Published papers

PURPOSE Circulating tumor DNA (ctDNA) genotyping on the basis of next-generation sequencing (NGS) may guide targeted therapy for metastatic colorectal cancer (mCRC). However, the validity of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment and the efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA results remains unclear. PATIENTS AND METHODS The performance of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment was compared with that of a validated polymerase chain reaction-based tissue testing in patients with mCRC enrolled in the GOZILA study, a nationwide plasma genotyping study. The primary end points were concordance rate, sensitivity, and specificity. The efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA were also evaluated. RESULTS In 212 eligible patients, the concordance rate, sensitivity, and specificity were 92.9% (95% CI, 88.6 to 96.0), 88.7% (95% CI, 81.1 to 94.0), and 97.2% (95% CI, 92.0 to 99.4) for RAS and 96.2% (95% CI, 92.7 to 98.4), 88.0% (95% CI, 68.8 to 97.5), and 97.3% (95% CI, 93.9 to 99.1) for BRAF V600E, respectively. In patients with a ctDNA fraction of ≥1.0%, sensitivity rose to 97.5% (95% CI, 91.2 to 99.7) and 100% (95% CI, 80.5 to 100.0) for RAS and BRAF V600E mutations, respectively. In addition to a low ctDNA fraction, previous chemotherapy, lung and peritoneal metastases, and interval between dates of tissue and blood collection were associated with discordance. The progression-free survival of anti-EGFR therapy and BRAF-targeted treatment was 12.9 months (95% CI, 8.1 to 18.5) and 3.7 (95% CI, 1.3 to not evaluated) months, respectively, for matched patients with RAS/BRAF V600E results by ctDNA. CONCLUSION ctDNA genotyping effectively detected RAS/BRAF mutations, especially with sufficient ctDNA shedding. Clinical outcomes support ctDNA genotyping for determining the use of anti-EGFR and BRAF-targeted therapies in patients with mCRC.

Purpose: Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard. Patients and Methods: The performance of plasma-based MSI assessment using Guardant360, a nextgeneration sequencing.based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction.based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study. The primary end points were overall percent agreement, positive percent agreement (PPA), and negative percent agreement. The efficacy of immune checkpoint inhibitor therapy was also evaluated. Results: In 658 patients with advanced GI cancers who underwent both plasma and tissue testing for MSI, the overall percent agreement, PPA, and negative percent agreement were 98.2%(95% CI, 96.8 to 99.1), 71.4% (95% CI, 47.8 to 88.7), and 99.1% (95% CI, 98.0 to 99.7), respectively. In patients whose plasma samples had a ctDNA fraction ≥ 1.0%, the PPA was 100.0%(15/15; 95%CI, 78.2 to 100.0). Three patients withMSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti.programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months. One patient with an aggressive cancer of an unknown primary site benefited from pembrolizumab after rapid detection of MSI-H by ctDNA genotyping. Conclusion: ctDNA genotyping was able to detect MSI with high concordance to validated tissue-based MSI testing, especially in patients with tumors that have sufficient ctDNA shedding. Furthermore, ctDNA genotyping enabled identification of patients with MSI-H tumors who benefited from immune checkpoint inhibitor treatment.

