Published papers

PURPOSE: The adjuvant treatment for stage III colon cancer (CC) is chemotherapy combining fluoropyrimidine (FP) and oxaliplatin (OX). FP regimen plus OX (FPOX) may benefit in high-risk stage II CC. We performed a pooled analysis of pivotal MOSAIC and C-07 studies evaluating FPOX for the treatment of high-risk stage II CC according to prognostic factors, number of high-risk factors, and current clinicopathologic risk classification on the basis of T stage, tumor perforation, and number of lymph nodes examined. PATIENTS AND METHODS: One thousand five hundred and ninety-five patients with stage II CC receiving FP or FPOX were pooled. The overall survival (OS) benefit of OX was analyzed using Kaplan-Meier curves and unadjusted Cox models stratified by study. Three thousand and fifty-nine patients with stage III CC were used only for interaction tests between the allocated chemotherapy and stage. RESULTS: In the pooled analysis of stage II patients, independent prognostic factors in multivariable analysis were sex, age, perforation/obstruction, and tumor sidedness. There was a significant interaction in OS between stage and allocated chemotherapy with hazard ratios (HRs) of 1.03 for stage II (95% CI, 0.82 to 1.29; P = .813) and 0.82 for stage III (95% CI, 0.73 to 0.92; P = .001; Pint = .073). There was no benefit from the addition of OX to FP for any of the prognostic factors. The number of high-risk factors tested was not predictive of OX benefit. According to the currently agreed clinicopathologic risk classification, no OS benefit of OX was observed, as HR was 0.86 (95% CI, 0.63 to 1.18; P = .349). CONCLUSION: No OS benefit of adjuvant OX was found in high-risk stage II CC, regardless of the definition used to characterize tumors as having a high risk for recurrence. Hence, our analysis suggests that OX should not be the standard of care for adjuvant chemotherapy for stage II CC, even in high-risk patients.

Background: The prevalence of nocturia-related sleep problems is higher in older people. This study investigated whether morning and evening light exposure is associated with the sleep problems related to objectively identified nocturnal urination in community-dwelling older adults. Methods: This cross-sectional study analyzed data collected between 2013 and 2016 for the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study). The study included 1585 participants aged ≥ 65 years who met the criteria for inclusion in the present analysis. An actigraph was used to measure sleep, nocturnal voiding time, and light exposure. The frequency of nocturnal voiding was derived from self-reported entries in the participants’ sleep diaries. Morning light (ML) exposure was defined as the period between waking and 12:00, while evening light (EL) exposure was defined as the period between 18:00 and bedtime. The first uninterrupted sleep period (FUSP) was calculated as the interval between the sleep onset time and the first nocturnal void. Additionally, the ratio of FUSP to sleep period time (FUSP/SPT) was calculated. Associations between light exposure parameters and the frequency of nocturnal voiding, FUSP, or FUSP/SPT were examined using multivariable linear regression models. Results: Of the 1585 participants, 38.7% were male median age was 70 years. The median nocturnal voiding frequency was 1.0 times (IQR: 0.4, 1.4) and the median FUSP was 4.6 h (IQR: 3.2, 5.9). In multivariable linear regression, log ML exposure was significantly associated with FUSP and FUSP/SPT (B = 0.17, 95% CI: 0.02, 0.32; B = 2.20, 95% CI: 0.26, 4.14, respectively). In contrast, the duration of ML exposure ≥ 1,000 lx, EL exposure, and the duration of EL exposure ≥ 50 lx were not significantly associated with the frequency of nocturnal voiding, FUSP or FUSP/SPT. Conclusions: Greater morning light exposure was associated with a longer FUSP. Morning bright light exposure may therefore help delay nocturia-related sleep interruptions, potentially contributing to improved sleep quality among older people.

