Manabu Muto’s research while affiliated with Kyoto University Hospital and other places

e15563 Background: FOLFIRI plus aflibercept (AFL) or bevacizumab (BEV) are significant therapeutic options for patients with metastatic colorectal cancer (mCRC) who have failed prior oxaliplatin-based chemotherapy. While accumulating evidence suggests an association between the tumor microenvironment, inflammation, and the prognosis of mCRC, biomarkers predictive of response to these chemotherapy regimens remain unknown. Studies have demonstrated that AFL exerts biological effects on macrophages within the tumor microenvironment. Methods: We conducted a multi-institutional retrospective biomarker study to analyze the relationship between CD68, CD163 (M2 macrophage), iNOS (M1 macrophage), and S100A4 expression in biopsy or surgical colon samples and the efficacy of FOLFIRI plus AFL (cohort A) or plus BEV (cohort B) in Japanese patients with mCRC who failed prior treatment with 5-fluorouracil + oxaliplatin + anti-EGFR agent. The primary outcome was overall response rate (ORR), and the secondary outcome was progression-free survival (PFS) according to the biomarker status. The expression of biomarkers was evaluated independently using immunohistochemical staining scores (IHCSS) by three investigators, including a board-certified pathologist. Statistical analyses were performed using the chi-square test and log-rank test. Results: Forty patients were enrolled in the study, including 19 in cohort A and 21 in cohort B. The median age was 67.5 years (range, 36-79), and 25 patients (62.5%) were male. The ORR was 26.3% in cohort A and 19.0% in cohort B, while median PFS was 11.1 months and 7.1 months, respectively. The percentage of cases that were positive for CD68, CD163, iNOS, and S100A4 were 78.9%, 26.3%, 57.9%, and 89.5% in cohort A, 42.9%, 38.1%, 81.0%, and 81.0% in cohort B. Among these biomarkers, none demonstrated a statistically significant association with outcomes, although the Kaplan-Meier plot and PFS at 6 and 12 months indicated a potential trend suggesting that patients with iNOS-negative tumors may exhibit improved PFS, particularly in cohort A (Table). Conclusions: In our biomarker study of patients with mCRC treated with FOLFIRI plus AFL or BEV, none of the analyzed biomarkers associated with macrophages in the tumor microenvironment demonstrated significant correlations with treatment outcomes. The observed trend towards improved PFS in iNOS-negative tumors treated with AFL merits further investigation, and larger prospective studies are necessary to elucidate this potential relationship. Progression-free survival at 6 and 12 months. Progression-free survival 6 months 12 months All iNOS pos (n=28 ) 46.4 % (13) 21.4 % (6) iNOS neg (n= 12) 83.3 % (10) 50.0 % (6) Cohort A iNOS pos (n= 11) 45.5 % (5) 18.2 % (2) iNOS neg (n= 8) 87.5 % (7) 50.0 % (4) Cohort B iNOS pos (n= 17) 47.1 % (8) 23.5 % (4) iNOS neg (n= 4) 75.0 % (3) 50.0 % (2)

Background Predicting individual prognosis is required for patients with colorectal cancer in the era of precision medicine. However, this may be challenging for the conventional survival analysis such as the Cox proportional hazards model. This study aims to develop a personalized prognostic prediction that incorporates longitudinal data to improve predictions for colorectal cancer patients. Methods Patients with advanced or recurrent colorectal cancer, who received treatment at Kyoto University Hospital between April 2015 and December 2021, were retrospectively analyzed. The Joint model is one of the dynamic prediction models. Using longitudinal clinical data, a carcinoembryonic antigen (CEA) prediction equation was developed for each patient. Additionally, a personalized prognostic prediction model was created using the Joint model. The prediction accuracy of the Joint model was compared with one of the Cox proportional hazards model. Results Among the 1010 patients, 614 patients were enrolled. The median frequency of tumor marker measurement (per patient) was 20 times (range: 3–117 times). CEA values could be predicted accurately and the Pearson’s correlation coefficient between measured CEA and predicted CEA was 0.931. In the Joint model, the significant prognostic factors were baseline age (HR, 1.039; 95% CI, 1.025–1.054), poor-differentiated tumor (HR, 2.600; 95% CI 1.446–4.675) and log 2 (predicted CEA) (HR, 1.551; 95% CI 1.488–1.617). The areas under the curve at 2, 3, 4, and 5 were significantly higher for the Joint model than for the Cox proportional hazards model, respectively. Conclusion The Joint model may accurately predict personalized prognosis that reflects changes in longitudinal tumor marker values.