Background: TP53 mutations are among the most frequent alterations in biliary tract cancer (BTC), but their prognostic relevance and predictive value for immune checkpoint inhibitors (ICI) remain unclear. We assessed clinico-molecular features, prognosis, and ICI efficacy by TP53 status in advanced BTC. Methods: Patients with advanced BTC from Japan and the United States who underwent tissue- or plasma-based next-generation sequencing were retrospectively analyzed. Tissue-based sequencing was used for the primary analysis, and plasma ctDNA sequencing was evaluated as an exploratory cohort. Outcomes were compared between TP53 wild-type (WT) and TP53-mutated groups. Treatment–TP53 interactions for non-ICI versus ICI-containing regimens were assessed using multivariable Cox models. Whole-transcriptome sequencing data were analyzed using TIDE and Hallmark gene set enrichment analysis. Results: Among 336 patients in the tissue-based cohort, 177 (52.7%) had TP53-mutated tumors. SMAD4, ERBB2, PTEN and CCNE1 co-alterations were enriched in TP53-mutated tumors, whereas IDH1, BAP1, and FGFR2 fusions were more frequent in WT tumors. TP53 mutations were independently associated with shorter PFS, whereas OS showed a similar but nonsignificant trend (PFS: HR 1.32, P = 0.04; OS: HR 1.32, P = 0.09). TP53 mutations were associated with shorter PFS in the non-ICI cohort but numerically longer PFS in the ICI cohort, with a significant treatment–TP53 interaction for PFS (P < 0.01). Similar trends were observed in the plasma cohort. Transcriptomic analyses (n = 59; all MSS) showed lower TIDE scores in TP53-mutated tumors. Conclusion: TP53 mutations were associated with poor prognosis and may predict greater benefit from ICI, supporting biomarker-driven stratification.

PURPOSE: This study aimed to investigate the clinicomolecular profiles and the efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy in HER2-amplified biliary tract cancer (BTC). METHODS: This study was an international collaboration that used combined data from the prospective SCRUM-Japan GOZILA and MONSTAR-SCREEN in Japan and retrospective reviews in the United States; patients with advanced BTC who had received systemic therapy were included. The clinicomolecular profiles were evaluated in an exploratory cohort, whereas the efficacy of HER2-targeted therapy was assessed in a biomarker-selected cohort. RESULTS: Of the 439 patients in the exploratory cohort, 43 (10%) had HER2 amplification. The frequencies of coalterations were higher in patients with HER2 amplification versus patients without HER2 amplification including HER2 mutations (26% v 5%, P < .001), TP53 mutations (84% v 61%, P = .003), and BRAF amplification (9% v 2%, P = .030). There were no KRAS mutations identified in patients with HER2-amplified BTC. No significant difference in overall survival (OS) was observed between patients with and without HER2 amplification (median, 17.7 v 16.9 months; hazard ratio [HR], 0.95 [95% CI, 0.65 to 1.40]). Of the 60 patients with HER2-amplified BTC in the biomarker-selected cohort (43 from Japan and 17 from the United States), the OS was significantly longer in 29 patients who received HER2-targeted therapy than in those who did not receive HER2-targeted therapy (median, 24.3 v 12.1 months; HR, 0.39 [95% CI, 0.23 to 0.82]). Multivariate analysis identified HER2-targeted therapy as an independent prognostic factor for OS (HR, 0.29 [95% CI, 0.14 to 0.58]; P < .001). CONCLUSION: HER2 amplification was found in 10% of advanced BTC and was not identified as an independent prognostic factor for OS. Patients with HER2-amplified BTC derive significant benefit from HER2-targeted therapy.

BACKGROUND: Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing. METHODS: Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided. RESULTS: Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P < .001), disease-free survival (HR = 0.91, 95% CI = 0.84 to 0.98; P = .01), and survival after recurrence (HR = 0.88, 95% CI = 0.80 to 0.97; P = .008) in the analysis without molecular markers; however, age at onset of CC lost its prognostic value when outcome was adjusted for molecular markers. CONCLUSION: Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.

In our previous papers [arXiv:2106.03150, arXiv:2110.10917, arXiv:2208.00822], we analyzed the asymptotic behavior of future directed null geodesics near future null infinity and then we showed a proposition on the accessibility of the null geodesics to future null infinity in a specific class of asymptotically flat spacetimes. In this paper, we adopt the retarded time of the Bondi coordinate as the parameter for the null geodesics and then see that one can relax the assumptions imposed in our previous studies. As a consequence, we obtain a new null-access theorem for generic asymptotically flat spacetimes.

