cancer (p = 0.011)., Conclusions: The CXI proved useful for predicting the post-recurrence prognosis of patients with recurrent pancreatic cancer. Patients with a low CXI at the time of recurrence have poorer prognostic outcomes than those with a high CXI., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Introduction: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown., Methods: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox regression analysis was used., Results: Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 was on observation alone. Baseline characteristics were similar across the three cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (interquartile range: NR-NR) and was 5.5 (interquartile range: 2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those treated with durvalumab or in the observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p < 0.001 for both comparisons). There was no difference in rwPFS between the durvalumab and the observation cohorts. No significant difference in overall survival across the three cohorts was detected, likely due to the limited follow-up. Any-grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors. Of these, 14 (38%) patients developed trAEs including five patients with pneumonitis (14%; 2 [5.4%] grade ≥3) and five patients with diarrhea (14%; 1 [2.7%] grade ≥3)., Conclusions: This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with a significantly longer rwPFS compared to durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib., Competing Interests: Disclosure Dr. Nassar receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology and consulting fees from Guidepoint Global. Dr. Kim is on the advisory board for Amgen. Dr. Shepherd reports having stock and other ownership interests from Eli Lilly and AstraZeneca; receiving honoraria from AstraZeneca, Merck Serono, Takeda, and Daiichi Sankyo; having consulting/advisory role at AstraZeneca and Merck Serono; and receiving research funding from Eli Lilly (inst), Pfizer (inst), Bristol-Myers Squibb (inst), AstraZeneca/MedImmune (inst), and Roche Canada (inst). Dr. Gray reports receiving grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co., Inc., Novartis, and Pfizer; receiving consulting fees from AbbVie, AstraZeneca, Blueprint Medicines, EMD Serono, Gilead Sciences, Inc., Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co., Inc., Novartis, OncoCyte Biotechnology, Spectrum ODAC, Takeda Pharmaceuticals, and Triptych Health Partners; and having leadership role as SWOG Lung Committee Chair, IASLC Board of Director member, and ASCO Education Committee Ex-Chair. Dr. Dilling reports receiving consulting fees from AstraZeneca and support for travel from NCCN. Dr. Neal reports receiving grants from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GlaxoSmithKline, Janssen, AbbVie, and Novocure; receiving consulting fees from AstraZeneca, Genentech/Roche, Exelixis, Takeda Pharmaceuticals, Eli Lilly and Company, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, AbbVie, Summit Therapeutics, Novartis, Novocure, Janssen Oncology, and AnHeart Therapeutics; and receiving honorarium from CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium, and HMP Education. Dr. Wakelee reports receiving grants from Arrys Therapeutics Research, AstraZeneca/Medimmune, Bristol-Myers Squibb, Genentech/Roche, Merck, Helsinn, Seagen, and Xcovery; and serving on the advisory board of Mirati (compensated)—ended November 2022, IOBiotech (compensated)—October 2023, Merck (NOT compensated), and Genentech/Roche/Bristol-Myers Squibb/AstraZeneca (NOT compensated). Dr. S.H. Lin reports receiving grants from STCube Pharmaceuticals, Beyond Spring, and Nektar Therapeutics; consulting fees from XRAD Therapeutics; serving on the advisory board of AstraZeneca; having stock/stock options from Apple, Google, Amazon, Tesla, Meta, Rivian, and CreatvMicrotech; and having other support from SEEK Diagnostics (co-founder). Dr. Patil reports receiving grants from Gilead Research Scholars and LUNGevity Foundation Award; consulting fees from AstraZeneca, Boehringer Ingelheim, Bicara, Daiichi, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Pfizer, Sanofi, Regeneron, Roche/Genentech, Takeda, Gilead Research Scholars, and LUNGevity Foundation Award; and honorarium from Janssen. Dr. Bar reports receiving grants from Merck Sharp & Dohme, AstraZeneca, Roche, Bristol-Myers Squibb, Takeda, AbbVie, Bayer, Boehringer Ingelheim, and Pfizer; receiving consulting fees from AstraZeneca, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Takeda, AbbVie, Pfizer, Bayer, and VBL; and having leadership role from Lung Ambition Consortium, Israel Lung Cancer Group, and IASLC committee. Dr. Marron receives grants from Regeneron, Bristol-Myers Squibb, Merck, Boehringer Ingelheim, NCI, and Cancer Research Institute; and serving on the advisory board of AbbVie, Celldex, and Rockefeller University. Dr. Yu receives grants/contracts from AstraZeneca, Pfizer, Daiichi Cullinan Oncology, Janssen, Novartis, Blueprint med, Black Diamond, and Systimmune and consulting fees from AstraZeneca, Daiichi, Taiho, Takeda, Janssen, Amgen, AbbVie, Novocure, and Ipsen. Dr. Owen receives grants/contracts from Bristol-Myers