Published papers

Single-cell spatial omics analysis requires consideration of biological functions and mechanisms in a microenvironment. However, microenvironment analysis using bioinformatic methods is limited by the need to detect histological morphology and extend it to the surrounding area. In this study, we developed SpatialKNifeY (SKNY), an image-processing-based toolkit that detects spatial domains that potentially reflect histology and extends these domains to the microenvironment. Using spatial transcriptomic data from breast cancer, we applied the SKNY algorithm to identify tumor spatial domains, followed by clustering of the domains, trajectory estimation, and spatial extension to the tumor microenvironment (TME). The results of the trajectory estimation were consistent with the known mechanisms of cancer progression. We observed tumor vascularization and immunodeficiency at mid- and late-stage progression in TME. Furthermore, we applied the SKNY to integrate and cluster the spatial domains of 14 patients with metastatic colorectal cancer, and the clusters were divided based on the TME characteristics. In conclusion, the SKNY facilitates the determination of the functions and mechanisms in the microenvironment and cataloguing of the features.

This paper establishes a rigorous geometrical framework for spherical origami, origami using spherical sheets based on spherical geometry. Two settings are treated: origami restricted to the unit sphere ($\mathbb{S}^2$), and three-dimensional folding of spherical sheets in space. For origami on $\mathbb{S}^2$, the definitions of Euclidean origami are systematically extended to the spherical setting, and all seven Huzita--Justin axioms are shown to admit explicit equations in spherical geometry. For three-dimensional folding, equidistant curves are introduced as fold curves, replacing geodesics and enabling a richer family of folds. The framework is validated by successfully constructing computer graphics of spherical origami birds, demonstrating both the theoretical completeness and practical utility of the proposed approach.

In recent years, there has been a development in approaching rationality problems through the motivic methods (cf. [Kontsevich--Tschinkel'19], [Nicaise--Shinder'19], [Nicaise--Ottem'21]). This method requires the explicit construction of degeneration families of curves with favorable properties. While the specific construction is generally difficult, [Nicaise--Ottem'22] combines combinatorial methods to construct degeneration families of hypersurfaces in toric varieties and shows the non-stable rationality of a very general hypersurface in projective spaces. In this paper, we extend the result of [Nicaise--Ottem'22] not only for hypersurfaces in algebraic tori but also to those in schön affine varieties. In application, we show the irrationality of certain hypersurfaces in the complex Grassmannian variety Gr(2, n) using the motivic method, which coincides with the result obtained by the same author in the previous research.

We introduce a mock toric variety, a generalization of a toric variety. For a non-toric example, Del-Pezzo surfaces are mock toric varieties. These new varieties inherit some properties of mock toric varieties. In application, we give sufficient conditions for the concrete construction of a strictly toroidal model of a hypersurface in a mock toric variety.

In recent years, there has been a development in approaching rationality problems through motivic methods (cf. [Kontsevich--Tschinkel'19], [Nicaise--Shinder'19], [Nicaise--Ottem'21]). This method requires the explicit construction of degeneration families of curves with favorable properties. While the specific construction is generally difficult, [Nicaise--Ottem'22] combines combinatorial methods to construct degeneration families of hypersurfaces in toric varieties and mentions the stable rationality of a very general hypersurface in projective spaces. In this paper, we substitute mock toric varieties for toric varieties and we prove the following theorem from the motivic method: If a very general hypersurface of degree $d$ in $\mathbb{P}^{2n-5}_\mathbb{C}$ is not stably rational, then a very general hypersurface of degree $d$ in $\mathrm{Gr}_\mathbb{C}(2, n)$ is not stably rational.

BACKGROUND: Despite contributions provided by the recent clinical trials, several issues and challenges still remain unsolved in adjuvant colon cancer (CC). Hence, further studies should be planned to better refine risk assessment as well as to establish the optimal treatment strategy in the adjuvant setting. However, it is necessary to request adequate, contemporary and relevant variables and report them homogeneously in order to bring maximal information when analyzing their prognostic value. MATERIAL AND METHODS: The project was devised to gain a consensus from experts engaged in the planning, accrual and analyses of stage II and III CC clinical trials, to identify mandatory and recommended baseline variables in order to i) harmonize future data collection worldwide in clinical trials dedicated to adjuvant treatment of CC; ii) propose guidance for Case Report Forms to be used for clinical trials in this setting. A total of 72 questions related to variables that should be reported and how to report them in adjuvant clinical trials were approved and then voted to reach a final consensus from panelists. RESULTS: Data items on patient-related factors, histopathological features, molecular profile, circulating biomarkers and blood analyses were analyzed and discussed by the whole expert panel. For each item, we report data supporting the acquired consensus and the relevant issues that were discussed. Nineteen items were deemed to be mandatory for resected stage III patients and 24 for resected stage II disease. In addition, 9 and 4 items were judged as recommended for stage III and II, respectively. CONCLUSION: In our opinion, these 28 variables should be used and uniformly reported in more comprehensive CRFs as research groups design future clinical trials in the field of adjuvant colon cancer.