Clones harboring cancer driver mutations can expand in normal tissues, known as somatic mosaicism, and can be influenced by age and environmental and germline factors. Somatic mosaicism in the blood predicts the risk of hematological malignancies; however, the relevance of somatic mosaicism to solid tumors remains unclear, in part because of limited sample availability. Lifestyle habits, including alcohol consumption and tobacco smoking, and pathogenic germline variants increase the risk of developing esophageal squamous cell carcinoma (ESCC). Because somatic mosaicism in the esophagus is known to be associated with aging and lifestyle habits and considering the contiguity of squamous epithelium from the esophagus to the oral cavity, we noninvasively collected buccal mucosa samples from patients with and without ESCC using swabs of different sizes and conducted deep error-corrected sequencing of 26 cancer driver genes to obtain comprehensive landscapes of tissue remodeling by driver-mutant clones. We found that the number of mutations increased with drinking, but only in individuals with germline risks. Moreover, across positively selected genes in the buccal mucosa, mutations increased with age and smoking regardless of germline risks, whereas drinking affected only those with germline risks. The buccal mucosa of patients with ESCC was extensively remodeled, and models predicting the presence of ESCC demonstrated high accuracy with smaller swab sizes, possibly because of their higher sensitivity in detecting small mutant clones. In conclusion, we showed that buccal mucosal remodeling reflects lifestyle and germline risks, as well as age, which might be exploited for noninvasive risk assessment of ESCC.

Background Barrett’s esophagus (BE) is a known precursor of esophageal adenocarcinoma (EAC). EAC is comparatively rare in Japan compared to Western countries, where BE management guidelines have been well established based on robust evidence. This study evaluated for gaps between evidence-based medicine (EBM) and real-world clinical practice for BE management in Japan and examined endoscopist adherence to Japanese and Western guidelines. Methods A nationwide survey consisting of 19 questions was conducted among Japanese endoscopists to assess their diagnostic and surveillance practices for BE. Descriptive statistics and multivariate logistic regression analysis were employed to interpret key data. Results Responses from 804 endoscopists revealed significant differences between Western guidelines and Japanese practices. Local adherence to standardized inspection times was 7.6%, and 30.7% of endoscopists used the Prague classification. Biopsies for BE diagnosis and random biopsies following the Seattle protocol were rarely performed. For long-segment BE, 51.4% of respondents reported using magnifying endoscopy. Regarding ultra-short-segment BE (USSBE), opinions were divided on whether it should be diagnosed as BE and if patients should be informed of its diagnosis. Approximately 40% of respondents advocated annual surveillance for USSBE, with a general tendency to recommend closer follow-up regardless of BE length as compared with Western guidelines. Conclusions This survey highlighted several incongruities between EBM and real-world practices for BE, as well as differences between Western and Japanese approaches. Bridging these gaps will require generating more Japan-specific evidence, refining guidelines, and then promoting their dissemination to harmonize best BE practices with international standards and Japanese clinical settings.

The FIRST‐Dx study prospectively evaluated the clinical utility of the comprehensive genomic profiling (CGP) test (FoundationOne CDx) in the first‐line setting for patients with chemotherapy‐naïve advanced solid tumors (gastrointestinal, biliary, pancreatic, lung, breast, gynecologic, melanoma) in six hospitals in Japan. Here, we report the results of the 1‐year interim analysis of the follow‐up study about the clinical benefits provided by the upfront CGP test. The primary endpoint was overall survival (OS), and secondary endpoints were the proportion of patients who actually received molecular‐based recommended therapy (MBRT) determined by the molecular tumor board, best overall response rate (ORR) in each line of therapy, and progression‐free survival (PFS) ratio (PFS on MBRT/PFS on the first‐line therapy). Data from 172 patients with a median follow‐up of 15.1 months (range: 0.1–21.5 months) were available. The median OS was not reached. Thirty‐nine patients (22.7%) received MBRT during this follow‐up period. ORR in first‐line therapy was 56.3% in the MBRT group (n = 16) vs. 42.3% in the non‐MBRT group (n = 137), and in the second‐line was 26.3% in the MBRT group (n = 19) vs. 17.1% in the non‐MBRT group (n = 82). Regarding the PFS ratio of second‐line MBRT (n = 12), the median PFS ratio was 1.1, and four patients (33.3%) had a ratio ≥ 1.3, indicating that MBRT might be effective in changing the clinical outcome. The findings of this study imply that CGP testing before the standard of care for patients with advanced solid tumors could prove to be a clinically beneficial strategy for guiding subsequent precision anticancer treatments. Trial Registration: Japan Registry of Clinical Trials (jRCT) ID: jRCT1050220041

