Published papers

Colorectal cancer (CRC) is one of the most common malignant diseases. Generally, stoma construction is performed following surgery for the resection of the primary tumor in patients with CRC. The association of CRC with the gut microbiota has been widely reported, and the gut microbiota is known to play an important role in the carcinogenesis, progression, and treatment of CRC. In this study, we compared the microbiota of patients with CRC between with and without a stoma using fecal metagenomic sequencing data from SCRUM-Japan MONSTAR-SCREEN, a joint industry-academia cancer research project in Japan. We found that the composition of anaerobes was reduced in patients with a stoma. In particular, the abundance of Alistipes, Akkermansia, Intestinimonas, and methane-producing archaea decreased. We also compared gene function (e.g., KEGG Orthology and KEGG pathway) and found that gene function for methane and short-chain fatty acids (SCFAs) production was underrepresented in patients with a stoma. Furthermore, a stoma decreased Shannon diversity based on taxonomic composition but increased that of the KEGG pathway. These results suggest that the feces of patients with a stoma have a reduced abundance of favorable microbes for cancer immunotherapy. In conclusion, we showed that a stoma alters the taxonomic and functional profiles in feces and may be a confounding factor in fecal microbiota analysis.

Fibroblast growth factor receptor 2 (FGFR2), a therapeutic target for advanced gastric and gastroesophageal junction cancers (GC/GEJCs), exists as two functionally distinct isoforms: FGFR2-IIIb and FGFR2-IIIc. We investigated the clinical significance of FGFR2 splice variant distribution in advanced GC/GEJCs and its implications for therapeutic targeting.Whole-transcriptome sequencing was carried out on 235 patients with advanced GC/GEJCs enrolled in MONSTAR-SCREEN-2 (UMIN000043899). FGFR2-IIIc proportion was quantified using splice junction analysis, and its association with clinical outcomes was evaluated through survival analysis, comprehensive molecular profiling, and longitudinal assessment of treatment-induced isoform dynamics.Among 209 patients with detectable FGFR2 expression, high-proportion FGFR2-IIIc (>0.28) was associated with significantly shorter overall survival compared with low-proportion FGFR2-IIIc (median 9.59 versus 16.0 months, hazard ratio 2.08, 95% confidence interval 1.33-3.26, P < 0.001). Multivariable Cox regression confirmed FGFR2-IIIc proportion as an independent predictor of poor prognosis (P = 0.008), superior to total FGFR2 expression levels. Longitudinal analysis of 33 paired pre- and post-treatment samples revealed treatment-induced increases in FGFR2-IIIc proportion (P = 0.0085), suggesting adaptive isoform switching. Notably, all tumors with elevated FGFR2 expression exclusively belonged to the low-IIIc group, indicating that current FGFR2-targeted therapies primarily benefit patients with FGFR2-IIIb-dominant expression profiles. High-proportion FGFR2-IIIc was significantly associated with epithelial-to-mesenchymal transition and myogenesis pathway activation. Differential splicing analysis identified coordinated alternative splicing events in ESRP1-regulated targets, suggesting potential broader splicing dysregulation and providing mechanistic insights into the aggressive phenotype.FGFR2-IIIc proportion represents a clinically relevant prognostic biomarker in advanced GC/GEJCs. Treatment-induced isoform switching toward FGFR2-IIIc suggests a novel resistance mechanism requiring targeted therapeutic approaches. These findings underscore the importance of developing isoform-specific therapeutic strategies and implementing FGFR2-IIIc assessment in precision oncology approaches for GC/GEJCs.

PURPOSE: The phase III ACHIEVE trial conducted in Japan was one of six prospective studies included in the International Duration Evaluation of Adjuvant Therapy collaboration, which explored whether 3 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) therapy would be noninferior to 6 months of treatment in patients with curatively resected stage III colon cancer. We report the final analyses of survival and long-term safety. PATIENTS AND METHODS: Eligible patients were randomly assigned (1:1) to either 3 or 6 months of adjuvant chemotherapy (modified [m]FOLFOX6 or CAPOX, as selected by the treating physician). Random assignment was stratified according to number of involved lymph nodes, center, regimen, primary site, and age. The primary end point was disease-free survival, assessed in the modified intention-to-treat population. Overall survival (OS) was a secondary end point. RESULTS: The modified intention-to-treat population comprised 1,291 patients: 641 in the 6-month treatment group and 650 in the 3-month treatment group. Median follow-up for this analysis was 74.7 months. Five-year OS rates were comparable: 87.0% in the 3-month treatment group and 86.4% in the 6-month treatment group (hazard ratio, 0.91; 95% CI, 0.69 to 1.20; P = .51). Subgroup analysis of OS did not reveal a significant interaction between baseline characteristics and treatment duration. Peripheral sensory neuropathy lasting longer than 5 years was more common in the 6- compared with 3-month treatment group (16% v 8%, respectively), and in those receiving mFOLFOX6 compared with CAPOX (14% v 11%, respectively). CONCLUSION: In Asian patients, shortening adjuvant therapy duration from 6 to 3 months did not compromise efficacy and reduced the rate of long-lasting peripheral sensory neuropathy. In this setting, 3 months of CAPOX therapy is an appropriate adjuvant treatment option.

DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH-), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC.

Uncovering neutrinoless double beta decay (0$ν$2$β$) is crucial for confirming neutrinos' Majorana characteristics. The decay rate of 0$νββ$ is theoretically uncertain, influenced by nuclear matrix elements that vary across nuclides. To reduce this uncertainty, precise measurement of the half-life of neutrino-emitting double beta decay (2$ν$2$β$) in different nuclides is essential. We have launched the PIKACHU (Pure Inorganic scintillator experiment in KAmioka for CHallenging Underground sciences) project to fabricate high-purity Ce-doped Gd$_{3}$Ga$_{3}$Al$_{2}$O$_{12}$ (GAGG) single crystals and use them to study the double beta decay of $^{160}$Gd. Predictions from two theoretical models on nuclear matrix element calculations for 2$ν$2$β$ in $^{160}$Gd show a significant discrepancy in estimated half-lives, differing by approximately an order of magnitude. If the lower half-life estimation holds true, detecting 2$ν$2$β$ in $^{160}$Gd could be achievable with a sensitivity enhancement slightly more than an order of magnitude compared to prior investigations using Ce-doped Gd$_2$SiO$_5$ (GSO) crystal. We have successfully developed GAGG crystals with purity levels surpassing previous standards through refined purification and selection of raw materials. Our experiments with these crystals indicate the feasibility of reaching sensitivities exceeding those of earlier studies. This paper discusses the ongoing development and scintillator performance evaluation of High-purity GAGG crystals, along with the anticipated future prospects of the PIKACHU experiment.

4052Background: We previously reported anti-tumor activity of regorafenib plus nivolumab for advanced gastric cancer (AGC) patients at a third or later line (1). Recently, first-line regorafenib with nivolumab and FOLFOX in AGC showed promising results in a phase 2 in the United States. CapeOX requires less frequent outpatient visits than FOLFOX and is preferred in Asian countries. We investigated the safety and efficacy of regorafenib with nivolumab and chemotherapy including CapeOX for AGC in the first-line treatment. Methods: Enrolled patients received regorafenib with nivolumab and CapeOX (Cohort A) or FOLFOX (Cohort B) in the phase Ib part (safety lead-in) to determine the recommended dose. Additional patients were enrolled in the phase II part. Regorafenib of 90 mg was administered once daily for 21 days on/7 days off with nivolumab 360 mg every 3 weeks (Cohort A) or 240 mg every 2 weeks (Cohort B) and chemotherapy. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks in the phase Ib part and objective response rate (threshold 60%, expected 80%, α = 0.1, β = 0.2) in patients with the recommended dose in the phase Ib/II part. The primary endpoint would be met if at least 22 of 30 patients showed objective tumor response. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 30 patients (14 in Cohort A and 16 in Cohort B) were enrolled from June 2022 to April 2023. All patients had MSS/pMMR tumors. No DLTs were observed in both cohorts. Objective tumor response was observed in 22 of 30 (73%; 80%CI 60.3-83.8) patients, thus the primary endpoint was achieved. Disease control rate was 97%. Six-month progression-free survival was 66.7% (95%CI 46.9-80.5). The most common grade 3 or worse treatment-related adverse events included neutropenia (33%), AST/ALT increased (13%), hypertension (13%), and leucopenia (7%) without unexpected safety signals. Conclusions: First-line regorafenib with nivolumab and chemotherapy including CapeOX showed anti-tumor activity with acceptable safety profiles in AGC patients. The results of biomarker analysis will be presented. A randomized, phase III trial is planned. 1. Fukuoka S, J Clin Oncol 2020. Clinical trial information: NCT05394740.

Abstract Background KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. Methods Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. Results 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84–0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68–0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68–0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86–1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). Conclusion The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

The liver is the most common site of metastatic disease in patients with colorectal cancer. However, the multidisciplinary management of colorectal liver metastases (CLMs) remains suboptimal. Over the past several decades, numerous randomized trials have evaluated the efficacy of adjuvant chemotherapy following CLM resection, revealing improvements in disease-free survival. Nevertheless, these studies have not consistently demonstrated benefits in overall survival, resulting in controversy with regard to the role of routine postoperative chemotherapy. Circulating tumor DNA (ctDNA) has recently emerged as a promising biomarker for detecting molecular residual disease after surgery. Multiple studies have consistently shown that postoperative ctDNA positivity is strongly associated with inferior recurrence-free survival and overall survival in patients with colorectal cancer. In addition to its prognostic value, ctDNA may also assist in guiding postoperative therapeutic decisions. In prospective observational studies of CLM, adjuvant chemotherapy provided potential clinical benefits primarily in patients with ctDNA-positive disease, whereas limited benefits were observed in ctDNA-negative patients. These findings suggest that ctDNA-based detection of molecular residual disease may aid in developing a framework for risk-adapted postoperative management after CLM resection. However, several challenges remain, including the identification of an optimal treatment regimen for ctDNA-positive patients and the improvement of ctDNA assay sensitivity. Ongoing biomarker-driven clinical trials may clarify whether ctDNA-guided strategies can improve patient selection and clinical outcomes following curative resection of CLM.

