The present genome-wide association study (GWAS) aimed to reveal the genetic loci associated with folate metabolites, as well as to detect related gene-environment interactions in Japanese. We conducted the GWAS of plasma homocysteine (Hcy), folic acid (FA), and vitamin B12 (VB12) levels in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study participants who joined from 2005 to 2012, and also estimated gene-environment interactions. In the replication phase, we used data from the Yakumo Study conducted in 2009. In the discovery phase, data of 2,263 participants from four independent study sites of the J-MICC Study were analyzed. In the replication phase, data of 573 participants from the Yakumo Study were analyzed. For Hcy, MTHFR locus on chr 1, NOX4 on chr 11, CHMP1A on chr 16, and DPEP1 on chr 16 reached genome-wide significance (P < 5 × 10-8). MTHFR also associated with FA, and FUT2 on chr 19 associated with VB12. We investigated gene-environment interactions in both studies and found significant interactions between MTHFR C677T and ever drinking, current drinking, and physical activity >33% on Hcy (β = 0.039, 0.038 and -0.054, P = 0.018, 0.021 and <0.001, respectively) and the interaction of MTHFR C677T with ever drinking on FA (β = 0.033, P = 0.048). The present GWAS revealed the folate metabolism-associated genetic loci and gene-environment interactions with drinking and physical activity in Japanese, suggesting the possibility of future personalized cardiovascular disease prevention.

The aim of this study was to explore the clinical utility of serum HER2 extracellular domain (sHER2 ECD) using data from a clinical trial evaluating trastuzumab combined S-1 plus oxaliplatin (SOX) in HER2 positive gastric cancer. sHER2 ECD were prospectively measured at baseline and subsequent treatment courses. Based on each quantile point of baseline sHER2 ECD levels and its early changes, patients were divided into two groups and compared clinical outcomes. 43 patients were enrolled, and 17 patients (39.5%) were positive for baseline sHER2 ECD. Higher baseline sHER2 ECD levels tended to have lower hazard ratios (HRs). When divided into two groups by baseline sHER2 ECD of 19.1ng/ml, median progression-free survival (PFS) and overall survival (OS) was longer in the higher group (mPFS: 16.8 vs 8.7months, p = 0.359. mOS: 35.5 vs 20.6months, p = 0.270), respectively. After initiation of treatment, sHER2 ECD significantly decreased up until the third cycle. Higher reduction rates of sHER2 ECD within 3 cycles also tended to have lower HRs. When divided into two groups by reduction rate of 42.5%, mPFS and mOS was longer in the higher reduced group (mPFS: 17.2 vs 8.7months, p = 0.095. mOS: 65.0 vs 17.8months, p = 0.047), respectively. Furthermore, higher reduction rates could surrogate higher objective response rates (ORR) (ORR: 90% vs 63.2% for 29.5%, p = 0.065. 100% vs 70% for 42.5%, p = 0.085), respectively. Baseline sHER2 ECD levels and its early decline may be useful biomarkers for SOX plus trastuzumab efficacy in HER2 positive gastric cancer.

Metastasis is a major contributor to treatment failure and death in urological cancers, representing an important biomedical challenge at present. Metastases form as a result of cancer cells leaving the primary site, entering the vasculature and lymphatic vessels, and colonizing clones elsewhere in the body. However, the specific regulatory mechanisms of action underlying the metastatic process of urological cancers remain incompletely elucidated. With the deepening of research, circular RNAs (circRNAs) have been found to not only play a significant role in tumor progression and prognosis but also show aberrant expression in various tumor metastases, consequently impacting tumor metastasis through multiple pathways. Therefore, circRNAs are emerging as potential tumor markers and treatment targets. This review summarizes the research progress on elucidating how circRNAs regulate the urological cancer invasion-metastasis cascade response and related processes, as well as their role in immune microenvironment remodeling and circRNA vaccines. This body of work highlights circRNA regulation as an emerging therapeutic target for urological cancers, which should motivate further specific research in this regard.

Patient-derived organoids (PDOs) retain the original tumor's characteristics to a large degree and allow direct evaluation of the drug sensitivity, thereby emerging as a valuable resource for both basic and preclinical researches. Whereas most past studies stereotypically adopted a single PDO as an avatar of the patient, it remains to be investigated whether this assumption can be justified even for the tumor with spatial diversity. To address this issue, we established and characterized multiple PDOs originating from various sites of a patient with advanced uterine carcinosarcoma (UCS). Specifically, cancer cells were separately sampled from three sites; resected UCS tumor tissue, the peritoneal lavage fluid, and an intra-uterine brushing of the tumor. The three derived PDOs were morphologically undistinguishable, displaying typical carcinoma organoids-like appearance, but two of them proliferated at a faster rate. The primary tumor harbored mutations in TP53 and STK11 along with amplifications in CCNE1, ERBB2, and KRAS. These two mutations and the CCNE1 amplification were detected in all PDOs, while either KRAS or ERBB2 amplification was selectively observed in each PDO in a mutually exclusive manner. Observed intra-tumor heterogeneity in HER2 expression was differentially reproduced in the PDOs, which mirrored each PDO's sensitivity to HER2 inhibitors. Inter-PDO heterogeneity was also evident in sensitivity to standard cytotoxic agents. Lastly, a drug screening identified four candidate reagents commonly effective to all PDOs. Collectively, we showed that multiple PDOs could help reproduce the spatial diversity of a tumor and serve as a valuable resource in UCS research in many respects.