Background: The prognostic role of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection and its utility for postsurgical risk stratification has been reported in colorectal cancer. In this study, we explored the use of ctDNA-based MRD detection in patients with colorectal liver metastases (CLM), for whom the survival benefit of adjuvant chemotherapy (ACT) after surgical resection remains unclear. Methods: Patients with CLM without extrahepatic disease from the GALAXY study (UMIN000039205) were included. The disease-free survival (DFS) benefit of ACT was evaluated in MRD-positive and -negative groups after adjusting for age, gender, number, and size of liver metastases, RAS status, and previous history of oxaliplatin for primary cancer. ctDNA was detected using a personalized, tumor-informed 16-plex polymerase chain reaction-next-generation sequencing (mPCR-NGS) assay. ctDNA-based MRD status was evaluated 2-10 weeks after curative surgery, before the start of ACT. Results: Among 6061 patients registered in GALAXY, 190 surgically resected CLM patients without any preoperative chemotherapy were included with a median follow-up of 24 months (1-48 months). ctDNA positivity in the MRD window was 32.1% (61/190). ACT was administered to 25.1% (48/190) of patients. In the MRD-positive group, 24-month DFS was higher for patients treated with ACT [33.3% versus not reached, adjusted hazard ratio (HR): 0.07, P < 0.0001]; whereas no benefit of ACT was seen in the MRD-negative group (24-month DFS: 72.3% versus 62.2%, adjusted HR: 0.68, P = 0.371). Multivariate analysis showed that the size of liver metastases (HR: 3.94, P = 0.031) was prognostic of DFS in the MRD-positive group. In the MRD-negative group, however, none of the clinicopathological factors were prognostic of DFS. Conclusions: Our data suggest that ACT may offer notable clinical benefits in MRD-positive patients with CLM. MRD status-based risk stratification could be potentially incorporated in future clinical trials for CLM.

PURPOSE – Homologous recombination deficiency (HRD) is a key determinant of sensitivity to DNA-damaging agents; however, its genomic characterization in colorectal cancer (CRC) remains limited. This study investigated whether low RNA expression of homologous recombination (HR) genes identifies patients with metastatic CRC who derive survival benefit from oxaliplatin- or irinotecan-based therapy.METHODS – A total of 22, 957 metastatic CRC samples were subjected to DNA and RNA sequencing (Caris Life Sciences, Dallas, TX). Patients with microsatellite instability–high or pathogenic HR gene mutations were excluded to define a HR-proficient cohort. Overall survival (OS) was compared between patients with low (bottom 25%) versus high (top 25%) RNA expression of HR genes after oxaliplatin or irinotecan exposure. Validation was performed in the PARADIGM phase III trial cohort (n = 262) of first-line modified fluorouracil, leucovorin, and oxaliplatin-treated patients with available RNAseq data.RESULTS – In the discovery cohort, low expression of core HR genes correlated with significantly longer OS after oxaliplatin or irinotecan exposure, specifically RAD51 (43.0 v 36.3 months; P < .005) and BLM (42.9 v 34.2 months; P < .005). Similar associations were observed for RAD51 (28.1 v 22.9 months; P = .02) and BLM (29.1 v 23.2 months; P < .005) in irinotecan-treated patients. In the PARADIGM validation cohort, low BLM expression was associated with improved OS (41.5 v 22.4 months; HR = 0.52; P = .002), whereas RAD51 showed a favorable but nonsignificant trend. These findings remained significant after adjustment for treatment arm, tumor sidedness, and metastatic burden.CONCLUSION – Low BLM RNA expression is associated with improved survival after treatment with DNA-damaging agents, whereas low RAD51 expression shows a favorable but nonsignificant trend. These findings are exploratory and suggest that RNA-based HR gene expression may warrant further investigation as a potential prognostic biomarker in metastatic CRC.

