Published papers

In asymptotically flat spacetimes, bearing the null geodesics reaching the future null infinity in mind, we propose new concepts, the "dark horizons" as generalizations of the photon sphere. They are defined in terms of the structure of escape/capture cones of photons with respect to a unit timelike vector field. More specifically, considering a two-sphere that represents a set of emission directions of photons, the dark horizons are located at positions where a hemisphere is marginally included in the capture and escape cones, respectively. We show that both of them are absent in the Minkowski spacetime, while they exist in spacetimes with black hole(s) under a certain condition. We derive the general properties of the dark horizons in spherically symmetric spacetimes and explicitly calculate the locations of the dark horizons in the Vaidya spacetime and the Kerr spacetime.

We present a new stellar dynamical measurement of the supermassive black hole (SMBH) in the compact elliptical galaxy NGC 4486B, based on integral field spectroscopy with JWST/NIRSpec. The two-dimensional kinematic maps reveal a resolved double nucleus and a velocity dispersion peak offset from the photometric center. Utilizing two independent methods-Schwarzschild orbit-superposition and Jeans Anisotropic Modeling-we tightly constrain the black hole mass by fitting the full line-of-sight velocity distribution. Our axisymmetric Schwarzschild models yield a best-fit black hole mass of $M_{BH} = 3.6^{+0.7}_{-0.7} \times 10^8 \, M_{\odot}$, slightly lower but significantly more precise than previous estimates. However, since our models do not account for the non-equilibrium nature of the double nucleus, this value may represent a lower limit. Across all tested dynamical models, the inferred $M_{BH}/M_*$ ratio ranges from ~ 4-13%, providing robust evidence for an overmassive SMBH in NGC 4486B. Combined with the galaxy's location deep within the Virgo Cluster, our results support the interpretation that NGC 4486B is the tidally stripped remnant core of a formerly massive galaxy. As the JWST/NIRSpec field of view is insufficient to constrain the dark matter halo, we incorporate archival ground-based long-slit kinematics extending to 5 arcsec. While this provides some leverage on the dark matter content, the constraints remain relatively weak. We place only an upper limit on the dark matter fraction, with $M_{DM}/M_{*} < 0.5$ within 1 kpc-well beyond the effective radius. The inferred black hole mass remains unchanged with or without a dark matter halo.

Importance: Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential. Objective: To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)-based annotation system. Design, Setting, and Participants: This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021. Exposures: The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels. Main Outcomes and Measures: The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point. Results: Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P <.001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P =.02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P =.03). Conclusions and Relevance: The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

The first-line treatment choice of EGFRIs plus doublet chemotherapy vs. bevacizumab plus doublet chemotherapy remains a topic of interest for patients with left-sided RAS WT mCRC. We conducted a systematic literature review and meta-analysis of clinical trial data published between 2015 and 2024. We evaluated the relative efficacy and safety of first-line EGFRIs plus doublet chemotherapy (FOLFIRI or FOLFOX) vs. bevacizumab plus doublet chemotherapy for patients with RAS WT left-sided mCRC, as well as in all- and right-sided tumors. We identified eight trials with 2624 patients. Five trials reported outcomes by tumor sidedness. In the left-sided population, overall survival (OS) (Hazard Ratio (HR) = 0.80, 95% Confidence Interval (CI): 0.71-0.90) and objective response rate (ORR) (Odds ratio [OR]=1.61, 95% CI: 1.30-1.99) favored EGFRI plus chemotherapy, while no statistically significant differences were observed for progression-free survival (PFS) (HR=0.93, 95% CI: 0.84-1.04) or resection rate (RR). Similar results were found in the all-sided population. In the right-sided population, PFS favored bevacizumab plus chemotherapy (HR=1.45, 95% CI: 1.19-1.78), while no statistically significant differences were observed for OS (HR=1.17, 95% CI: 0.95-1.44), ORR (OR=0.99, 95% CI: 0.69-1.41), and RR. Early tumor shrinkage in the all-sided population favored EGFRI plus chemotherapy (OR=1.72; 95% CI: 1.36-2.17); limited data precluded evaluation by sidedness. Safety was available in 6 trials for all-sided tumors and 1 trial for left-sided tumors, each demonstrating typical class-specific adverse events. This most comprehensive meta-analysis indicates a benefit for first-line EGFRI plus chemotherapy over bevacizumab plus chemotherapy in patients with left-sided RAS WT mCRC.