Background: Patients with pathological T1 (pT1) colorectal cancer (CRC) at high risk for lymph node metastasis (LNM) after complete local resection are recommended to receive additional intestinal resection along with lymph node dissection. However, the existing pathological criteria for risk stratification of LNM are inadequate, such that ~90% of patients without LNM are exposed to potentially unnecessary treatment. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective substudy within the GALAXY observational study, to explore the ability of predicting LNM using circulating tumor DNA (ctDNA) detection compared to the standard pathological criteria. Methods: This study included patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk-stratification criteria for LNM. The additional surgery was indicated for patients meeting any of the following criteria: (1) depth of submucosal invasion (>1000µm); (2) lymphovascular invasion; (3) poorly differentiated adenocarcinoma, signet-ring cell carcinoma, or mucinous carcinoma; and (4) high-grade tumor budding (BD2/3) at the site of deepest invasion according to the Japanese guideline. ctDNA was analyzed from plasma samples collected within 4 weeks before the additional intestinal resection using a personalized, tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay). The study assessed the diagnostic concordance rate between ctDNA detection and the occurrence of LNM. Results: Of 208 CRC patients enrolled between July 2021 and May 2023 in DENEB, 166 patients met the inclusion criteria. Of these, 22 (13.3%) were ultimately diagnosed with pStage III due to the presence of LNM in additional intestinal resection. Among the 166 patients, 6 patients tested ctDNA-positive; all 6 had LNM, yielding a positive predictive value of 100.0%. On the other hand, 160 patients had ctDNA-negative results, 144 of whom did not have LNM, resulting in a negative predictive value of 90.0%. The overall diagnostic concordance rate for ctDNA in detecting LNM was 90.4% (95% confidence interval, 84.8% to 94.4%). All 6 patients with a ctDNA-positive result and LNM had left-sided colorectal cancer and a tumor diameter greater than 13 mm. Conclusions: This analysis showed that ctDNA testing has the potential to improve risk stratification of LNM in patients with pT1 CRC who underwent complete local resection. Clinical trial information: UMIN000039205.

INTRODUCTION: LUME-Colon 1 (NCT02149108) was a global, placebo-controlled phase III study of nintedanib in advanced colorectal cancer (CRC). Pre-specified biomarker analyses investigated the association of CRC consensus molecular subtypes (CMS) and tumor genomic and circulating biomarkers with clinical outcomes. MATERIALS AND METHODS: Archival tumor tissue, cell-free DNA (cfDNA), and plasma samples were collected for genomic, transcriptomic, and proteomic analyses to investigate potential associations between CRC CMS and other biomarkers with nintedanib response and clinical outcomes. RESULTS: Of the 765 treated patients, 735, 245, and 192 patient samples were analyzed in the circulating protein, tumor tissue, and cfDNA datasets, respectively. Patients were classified as CMS1 (1.7%), CMS2 (27.7%), CMS3 (0.9%), CMS4 (51.5%), or unclassified (18.2%). Unclassified/mixed CMS was associated with longer overall survival (OS) with nintedanib vs. CMS2 or CMS4 (interaction P-value = .0086); no association was observed for CMS4. Gene expression-based pathway analysis revealed an association between vascular endothelial growth factor-related signaling and OS for nintedanib (P = .0498). The most frequently detected somatic mutations were APC (72.0% [tumor tissue] vs. 56.8% [cfDNA]), TP53 (47.1% vs. 34.9%), KRAS (40.8% vs. 28.6%), and PIK3CA (16.6% vs. 11.5%); concordance rates were > 80%. Median OS differences were observed for APC and TP53 mutations vs. wild-type in cfDNA, indicating a potential prognostic value. Circulating ANG-2, CA-9, CEACAM1, collagen-IV, IGFBP-1, ICAM-1, IL-8, and uPAR were potentially prognostic for both OS and progression-free survival. CONCLUSION: We demonstrated the feasibility of large-scale biomarker analyses and CMS classification within a global clinical trial, and identified signals suggesting a potential for greater nintedanib treatment response in the unclassified/mixed CMS subgroup, despite these tumors showing heterogeneous patterns of CMS mixtures. Our results revealed a high degree of concordance in somatic mutations between tumor tissue and cfDNA. Associations with prognosis for cfDNA somatic mutations, as well as several protein-based biomarkers, may warrant further investigation in future trials.