INTRODUCTION: The primary treatment for locoregional failure following chemoradiotherapy for squamous cell carcinoma of the anus (SCCA) is salvage abdominoperineal resection (APR). However, it is necessary to distinguish between recurrent and persistent diseases because of their varied pathologies. We aimed to clarify the survival outcomes following salvage APR for recurrent and persistent diseases and investigate the significance of salvage APR. MATERIALS AND METHODS: This multicentre retrospective cohort study used clinical data from 47 hospitals. All patients were diagnosed with SCCA and underwent definitive radiotherapy as the primary treatment between 1991 and 2015. Overall survival (OS) was compared between the following cohorts: salvage APR for recurrence, salvage APR for persistence, non-salvage APR for recurrence, and non-salvage APR for persistence. RESULTS: Five-year OS of salvage APR for recurrence, salvage APR for persistence, non-salvage APR for recurrence, and non-salvage APR for persistence were 75% (46%-90%), 36% (21%-51%), 42% (21%-61%), and 47% (33%-60%), respectively. OS of salvage APR for the recurrent disease was significantly higher than that for persistent disease (p = 0.00597). For recurrent disease, OS following salvage APR was significantly higher than that following non-salvage APR (p = 0.0204); however, for persistent disease, there was no significant difference between salvage and non-salvage APR (p = 0.928). CONCLUSION: Survival outcomes following salvage APR for persistent disease were significantly worse than that for recurrent disease. Salvage APR did not improve survival outcomes for persistent disease compared to non-salvage APR. These results will elicit a review of persistent disease treatment strategies.

BACKGROUND: HER2-positive or ERBB2 amplified (ERBB2 amp+) metastatic colorectal cancer (mCRC) is an important subgroup due to emerging HER2-targeted therapies. Although ERBB2 amplification is associated with anti-EGFR antibody resistance, optimal first-line treatment remains unclear. METHODS: We analysed data from the Flatiron Health-Foundation Medicine CRC clinico-genomic database, including patients with stage IV or recurrent mCRC diagnosed between January 2012 and March 2022 who underwent tissue-based comprehensive genomic profiling. ERBB2 amp+ was defined as an ERBB2 copy number ≥+3 of the tumour base ploidy. RESULTS: Among 5545 patients, 144 (3.1%) had ERBB2 amp+ mCRC. These patients showed significantly worse real-world progression-free survival (rwPFS) than ERBB2 amp- patients (median 7.6 vs. 8.7 months; hazard ratio [HR]: 1.20, 95% confidence interval [CI]: 1.01-1.43, p = 0.04). This trend persisted in patients with left-sided RAS/BRAF V600E wild-type and non-MSI-H mCRC treated with chemotherapy plus anti-EGFR antibody (median 8.7 vs. 12.5 months; HR: 2.18, p = 0.02; adjusted HR: 2.33, p = 0.046) or chemotherapy plus bevacizumab (median 8.9 vs. 10.5 months; HR: 1.65, p = 0.04; adjusted HR: 1.75, p = 0.04). Real-world overall survival did not differ significantly. CONCLUSION: ERBB2 amp+ mCRC is a small but clinically relevant subgroup with inferior rwPFS across current first-line treatments, highlighting the need for better strategies.

Purpose: The negative impact of the BRAF V600E mutation (mBRAF) on survival outcomes has been reported for metastatic colorectal cancer (mCRC), but the role of mBRAF testing in resectable extrahepatic cases remains unclear. This study aimed to assess survival outcomes in patients with extrahepatic mCRC harboring mBRAF who underwent upfront metastasectomy, compared with patients with unresectable mBRAF tumors. Methods: A single-center retrospective study was conducted between January 2005 and December 2017. Of 109 patients who underwent initial metastasectomy for extrahepatic mCRC without preoperative chemotherapy, mBRAF, RAS mutations (mRAS), and wild-type RAS/BRAF (wtRAS/BRAF) were found in 6 (5.5%), 64 (58.7%), and 39 (35.8%) patients, respectively. Results: After a median follow-up of 39.5 months, patients with mBRAF had a median recurrence-free survival (RFS) of 4.4 months and overall survival (OS) of 40.6 months. In multivariate survival analysis, mBRAF status was the strongest independent predictor of poor survival, even after adjusting for conventional clinicopathological factors and other mutational statuses (RFS: HR 3.15, p = 0.035; OS: HR 3.85, p = 0.037). The OS after upfront metastasectomy in mBRAF cases was nearly identical to that of unresectable mCRC treated with systemic chemotherapy (HR 1.01, p = 0.99). Conclusion: Technically resectable extrahepatic oligometastases with mBRAF may be considered oncologically unresectable. Preoperative mBRAF testing should be considered for all patients with resectable extrahepatic mCRC, regardless of technical resectability.