Esophageal stricture causes severe distress to patients; however, there are no established treatments for esophageal anastomotic strictures refractory to endoscopic balloon dilation (EBD). Steroid injection added to EBD and radial incision and cutting (RIC) are effective for such strictures, but it is unclear which is more effective. The objective of this study was to investigate the safety and efficacy of RIC plus steroid injection compared with EBD plus steroid injection for patients with refractory anastomotic strictures after esophagectomy. This was a multicenter, randomized phase II/III trial. Patients with esophageal anastomotic strictures refractory to three or more dilations were eligible. The primary endpoint in phase II was the proportion of predefined grade 3/4 adverse events (AEs). The co-primary endpoints in phase III were restricture-free survival and number of EBDs in the 24 weeks after treatment. 130 patients were enrolled, with a dysphagia score of grade 2 in 104 patients (80.0%). The median number of dilations before registration was five in each arm. Predefined grade 3/4 AEs occurred in two patients (3.1%) in each arm. Restricture-free survival was 10.6 weeks (95%CI 6.9–20.1 weeks) with EBD and 8.7 weeks (95%CI 7.1–10.9 weeks) with RIC (one-sided P=0.82). The median number of EBDs in the 24 weeks after initial treatment was one (interquartile range [IQR] 0–2) for EBD and two (IQR 0–3) for RIC (one-sided P=0.99). EBD combined with steroid injection is the standard treatment for refractory anastomotic stricture after esophagectomy.

Purpose Bevacizumab (BV) is an effective therapeutic antibody utilized in various cancers. Serum BV concentration can be a factor that potentially affects its therapeutic efficacy. Although proteinuria could affect BV pharmacokinetics, its influence was not evaluated in the previous population pharmacokinetic (PopPK) studies. Because BV can cause proteinuria as an adverse event, the present study aimed to develop a PopPK model in patients with proteinuria and to evaluate the influence of proteinuria on BV pharmacokinetics. Methods This prospective cohort study enrolled 70 Japanese cancer patients newly starting BV, and 368 concentration samples from these patients were analyzed. Serum BV concentrations were measured at several time points including at the onset of proteinuria. PopPK analysis was conducted using a non-linear mixed-effects modeling program. A two-compartment model was used to estimate total body clearance (CL). Results Serum BV concentrations divided by the dose per body weight and dosing interval tended to be lower in patients with higher urinary protein to creatinine ratio (UPCR). The covariate analysis showed that increasing BV CL was associated with decreasing serum albumin concentration and increasing body weight and UPCR. The simulated median trough concentrations of BV in patients with Common Terminology Criteria for Adverse Events grades 1, 2, and 3 proteinuria were decreased by 12.0%, 20.6%, and 31.5%, respectively, compared to those in patients with grade 0. Conclusion We successfully established a PopPK model incorporating UPCR to predict serum BV concentrations in patients with proteinuria. Our study provides additional insights to better understand BV pharmacokinetics.

Despite the high effectiveness of the coronavirus disease (COVID-19) mRNA vaccines, both immunogenicity and reactogenicity show substantial interindividual variability. One key challenge is predicting high and low responders using easily measurable parameters. In this study, we performed multivariate linear regression analysis, which allows adjustment for confounding, to explore independent predictive factors for antibody responses. Using data from 216 healthy vaccinated donors aged 23-81 years, we evaluated baseline characteristics, pre-vaccination blood and T-cell phenotypes, and post-vaccination T-cell responses as variables, with anti-receptor-binding domain (RBD) immunoglobulin G (IgG) titers following two doses of BNT162b2 vaccination as the primary outcome. Consistent with previous reports, higher age, a history of allergic disease, and autoimmune disease were associated with lower peak IgG titers. Additionally, the frequencies of interferon-γ+ spike-specific CD4+ T cells (T-cell response) following the first vaccination strongly correlated with higher IgG responses, while those of pre-existing spike-reactive T cells showed no association with peak IgG titers. Furthermore, we identified lower percentages of naïve CD8+ T cells, lower hemoglobin levels, lower lymphocyte counts, and higher mean corpuscular volume as independent pre-vaccination predictors of lower peak IgG levels. Notably, the frequency of naïve CD8+ T cells showed a positive correlation with the peak IgG levels even in univariate analysis. These findings contribute to the individualized prediction of mRNA vaccine efficacy and may provide insights into the mechanisms underlying individual heterogeneity in immune responses.