BACKGROUND: Based on the reported antitumor effects of microtubule inhibitors in xenograft models of BRAF V600E mutant colorectal cancer, this multicenter phase II study aimed to evaluate the efficacy and safety of eribulin in patients with BRAF V600E mutant metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with BRAF V600E mutant mCRC who received at least one prior regimen were administered intravenous eribulin. The primary endpoint was the objective response rate (ORR). Biomarker analyses were carried out using tumor and serial blood samples. Patients with reduced tumor size and/or progression-free survival (PFS) of >6 months were classified into the good response group, and the remaining patients were classified into the poor response group. RESULTS: Among the 27 patients enrolled, the ORR was 0% (95% confidence interval 0.0% to 12.8%), the disease control rate was 41%, the median PFS was 1.4 months, and the median survival time was 5.3 months (median follow-up, 5.3 months). Of 26 patients for whom tumors for RNA sequencing were available, all four patients in the good response group had the BRAF mutant (BM)2 subtype on gene expression analysis of BM subtype, whereas 22 patients in the poor response group had the BM1 (n = 8) or BM2 (n = 14) subtypes (P = 0.07). The proportion of patients with decreasing BRAF V600E relative clonality at the start of the second cycle was 75% and 11% in the good response and poor response groups, respectively (P = 0.02). Grade 3 and 4 adverse events included neutropenia (63%) and febrile neutropenia (22%). CONCLUSIONS: This phase II study of eribulin for patients with BRAF V600E mutant mCRC did not meet the primary endpoint. Although BM2 on gene expression analysis of BM subtype may be a predictive marker of eribulin efficacy, further studies are required to validate this hypothesis.

Background: Genomic screening is an essential, but potentially time-consuming procedure, especially in neoadjuvant settings. We evaluated the preoperative screening of the BRAF V600E mutation for recruitment to a clinical trial among patients with resectable colorectal oligometastases (CRM). Methods: In April 2022, an investigator-initiated trial was launched to investigate the efficacy and safety of perioperative use of the BEACON triplet regimen for BRAF V600E mutant resectable CRM. BRAF screening was retrospectively conducted in patients with resected colorectal liver metastases in 2019 for planning the trial and prospectively conducted in preoperative patients with resectable CRM from January 2022 to June 2025 for patient recruitment to the trial. Results: BRAF V600E mutation was detected in 12 (3.2%) of 379 postoperative patients retrospectively and in 36 (1.7%) of 2140 preoperative patients prospectively, with 1840 patients (86.0%) carrying the wild-type and 264 patients (12.3%) classified as untested. The detection rate of the BRAF V600E mutation was significantly lower when the screening was performed prospectively in preoperative patients (P < 0.001). The untested rates varied across metastatic organs, with 10.3% in the liver, 18.1% in the lungs, 12.0% in the lymph nodes, 16.7% in the peritoneum, and 7.8% in other organs. The untested rates decreased consistently across semiannual comparisons: 28.5% in the first evaluation, followed by 15.0%, 12.0%, 8.4%, 9.1%, 7.3%, and 7.1% (P < 0.01 when compared with the first period). Conclusion: Raising physician awareness, as reflected by the untested rate, is a crucial factor in conducting clinical trials to implement perioperative cancer genomic medicine.