Squibb, Merck, Palobiofarma, Genentech, Onc.AI, and Pfizer; and travel support from Amgen, AstraZeneca, and Genentech. Rocha receives grants/contracts from SEOM, ESMO Fellowship, and AECC; and travel support from Merck Sharp & Dohme, AstraZeneca, and Bristol-Myers Squibb. Dr. Arriola receives grants/contracts from AstraZeneca and Bristol-Myers Squibb; honorarium from Eli Lilly, AstraZeneca, Roche, Takeda, Merck Sharp & Dohme, Pfizer, Janssen, and Bristol-Myers Squibb; and travel support from AstraZeneca, Roche, and Pfizer. Dr. Cheng receives grants/contracts from AstraZeneca and Genentech; and serving on the advisory board of Janssen, G1 Therapeutics, and AstraZeneca. Dr. Parikh receives consulting fees from Jazz Pharmaceuticals, Guardant Health, and AstraZeneca; and honorarium from MJH Life Sciences. Dr. Harris receives grants/contract from NIH P30CA062203, the UC Irvine Comprehensive Cancer Center using UCI Anti-Cancer Challenge Grant, and ACS Seed Grant 129801-IRG-16-187-13-IRG; and serving on the advisory board of UC Irvine as DSMB member. Dr. Nagasaka receives consulting fees from Caris Life Sciences; honorarium/speaker fees from AstraZeneca, Daiichi, Novartis, EMD Serono self, Pfizer, Eli Lilly, Genentech, Regeneron, Takeda, Janssen, Blueprint, and Mirati; travel support from AnHeart Therapeutics; and stock/stock options from Mbrace Therapeutics. Dr. Valazquez receives grants/contracts from ASCO, American Association for Cancer Research (AACR), LUNGevity, NIA P30AG015272, NCI 5U54CA242646-03 Conquer Cancer and Niarchos Foundation, UCSF Clinical Practice Group, and AAMC; consulting fees from AstraZeneca, Merus, Novocure, and Cadence Communications & Research; and having stock/stock options from Corbus Pharmaceuticals. Dr. J.J. Lin receives grants/contracts from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; consulting fees from Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, AnHeart Therapeutics, Takeda, CLaiM Therapeutics, Regeneron, Pfizer, Turning Point Therapeutics, Daiichi Sankyo, AstraZeneca, and Merus. Dr. Piotrowska receives grants/contracts from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GlaxoSmithKline, Cullinan Oncology, Daiichi Sankyo, AbbVie, Janssen, and Blueprint; consulting fees from Taiho, Janssen, Takeda, AstraZeneca, Cullinan Oncology, C4 Therapeutics, Jazz Pharmaceuticals, and Blueprint; and honorarium from Daiichi Sankyo, Janssen, and Eli Lilly (honoraria for nonpromotional educational events). Dr. Reuss receives grants/contracts from Genentech/Roche, Verastem, Nuvalent, and LUNGevity Foundation; consulting fees from Genentech/Roche, Sanofi/Genzyme, Personalis, Guardant, AstraZeneca, Bristol-Myers Squibb, Arcus, AbbVie, Daiichi Sankyo, Catalym, Seagen, and Gilead; and honorarium from AstraZeneca and Merck. Dr. Baena Espinar receives consulting fees from AstraZeneca, Roche, and Merck Sharp & Dohme; honorarium from AstraZeneca, Roche, and Merck Sharp & Dohme; payment for expert testimony from Roche; and travel support from Roche and Janssen. Leal receives research funding to institution from Pfizer, Advaxis, and Bayer, outside the submitted work. Dr. Mak receives grants/contracts from ViewRay; consulting fees from AstraZeneca, Novartis, and Sio Capital Management; and other support from Founder of HealthAI. Dr. Naqash receives grants/contracts from SWOG Hope Foundation and FDA Broad Agency Contract; serving on the advisory board of JCO Precision Oncology; receiving travel support from SITC/American Association for Cancer Research (AACR)/Conquer Cancer Foundation/BinayTara Foundation and Foundation Med/Caris Life Sciences, and Jazz Pharmaceuticals; and funding to institution for trials from Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals, Immunophotonics, and Selexine. Dr. Goldberg receives grants/contracts from AstraZeneca, Boehringer Ingelheim, and Mirati; and serving on the advisory board of AstraZeneca, Bristol-Myers Squibb, Amgen, Sanofi, Genzyme, Daiichi Sankyo, Regeneron, Takeda, Janssen, Summit, and Merck. The remaining authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background and Aim: Nonsteroidal anti-inflammatory drugs (NSAIDs) damage the small intestine via neutrophil infiltration driven by the mucosal invasion of enterobacteria. The antimicrobial function of neutrophils is partially dependent on neutrophil extracellular traps (NETs). Excessive NET formation has been associated with several inflammatory diseases. Here, we aimed to investigate the role of NETs in NSAID-induced small intestinal damage using human samples and an experimental mouse model., Methods: Human small intestine specimens were obtained from NSAID users during double-balloon enteroscopy. Wild-type, protein arginine deiminase 4 (PAD4) knockout, and antibiotic-treated mice were administered indomethacin to induce small intestinal injury. The expression of NET-associated proteins, including PAD4, citrullinated histone H3 (CitH3), cell-free DNA, and myeloperoxidase (MPO), was evaluated., Results: The double-positive stained area with CitH3 and MPO, which is specific for neutrophil-derived extracellular traps, was significantly high in the injured small intestinal mucosa of NSAID users. In a mouse model, small intestinal damage developed