A new sufficient condition for photons emitted near future null infinity to reach future null infinity is derived by studying null geodesics in the Bondi coordinates in asymptotically flat spacetimes. In our previous works [arXiv:2106.03150, arXiv:2110.10917], such a condition was established for photons emitted in outward or tangential directions to constant radial surfaces. This paper improves our previous result by including photons emitted in inward directions. In four dimensions, imposing the same assumptions on the metric functions as previously, we prove that photons reach future null infinity if their initial values of $|dr/du|$ are smaller than a certain quantity, where $r$ and $u$ are the radial and retarded time coordinates, respectively. This quantity is determined by the asymptotic properties of the metric and is connected to the conjectured maximal luminosity. In higher dimensions, photons emitted with $dr/du>-(1-1/\sqrt{3})\approx -0.423$ are shown to reach future null infinity without the assumptions on the metric functions.

We investigate the behavior of null geodesics near future null infinity in asymptotically flat spacetimes. In particular, we focus on the asymptotic behavior of null geodesics that correspond to worldlines of photons initially emitted in the directions tangential to the constant radial surfaces in the Bondi coordinates. The analysis is performed for general dimensions, and the difference between the four-dimensional cases and the higher-dimensional cases is stressed. In four dimensions, some assumptions are required to guarantee the null geodesics to reach future null infinity, in addition to the conditions of asymptotic flatness. Without these assumptions, gravitational waves may prevent photons from reaching null infinity. In higher dimensions, by contrast, such assumptions are not necessary, and gravitational waves do not affect the asymptotic behavior of null geodesics.

Platinum-based definitive chemoradiotherapy (dCRT) is the standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) that invades the aorta, vertebral body or trachea; however, complete response rates remain low (11-25%), leading to poor survival. To evaluate the additive efficacy of the anti-PD-L1 antibody drug atezolizumab, we conducted a phase 2, multicenter, single-arm trial of 1 year of atezolizumab treatment following dCRT in 40 patients with unresectable locally advanced ESCC recruited from seven Japanese centers (UMIN000034373). The confirmed complete response (cCR) rate (primary end point) of the first consecutive 38 patients was 42.1% (90% CI 28.5-56.7%). Regarding the secondary end points, the median progression-free survival and 12-month progression-free survival rates of all 40 patients were 3.2 months and 29.6%, respectively, and the preliminary median overall survival with short-term follow-up and 12-month overall survival rate were 31.0 months and 65.8%, respectively. Other secondary end points evaluated included the cCR rate determined by an investigator's assessment in the locoregionally recurrent ESCC cohort, cCR rate determined by central assessment, overall response rate and incidence of adverse events. No treatment-related death occurred during the study. Atezolizumab monotherapy after dCRT resulted in a promising cCR rate, although long-term survival data are required.

We derive areal inequalities for five types of attractive gravity probe surfaces, which were proposed by us in order to characterize the strength of gravity in different ways including weak gravity region, taking into account of contributions of electric and magnetic charges, angular momentum, gravitational waves, and matters. These inequalities are generalizations of the Riemannian Penrose inequality for minimal surfaces, and lead to the concept of extremality for a given surface whose condition is given in terms of the gravitational mass and the electromagnetic charges. This means that the extremality is a characteristic property not only of black hole horizons or minimal surfaces but also of surfaces in weak gravity region. We also derive areal inequalities and extremality conditions for surfaces in asymptotically locally anti-de Sitter spacetimes.

A generalization of the Riemannian Penrose inequality in $n$-dimensional space ($3\le n<8$) is done. We introduce a parameter $α$ ($-\frac{1}{n-1}<α< \infty$) indicating the strength of the gravitational field, and define a refined attractive gravity probe surface (refined AGPS) with $α$. Then, we show the area inequality for a refined AGPS, $A \le ω_{n-1} \left[ (n+2(n-1)α)Gm /(1+(n-1)α) \right]^{\frac{n-1}{n-2}}$, where $A$ is the area of the refined AGPS, $ω_{n-1}$ is the area of the standard unit $(n-1)$-sphere, $G$ is Newton's gravitational constant and $m$ is the Arnowitt-Deser-Misner mass. The obtained inequality is applicable not only to surfaces in strong gravity regions such as a minimal surface (corresponding to the limit $α\to \infty$), but also to those in weak gravity existing near infinity (corresponding to the limit $α\to -\frac{1}{n-1}$).