What is this summary about? This summary discusses the genetic and molecular changes in tumors of participants with BRAF V600E–mutant metastatic colorectal cancer who were treated with encorafenib plus cetuximab, with or without binimetinib, in the BEACON study. What were the results? Encorafenib plus cetuximab, with or without binimetinib, reduced the risk of participants dying compared with cetuximab plus chemotherapy, regardless of genetic or molecular colorectal cancer subtypes. The study also found genetic and molecular changes in the participants’ tumors during treatment that were associated with how long they lived. What do the results of the study mean? The types of genetic and molecular changes that occur during treatment in participants’ tumors can affect their response to treatment with BRAF and MEK inhibitors.

BACKGROUND: The implementation of cancer precision medicine in Japan is deeply intertwined with insurance reimbursement policies and requires case-by-case reviews by Molecular Tumor Boards (MTBs), which impose considerable operational burdens on healthcare facilities. The extensive preparation and review times required by MTBs hinder their ability to efficiently assess comprehensive genomic profiling (CGP) test results. Despite attempts to optimize MTB operations, significant challenges remain. This study aims to evaluate the effectiveness of QA Commons, an artificial intelligence-driven system designed to improve treatment planning using CGP analysis. QA Commons utilizes a comprehensive knowledge base of drugs, regulatory approvals, and clinical trials linked to genetic biomarkers, thereby enabling the delivery of consistent and standardized treatment recommendations. Initial assessments revealed that the QA Commons' recommendations closely matched the ideal treatment recommendations (consensus annotations), outperforming the average results of MTBs at Cancer Genomic Medicine Core Hospitals. METHODS: A clinical performance evaluation study will be conducted by comparing the QA Commons' treatment recommendations with those of the Academia Assembly, which includes medical professionals from the Cancer Genomic Medicine Core and Hub Hospitals. One hundred cases selected from the "Registry of the Academia Assembly," based on defined inclusion and exclusion criteria, will be analyzed to assess the concordance of recommendations. CONCLUSION: The expected outcomes suggest that QA Commons could reduce the workload of MTB members, standardize the quality of MTB discussions, and provide consistent outcomes in repeated patient consultations. In addition, the global expansion of QA Commons could promote worldwide adoption of Japan's pioneering precision oncology system.

Background: Encorafenib + cetuximab (EC) and mFOLFOX6 or irinotecan, leucovorin, and fluorouracil (FOLFIRI) is approved in several countries for BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on results from the BREAKWATER trial. Patients and methods: In BREAKWATER Cohort 3, eligible patients with previously untreated BRAF V600E-mutant mCRC were randomly assigned 1:1 to receive EC+FOLFIRI or FOLFIRI with or without bevacizumab (control). The primary endpoint was objective response rate (ORR) by blinded independent central review (BICR), and the key secondary endpoint was progression-free survival (PFS) by BICR. Other secondary endpoints included overall survival (OS) and safety. Results: A total of 147 patients were randomly allocated in Cohort 3 (EC+FOLFIRI, n = 73; control, n = 74) with similar baseline demographics and disease characteristics across arms. EC+FOLFIRI demonstrated clinically meaningful and statistically significant improvement in ORR by BICR {64.4% versus 39.2%, odds ratio = 2.756 [95% confidence interval (CI) 1.420-5.348], one-sided P-value = 0.0011}, meeting the primary endpoint (1 March 2025, data cutoff). At the 6 January 2026 data cutoff, the key secondary endpoint was met, with EC+FOLFIRI demonstrating a clinically meaningful and statistically significant PFS [hazard ratio = 0.44 (95% CI 0.27-0.70), one-sided P-value = 0.0002, 15.2 versus 8.3 months]. Prolonged OS was also observed with EC+FOLFIRI (hazard ratio = 0.56 [95% CI 0.34-0.94], not estimable versus 20.3 months). Serious adverse event rates were 49.3% versus 44.1% for the EC+FOLFIRI versus control arms, respectively. The safety profile was consistent with that known for each agent. Conclusions: EC+FOLFIRI demonstrated clinically meaningful and statistically significant improvements in ORR and PFS, with prolonged OS versus control in BRAF V600E-mutant mCRC. The safety profile was generally manageable, with no new safety signals. These data support EC+FOLFIRI as an additional new standard of care for patients with BRAF V600E-mutant mCRC, enabling treatment personalisation.