Gravitational waves from condensates of ultra-light particles, such as axion, around rotating black holes are a promising probe to search for unknown physics. For this purpose, we need to characterize the signal to detect the gravitational waves, which requires tracking the evolution of the condensates, including various effects. The axion self-interaction causes the non-linear coupling between the superradiant modes, resulting in complicated branching of evolution. Most studies so far have considered evolution under the non-relativistic approximation or the two-mode approximation. In this paper, we numerically investigate the evolution of the axion condensate without these approximations, taking higher multipole modes into account. We also investigate the possible signature in gravitational waves from the condensate. We show that the higher multipole modes are excited, leading to the gravitational wave signal by the transition of the axion between different levels. The most prominent signal of gravitational waves arises from the transition between modes with their angular quantum numbers different by two. The gravitational wave signal is emitted in the deci-Hz band for stellar mass black holes, which might be observable with the future gravitational wave detectors.

Background: Approximately 2-4% of patients with metastatic colorectal cancer (mCRC) harbor HER2 amplification, a subset notorious for poor response rates following conventional treatments. The TRIUMPH trial introduces anti-HER2 therapy, combining trastuzumab and pertuzumab. Despite its potential, the observed response rate stands at 30%, accompanied by an early recurrence within 3.5 months with acquired resistance, which emphasizes the need for further investigations into resistance mechanisms within this patient population. Here, we delineate the dynamic changes in both the tumor and its microenvironment in response to treatment and mechanisms of acquired resistance using spatial transcriptomics. Methods: Within the TRIUMPH trial, a total of 20 formalin-fixed paraffin-embedded (FFPE) biopsy slides from 13 patients were collected before and after treatment or at one time. Utilizing these FFPE slides, we employed imaging-based single-cell spatial transcriptomics, using a custom panel tailored for the tumor and its microenvironment. This panel includes gene sets related to tumor growth, drug resistance, and immune response. Results: To comprehend the complexities of the tumor and its surroundings, we categorized tumor tissue into distinct sections, encompassing tumor, stromal, and immune-enriched areas based on their neighbor cells. Remarkably, we noted a substantial rise in the infiltration of T cells and myeloid cells into tumor-enriched regions post-treatment. T cells increased from a median of 1.5% to 2.2%, and myeloid cells from 4.3% to 7.4%, particularly in patients showing a response. Additionally, ERBB2 expression in tumor cells was high, whereas the non-response group exhibited lower expression levels. Prior to treatment, fibroblast and endothelial cells were intricately intertwined with tumor cells. However, subsequent to treatment, these cells segregated into stromal regions, exhibiting an increase in their proportions. Notably, angiogenic tumor-associated macrophage (angio-TAM), expressing SPP1 and VEGFA, were localized at the interface of tumors and stromal cells and proliferated following disease progression. This spatial reorganization signifies dynamic alterations within the tumor microenvironment following treatment. Conclusions: Our study on HER2-amplified metastatic colorectal cancer in the TRIUMPH trial uncovers intriguing spatial changes post anti-HER2 therapy. Notably, dynamic reorganization of fibroblast and endothelial cells into stromal regions suggest complex treatment responses. Identification of angio-TAM expressing SPP1 and VEGFA adds depth to understanding the contribution of tumor microenvironment to the resistance mechanism. These findings highlight the intricate tumor microenvironment shifts, urging further exploration for optimized therapeutic strategies.

According to the current international guidelines, high-risk patients diagnosed with pathological T1 (pT1) colorectal cancer (CRC) who underwent complete local resection but may have risk of developing lymph node metastasis (LNM) are recommended additional intestinal resection with lymph node dissection. However, around 90% of the patients without LNM are exposed to the risk of being overtreated due to the insufficient pathological criteria for risk stratification of LNM. Circulating tumor DNA (ctDNA) is a noninvasive biomarker for molecular residual disease and relapse detection after treatments including surgical and endoscopic resection of solid tumors. The CIRCULATE-Japan project includes a large-scale patient-screening registry of the GALAXY study to track ctDNA status of patients with stage II to IV or recurrent CRC that can be completely resected. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective study, within the GALAXY study for 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 aim of this study is to explore the ability of predicting LNM using ctDNA analysis compared with the standard pathological criteria. The ctDNA assay will build new evidence to establish a noninvasive personalized diagnosis in patients, which will facilitate tailored/optimal treatment strategies for CRC patients.