The aging population is expected to increase the occurrences of bone sarcoma (BS) and soft tissue sarcoma (STS). Carbon ion radiotherapy (CIRT) is reported to be effective for BS and several STSs. However, the effect of CIRT on clinical outcomes, functional prognoses, and quality of life (QOL) in older patients who underwent CIRT has not been reported. Therefore, we aimed to evaluate the effect of CIRT on clinical outcomes, functional prognoses and QOL in older patients with BS or STS. This retrospective cohort study included 235 patients aged >70 years with BS or STS who underwent CIRT. Overall survival (OS), cancer-specific survival (CSS), and local control (LC) were evaluated in chordoma and non-chordoma patients. Furthermore, factors associated with post-CIRT Toronto Extremity Salvage Score (TESS) and EuroQoL 5-dimension 5-level (EQ-5D-5L) index were assessed. The overall 5-year LC, OS, and CSS rates were 81%, 62%, and 76%, respectively. In the chordoma and non-chordoma groups, the 5-year LC, OS, and CSS rates were 84%, 72%, and 87%; and 77%, 47%, and 60%, respectively. The mean post-CIRT TESS and EQ-5D-5L index were 75% and 0.71, respectively. The TESSs and EQ-5D-5L indices tended to be better among males, younger patients (<76 years old), patients with small tumor volumes, and patients with chordoma. CIRT is effective for older patients with BS, especially with chordoma, and STS with good LC and survival rates. Furthermore, post-treatment limb function and QOL were comparable with those of the other treatments and age groups.

Abstract Background and Aims: Bevacizumab, an anti-angiogenic agent, is reported to enhance antitumor immunity through various mechanisms, including the suppression of regulatory T (Treg) cells. Additionally, a combination therapy involving the anti-PD-L1 monoclonal antibody, atezolizumab, plus bevacizumab (AtezoBev) has emerged as a standard treatment for advanced hepatocellular carcinoma (aHCC). Given that more than half of treated patients do not respond effectively, identifying biomarkers predictive of clinical efficacy has become an urgent matter. However, the investigation into the tumor microenvironment (TME) has been lagging in aHCC compared to other malignancies due to the difficulty in obtaining tumor samples just before the commencement of systemic therapy. Methods: We have established a scheme to analyze the TME by obtaining tumor samples immediately before AtezoBev administration, and explored the relevance to its efficacy, focusing on the tumor-infiltrating lymphocytes (TILs) within those samples. Tumor samples from 94 aHCC patients were collected before AtezoBev administration. TME was assessed in 54 patients via flow cytometry and in 72 patients through RNA sequencing, with certain samples undergoing both analyses. Results: Predominant etiologies in 94 patients were HCV (n=22, 23%), followed by HBV (n=17, 18%), and alcohol abuse (n=16, 17%). The objective response (OR) and disease control rates were 17% and 81%, respectively, with a median progression-free survival (PFS) of 7.6 months. Groups exhibiting high PD-1 positivity of CD8+ T cells (median values as cutoffs) demonstrated superior AtezoBev treatment effects (PFS: 13.1 vs. 4.4 months, p=0.001). In contrast, PD-1 positivity of effector Treg (eTreg) cells in TILs, which reportedly can be one of resistant mechanisms to PD-1 blockade therapy (Togashi Y, et al. Nat Immunol 2020), was not correlated with efficacy. Gene set enrichment analysis highlighted the importance of antigen presentation for OR in groups exhibiting high PD-1 positivity of CD8+ T cells. Additionally, HLA class I expression was elevated in patients achieving an OR. Although previous studies suggest that immunotherapy efficacy could be reduced in non-alcoholic steatohepatitis-related HCC compared with viral-related HCC, no clear association was found between PD-1 positivity of CD8+ T cells or eTreg cells in TILs and etiology. Among the 94 patients, samples from 11 were analyzable at the point of AtezoBev refractoriness, revealing a trend toward reduction in PD-1 positivity of eTreg cells in TILs. Conclusions: Our findings suggest a correlation between the efficacy of AtezoBev for aHCC and the presence of PD-1+CD8+ T cells within the tumor. In contrast, PD-1+ eTreg cells did not induce resistance along with a trend toward reduction after the treatment possibly due to combination with bevacizumab. Citation Format: Hiroaki Kanzaki, Takamasa Ishino, Sadahisa Ogasawara, Sae Yumita, Miyuki Nakagawa, Ryuta Kojima, Keisuke Koroki, Masanori Inoue, Kazufumi Kobayashi, Naoya Kanogawa, Soichiro Kiyono, Masato Nakamura, Takayuki Kondo, Shingo Nakamoto, Tsukasa Takayashiki, Jason Lin, Masahito Kawazu, Mina Komuta, Jun-ichiro Ikeda, Masayuki Ohtsuka, Yosuke Togashi, Naoya Kato. Exploring the efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma in relation to tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7608.