The prognosis of advanced biliary tract cancer remains poor despite up to 40% of tumors harboring actionable molecular alterations. This international collaborative study from Mayo Clinic, Duke Cancer Institute, National Cancer Center East (Japan), and the SCRUM-Japan GOZILA/MONSTAR-SCREEN projects evaluated clinical outcomes in 1049 patients with advanced BTC based on tumor molecular profiling and matched treatment selection. Patients were categorized into non-actionable, actionable with matched targeted therapy (matched), and actionable without matched therapy (unmatched) groups. Among 358 patients (34.1%) with actionable alterations, 160 (44.7%) received matched therapy. The matched group demonstrated significantly longer median overall survival (23.3 months; 95% CI: 19.5-30.4) compared to unmatched (14.7 months; 95% CI: 12.8-17.9) and non-actionable groups (17.1 months; 95% CI: 15.5-18.7; HR 0.57, 95% CI: 0.46-0.71; p 0.0001). In 700 patients receiving ≥2 lines of therapy, matched therapy remained independently associated with improved survival (HR 0.62; 95% CI 0.43-0.90). Notably, patients with actionable tumors who did not receive matched therapy experienced worse outcomes than those with non-actionable disease. These findings highlight the critical need for universal molecular profiling and equitable access to targeted therapies in advanced BTC.

Numerous clinical studies in an adjuvant setting have been conducted and the combination therapy of 5-fluorouracil and oxaliplatin has been established as the standard treatment for Stage III and as an option for high-risk Stage II patients. Biologics such as bevacizumab and antiepidermal growth factor receptor antibodies have failed to show additional survival benefits. The indication of adjuvant chemotherapy has been determined according to the pathological stage. Nevertheless, a pathological diagnosis does not necessarily result in selection of the optimal treatment. To improve treatment decisions, many trials have aimed to stratify patients into treatment groups using genomic testing. Recently, gene signature, Immunoscore, and circulating tumor DNA (ctDNA) assays have been reported and among them, ctDNA was shown to be a promising accurate predictive marker for recurrence. Treatment of ctDNA-positive patients with aggressive chemotherapy may reduce recurrence rates. The ultimate goal is to accurately predict the risk of recurrence and to prevent recurrence in colon cancer patients. In this review we focus on the clinical development of adjuvant chemotherapy and stratification of patients according to risk of recurrence and the future direction of adjuvant chemotherapy.

Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.

We investigated the thermal stability of scintillation and the luminescence performances of (La, Gd)${}_{2}$Si${}_{2}$O${}_{7}$ single crystals at various Ce concentrations. We prepared (La${}_{0.25-x}$, Ce${}_{x}$, Gd${}_{0.75}$)${}_{2}$Si${}_{2}$O${}_{7}$ (x = 0.0001, 0.001, 0.005, 0.01, 0.02, 0.05, and 0.1; unit: molar concentration) single crystals by the Czochralski and micro-pulling-down methods. With increasing Ce concentration, the photoluminescence emission and photoluminescence excitation spectral bands shifted to low energies and the activation energy $\mathrm{Δ}E$ for thermal quenching decreased. For Ce $\mathrm{<}$ 0.5 at.% samples, the photoluminescence emission background value calculated in the exponential approximation started to increase at temperatures greater than 320 K, which is probably because of Ce${}^{3+}$ 5$\textit{d}$ excited-state ionization. However, the effect was weaker for the Ce $\ge $ 0.5% samples, which may indicate a comparatively larger contribution from other nonradiative relaxations. Thus the main reason for the thermal quenching of the Ce${}^{3+}$ emission in (La, Gd)${}_{2}$Si${}_{2}$O${}_{7}$ is the combination of the 5$\textit{d}$1 excited-state ionization and nonradiative relaxation via thermally excited crossover from the 5$\textit{d}$ excited state to the 4$\textit{f}$ ground state. The temperature dependence of the scintillation light yield was similar irrespective of the Ce concentration, with Ce 1.0% exhibiting the best performance within the temperature range 300 K to 450 K.