BACKGROUND: Early tumor shrinkage and depth of response have emerged as potential prognostic indicators in metastatic colorectal cancer (CRC). However, their associations with overall survival, progression-free survival (PFS), and postprogression survival in patients receiving anti-epidermal growth factor receptor (EGFR) antibodies or bevacizumab remain unclear. METHODS: We analyzed 3219 treatment-naive patients with RAS wild-type metastatic CRC from 8 randomized studies (CRYSTAL, OPUS, PRIME, CAIRO2, CALGB80405, WJOG4407G, ATOM, PARADIGM) in the Aid and Research in Digestive Cancerology database. Early tumor shrinkage was defined as a 20% or more reduction in tumor size at 8 ± 2 weeks, whereas depth of response was assessed by maximum tumor shrinkage at nadir. Cox regression models evaluated the associations of early tumor shrinkage and depth of response with overall survival, PFS, and postprogression survival, adjusting for confounders. A 2-sided test was conducted with a significance level of .05. RESULTS: Early tumor shrinkage and depth of response substantially stratified overall survival, PFS, and postprogression survival outcomes across all treatment groups. Early tumor shrinkage positivity was associated with improved overall survival, PFS, and postprogression survival in anti-EGFR and bevacizumab-based therapies, with a trend toward better outcomes in the anti-EGFR group. The depth of response analysis revealed optimal cutoff values of 0.55 for anti-EGFR-based therapy and 0.47 for bevacizumab-based therapy to achieve a median overall survival of approximately 32 months. CONCLUSIONS: Early tumor shrinkage and depth of response serve as valuable prognostic markers in RAS wild-type metastatic CRC, particularly for patients treated with anti-EGFR antibodies. These findings highlight the potential role of early tumor shrinkage and depth of response in guiding treatment strategies and improving outcomes for patients with CRC.

Bearing in mind our previous study on asymptotic behavior of null geodesics near future null infinity, we analyze the behavior of geometrical quantities such as a certain extrinsic curvature and Riemann tensor in the Bondi coordinates. In the sense of asymptotics, the condition for an $r$-constant hypersurface to be a photon surface is shown to be controlled by a key quantity that determines the fate of photons initially emitted in angular directions. As a consequence, in four dimensions, such a non-expanding photon surface can be realized even near future null infinity in the presence of enormous energy flux for a short period of time. By contrast, in higher-dimensional cases, no such a photon surface can exist. This result also implies that the dynamically transversely trapping surface, which is proposed as an extension of a photon surface, can have an arbitrarily large radius in four dimensions.

BACKGROUND: First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed to assess the prognostic and predictive impact of BRAFmt on the efficacy of targeted therapies with first-line chemotherapy. METHODS: Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomly assigned whenever possible. RESULTS: A total of 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%), and 3759 double wild type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] = 1.46, 95% confidence interval [CI] = 1.30 to 1.64) and patients with double wild-type tumors (HRadj = 2.14, 95% CI = 1.94 to 2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy with or without anti-epidermal growth factor receptor (anti-EGFR) (HRadj = 0.96, 95% CI = 0.71 to 1.30; and HRadj = 0.85, 95% CI = 0.66 to 1.14, respectively). CONCLUSIONS: Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.

Colorectal cancer(CRC)is one of the most commonly diagnosed cancers worldwide. Unresectable advanced, metastatic or recurrent CRC(mCRC)remains incurable for most patients. Systemic chemotherapy is standard treatment for patients with mCRC. The goals of systemic chemotherapy include prolonging survival by stopping cancer progression and palliation. In recent years, advances in the treatment of mCRC have enabled personalized care based on the tumor's molecular profile with improved outcomes for some subtypes. Targeted biologic therapies and immune checkpoint inhibitors have changed the approach to management of uncommon molecularly defined subsets of mCRC. The development of chemotherapy using cytotoxic drugs, biologic monoclonal antibodies, and immune checkpoint inhibitors has prolonged median overall survival up to approximately 30 months. In this report, we describe the evolution of systemic chemotherapy for mCRC, recent advances in standard treatment, and future prospects for the treatment of mCRC.

In Europe and the United States, the Foundation Aide et Recherche en Cancérologie Digestive(ARCAD)database project was initiated in 2006 and 43,488 patient data(IPD)for metastatic colorectal cancer from 59 trials have been collected and constructed as the integrated database. The ARCAD-Asia was launched in 2021 and has been actively collecting Asian clinical trials and converted IPD are stored into the integrated database. In addition, the ARCAD-Asian data are transferred to ARCAD and IPD are integrated to ARCAD global database. All the data are shared with 3 data centers of ARCAD-Asia and ARCAD, located in France, the United States and Japan. In the ARCAD database, there are 1,673 IPD treated with placebo in a salvage line setting. We are now planning to utilize placebo IPD as the synthetic control arms(SCAs)to compare the efficacies of active agents. Furthermore, we will continue to collect the Asian IPD and will expand the cancer type, leading to more comprehensive global database.