Abstract Background This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. Methods This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child–Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Results Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child–Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Conclusions Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Abstract Background Most evidence of the waning of vaccine effectiveness is limited to a relatively short period after vaccination. Methods Data obtained from a linked database of healthcare administrative claims and vaccination records maintained by the municipality of a city in the Kanto region of Japan were used in this study. The study period extended from April 1, 2020, to December 31, 2022. The duration of the effectiveness of the COVID-19 vaccine was analyzed using a time-dependent piecewise Cox proportional hazard model using the age, sex and history of cancer, diabetes, chronic obstructive pulmonary disease, asthma, chronic kidney disease, and cardiovascular disease as covariates. Results Among the 174,757 eligible individuals, 14,416 (8.3%) were diagnosed with COVID-19 and 936 (0.54%) were hospitalized for COVID-19. Multivariate analysis based on the time-dependent Cox regression model revealed a lower incidence of COVID-19 in the one-dose group (hazard ratio, 0.76 [95% confidence interval, 0.63–0.91]), two-dose (0.89 [0.85–0.93]), three-dose (0.80 [0.76–0.85]), four-dose (0.93 [0.88–1.00]), and five-dose (0.72 [0.62–0.84]) groups. A lower incidence of COVID-19-related hospitalization was observed in the one-dose group (0.42 [0.21–0.81]), two-dose (0.44 [0.35–0.56]), three-dose (0.38 [0.30–0.47]), four-dose (0.20 [0.14–0.28]), and five-dose (0.11 [0.014–0.86]) groups. Multivariable analyses based on the time-dependent piecewise Cox proportional hazard model revealed significant preventive effects of the vaccine at 0–1, 1–2, 2–3, 3–4, 7–8, ≥ 12 months for the incidence of COVID-19 and 0–1, 1–2, 2–3, 3–4, 4–5, 5–6, 7–8, and 9–10 months for hospitalization. Conclusions Vaccine effectiveness showed gradual attenuation with time after vaccination; however, protective effects against the incidence of COVID-19 and hospitalization were maintained for 4 months and ≥ 6 months, respectively. These results may aid in formulating routine vaccination plans after the COVID-19 pandemic.

Chemoresistance in rhabdomyosarcoma (RMS) is associated with poor survival, necessitating the development of novel anticancer drugs. Auranofin (AUR), an anti-rheumatic drug, is a thioredoxin reductase (TXNRD) inhibitor with anticancer properties. Although patient-derived xenograft (PDX) models are essential for studying cancer biology, reports on sarcomas using the PDX model are scarce because of their rarity. This study aimed to investigate the effectiveness of AUR treatment in RMS using a PDX model to evaluate its impact on local progression. A 20-year-old woman who was diagnosed with alveolar RMS was used to generate the PDX model. RMS PDX tumors were implanted in nude mice and divided into non-treated (vehicle) and treated (AUR) groups. Tumor volume and weight were evaluated, and immunohistochemical staining was performed to evaluate local progression of the sarcoma. The relationship between the TXNRD-1 expression and survival probability of patients with RMS was evaluated using publicly available expression cohorts. AUR significantly suppressed RMS tumor progression over time. It also significantly suppressed the tumor size and weight at the time of excision. Histological evaluation showed that AUR induced oxidative stress in the PDX mouse models and inhibited the local progression of RMS by inducing apoptosis. High TXNRD-1 expression was found to be a negative prognostic factor for overall survival in patients with RMS. AUR-induced inhibition of TXNRDs can significantly impede the local progression of RMS through the oxidative stress-apoptosis pathway as demonstrated in PDX models. Thus, targeting TXNRD inhibition may be a promising therapeutic strategy for the treatment of RMS.

To investigate the factors associated with introducing visiting-pharmacist services for community-dwelling older adults in Japan. We conducted a nested case-control study using claims data in a cohort from a city in Tokyo. Patients aged ≥65 years who received visiting-pharmacist services for the first time between April 2014 and March 2020 were considered case patients. A maximum of four controls to each case patient were randomly selected on the basis of sex, age, health insurance systems, and month-year. Medical and long-term care service usage and patient condition were assessed using claims data from the index and preceding months, along with long-term care needs certification data. Multivariable conditional logistic regression analysis was conducted to estimate the adjusted odds ratios with 95% confidence intervals for factors associated with visiting-pharmacist service introduction. A total of 22 949 participants (4591 cases and 18 358 controls) were included, with a median age of 85 years; 59.3% were women. The adjusted odds ratios (95% confidence intervals) of the three most related factors were 27.61 (23.98-31.80) for physicians' home visits, 5.83 (5.08-6.70) for hospitalization, and 4.97 (4.16-5.95) for designated-facility admission. Factors such as prescribing ≧10 medications, visiting nursing, and cancer were positively associated. In contrast, low household income and a high need for support due to cognitive function or disability were negatively associated. This study provides insights into the introduction of visiting-pharmacist services for older adults in Japan. Geriatr Gerontol Int 2024; 24: 344-351.