Background: As the number of female physicians in Japan increases, so does the number of female oncologists. This study investigates gender-related challenges and identifies factors influencing career progression among oncology professionals in Japan. Materials and methods: A survey was distributed to members of the Japanese Society of Medical Oncology (JSMO) and the Japan Society of Clinical Oncology (JSCO), based on the European Society for Medical Oncology (ESMO) Women for Oncology questionnaire. It covered demographics, professional environment, work–life balance, personal choices, and career-related challenges. Results: A total of 612 responses (47.5% women, 52.5% men) were analyzed; 58.9% were <50 years of age. Female respondents were significantly more likely to report that their careers impacted marital status, childbearing decisions, and time for childcare. Women also reported a greater influence of life choices—such as marriage, childbirth, and reduced working hours—on their careers than men. Notably, 66.4% of women perceived career barriers compared with 40.6% of men. Major obstacles included difficulty balancing work and life, limited opportunities for clinical research, and childcare responsibilities. Multivariate analysis showed that gender and age were significant predictors of perceived career barriers. Conclusions: Gender disparities remain a major issue for female oncologists in Japan, rooted in societal expectations, unequal childcare burdens, and institutional limitations. Systemic changes—such as promoting task sharing, expanding mentorship, and implementing inclusive workplace policies—are essential to foster equitable career advancement in oncology.

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS,PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62–0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83–1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795.

PURPOSE: The utility of capturing heterogeneity by circulating tumor DNA (ctDNA) genotyping combined with tissue analysis or applying it in a sequential manner remains uncertain. METHODS: We assessed the clinical value of ctDNA genotyping using data from 2,187 patients with advanced solid tumors enrolled in SCRUM-Japan MONSTAR-SCREEN-1, a nationwide cancer genome screening project, which examined ctDNA from longitudinally collected blood samples and tumor tissue samples (UMIN 000036749). RESULTS: Among 667 patients with both baseline ctDNA and tissue genotyping results, 51 (7.6%) had actionable biomarkers identified exclusively through ctDNA genotyping. The most frequent targets of genotype-matched therapy guided by solely ctDNA were immune checkpoint, estrogen receptor, and poly(ADP-ribose) polymerase (PARP). Comparison of objective response rates (ORRs) and progression-free survival (PFS) between patients treated based on tissue versus ctDNA alone showed no significant difference, with ORRs of 34.0% versus 23.1% (P = .54) and a median PFS of 11.5 versus 13.8 months (hazard ratio [HR], 1.4 [95% CI, 0.72 to 2.80]), respectively. Among 924 patients undergoing sequential ctDNA genotyping, the detection of actionable biomarkers increased from 63.2% to 72.5% following subsequent ctDNA. Targets for genotype-matched therapy guided by subsequent ctDNA alone commonly included PARP, immune checkpoint, and BRAF. The ORR was 23.2% and 26.7% (P = .75), and the median PFS was 5.2 and. 3.7 months (HR, 1.5 [95% CI, 0.79 to 2.80]) for genotype-matched therapy based on initial versus subsequent ctDNA alone, respectively. CONCLUSION: Combining ctDNA with tissue analysis, followed by sequential ctDNA assessments, effectively enhances the identification of actionable biomarkers. This strategy facilitates clinically beneficial, genetically informed therapies, underscoring its significant value in precision oncology.

Community Question Answering (CQA) sites have spread and multiplied significantly in recent years. Sites like Reddit, Quora, and Stack Exchange are becoming popular amongst people interested in finding answers to diverse questions. One practical way of finding such answers is automatically predicting the best candidate given existing answers and comments. Many studies were conducted on answer prediction in CQA but with limited focus on using the background information of the questionnaires. We address this limitation using a novel method for predicting the best answers using the questioner's background information and other features, such as the textual content or the relationships with other participants. Our answer classification model was trained using the Stack Exchange dataset and validated using the Area Under the Curve (AUC) metric. The experimental results show that the proposed method complements previous methods by pointing out the importance of the relationships between users, particularly throughout the level of involvement in different communities on Stack Exchange. Furthermore, we point out that there is little overlap between user-relation information and the information represented by the shallow text features and the meta-features, such as time differences.