at 6 h after indomethacin administration, accompanied by increased mRNA levels of interleukin-1β and keratinocyte chemoattractant and elevated NET-associated protein levels of PAD4, CitH3, and MPO in small intestine and serum levels of cell-free DNA. Both genetic deletion and pharmacological inhibition of PAD4 attenuated this damage by reducing the mRNA expression of inflammatory cytokines and NET-associated proteins. Furthermore, mice pretreated with antibiotics showed resistance to indomethacin-induced small intestinal damage, with less NET formation., Conclusion: These results suggest that NETs aggravate NSAID-induced small intestinal injury. Therefore, NET inhibition could be a potential treatment for NSAID-induced small intestinal injury., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Interleukin 32 (IL-32) is a proinflammatory cytokine secreted from several kinds of cancer cells. In the present study, we investigated the significance of IL-32 in lung adenocarcinoma by immunohistochemistry and bioinformatics analysis. IL-32 was positive in cancer cells of 21 cases (9.2%) of total 228 cases. Increased IL-32 gene expression was linked to worse clinical course in TCGA analysis, however, IL-32 expression in immunohistochemistry was not associated to clinical course in our cohort. It was also found that high IL-32 expression was seen in cases with increased lymphocyte infiltration. In vitro studies indicated that IFN-γ induced gene expression of IL-32 and PD1-ligands in lung adenocarcinoma cell lines. IL-32, especially IL-32β, also induced overexpression of PD1-ligands in human monocyte-derived macrophages. Additionally, Cancer-cell-derived IL-32 was elevated by stimulation with anticancer agents. In conclusion, IL-32 potentially induced by inflammatory conditions and anticancer therapy and contribute to immune escape of cancer cells via development the immunosuppressive microenvironment. IL-32 might be a target molecule for anti-cancer therapy., (© 2024. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Introduction: We examined the efficacy of a multidomain intervention in preventing cognitive decline among Japanese older adults with mild cognitive impairment (MCI)., Methods: Participants aged 65-85 years with MCI were randomized into intervention (management of vascular risk factors, exercise, nutritional counseling, and cognitive training) and control groups. The primary outcome was changes in the cognitive composite score over a period of 18 months., Results: Of 531 participants, 406 completed the trial. The between-group difference in composite score changes was 0.047 (95% CI: -0.029 to 0.124). Secondary analyses indicated positive impacts of interventions on several secondary health outcomes. The interventions appeared to be particularly effective for individuals with high attendance during exercise sessions and those with the apolipoprotein E ε4 allele and elevated plasma glial fibrillary acidic protein levels., Discussion: The multidomain intervention showed no efficacy in preventing cognitive decline. Further research on more efficient strategies and suitable target populations is required., Highlights: This trial evaluated the efficacy of multidomain intervention in individuals with MCI. The trial did not show a significant difference in preplanned cognitive outcomes. Interventions had positive effects on a wide range of secondary health outcomes. Those with adequate adherence or high risk of dementia benefited from interventions., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) blockade., Methods: The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti-PD-1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor-bearing mice to four treatment groups: control, anti-PD-1 antibodies, PDT, and a combination of anti-PD-1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated., Results: The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti-PD-1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba-1+ cells and the area expressing PD-L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti-PD-1 antibody alone, PDT alone, or the control., Conclusions: PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD-1/PD-L1 blockade., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

The purpose of this study was to investigate the risk of overexposure associated with automatic tube current modulation (ATCM) and automatic couch height positioning compensation mechanism (AHC) in computed tomography (CT) systems, particularly in scenarios involving a gap between the subject and the couch. Results revealed that when AHC was enabled, CT dose index volume (CTDI vol ) increased by approximately 10% at 2.5 cm, 20% at 5.0 cm, and 40% at 10.0 cm gaps compared to close contact conditions. While the AHC function ensures consistent exposure doses and image quality regardless of subject positioning relative to the CT gantry isocenter, the study highlights a potential risk of overexposure when a gap exists between the subject and the couch. These findings offer valuable insights for optimizing CT imaging protocols and underscore the importance of carefully considering subject positioning in clinical practice., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)