PURPOSE: To clarify the efficacy of perioperative chemotherapy for the patients with resectable colorectal liver metastases (CLM), we conducted a multicenter randomized phase III trial to compare surgery followed by postoperative FOLFOX regimen with perioperative FOLFOX regimen plus cetuximab in patients with KRAS wild-type resectable CLM. METHODS: Patients who had KRAS wild-type resectable CLM having one to eight liver nodules without extrahepatic disease were randomly assigned to the postoperative chemotherapy group, wherein up-front hepatectomy was performed followed by 12 cycles of postoperative modified FOLFOX6, and the perioperative chemotherapy group (experimental), wherein six cycles of preoperative modified FOLFOX6 plus cetuximab were performed followed by hepatectomy and six cycles of postoperative modified FOLFOX6 plus cetuximab. The primary endpoint was progression-free survival (PFS). RESULTS: There were 37 patients in postoperative chemotherapy group and 40 patients in the perioperative chemotherapy group who were analyzed. Baseline characteristics were well-balanced between groups. The PFS and overall survival (OS) showed no significant difference (PFS, hazard ratio 1.18 [95% confidence interval 0.69-2.01], P = 0.539: OS, 1.03 [0.46-2.29], P = 0.950). In the postoperative chemotherapy group, 35.1% had a 3-year PFS, and 86.5% had a 3-year OS. Meanwhile, in the perioperative chemotherapy group, 30.0% had a 3-year PFS, and 74.4% had a 3-year OS. CONCLUSION: There was no difference in survival found between the group of the perioperative chemotherapy plus cetuximab and that of the postoperative chemotherapy in the cohort of our study. The study was registered in the University Hospital Medical Information Network (UMIN000007787).

PURPOSE: Suboptimal treatment outcomes with 5-fluorouracil (5-FU)/folate, the standard of care for metastatic colorectal cancer (mCRC), have generated interest in optimizing the folate. Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is an immediately active folate and may improve outcomes over the existing standard of care (leucovorin). EXPERIMENTAL DESIGN: AGENT was a randomized, phase III study (NCT03750786). Patients with mCRC were randomized to arfolitixorin (120 mg/m2 given as two intravenous bolus doses of 60 mg/m2) or leucovorin (400 mg/m2 given as a single intravenous infusion) plus 5-FU, oxaliplatin, and bevacizumab. Assessments were performed every 8 weeks. The primary endpoint was the superiority of arfolitixorin for overall response rate (ORR). RESULTS: Between February 2019 and April 2021, 490 patients were randomized (245 to each arm). After a median follow-up of 266 days, the primary endpoint of superiority for ORR was not achieved (48.2% for arfolitixorin vs. 49.4% for leucovorin, Psuperiority = 0.57). Outcomes were not achieved for median progression-free survival (PFS; 12.8 and 11.6 months, P = 0.38), median duration of response (12.2 and 12.9 months, P = 0.40), and median overall survival (23.8 and 28.0 months, P = 0.78). The proportion of patients with an adverse event of grade ≥3 severity was similar between arms (68.7% and 67.2%, respectively), as was quality of life. BRAF mutations and MTHFD2 expression were both associated with a lower PFS with arfolitixorin. CONCLUSIONS: The study failed to demonstrate clinical benefit of arfolitixorin (120 mg/m2) over leucovorin. However, it provides some useful insights from the first-line treatment setting, including the effect of gene expression on outcomes. SIGNIFICANCE: This phase III study compared arfolitixorin, a direct-acting folate, with leucovorin in FOLFOX plus bevacizumab in mCRC. Arfolitixorin (120 mg/m2) did not improve the ORR, potentially indicating a suboptimal dose.