Published papers

BACKGROUND: Salvage concurrent chemoradiotherapy is effective against locoregional recurrence after curative resection of esophageal squamous cell carcinoma. However, there is no consensus on its application. We investigated the outcomes of salvage concurrent chemoradiotherapy (60 Gy in 30 fractions) with three-dimensional conformal radiotherapy and 5-fluorouracil/platinum-based chemotherapy. METHODS: We retrospectively investigated the outcomes and prognostic factors in 51 patients with esophageal squamous cell carcinoma treated with salvage concurrent chemoradiotherapy. RESULTS: The median follow-up was 17.5 (range, 2.8-116.1) months. The overall response, complete response, and partial response rates were 74.5%, 49.0%, and 25.5%, respectively. The median progression-free survival was 8.2 months; the 3-year progression-free survival rate was 22.9%. The median overall survival was 23.1 months; the 3-year overall survival rate was 40.7%. Overall survival was significantly longer in patients with a complete response than in those without (median overall survival: not reached vs. 15.3 months); 3-year overall survival rate: 62.5% vs. 20.3% (hazard ratio: 0.222; P < 0.001). Multivariate analysis showed that the independent prognostic factor for overall survival was < 25 mm longest diameter of metastatic lymph nodes (hazard ratio: 3.71). CONCLUSIONS: Salvage concurrent chemoradiotherapy (60 Gy in 30 fractions) with three-dimensional conformal radiotherapy and 5-fluorouracil/platinum-based chemotherapy was an effective and safe treatment for locoregional recurrence after curative resection of esophageal squamous cell carcinoma, especially in those approaching a complete response. Additionally, a shorter longest diameter of metastatic lymph nodes may be associated with better long-term survival.

Tumor tissue collections are used to uncover pathways associated with disease outcomes that can also serve as targets for cancer treatment, ideally by comparing the molecular properties of cancer tissues to matching normal tissues. The quality of such collections determines the value of the data and information generated from their analyses including expression and modifications of nucleic acids and proteins. These biomolecules are dysregulated upon ischemia and decompose once the living cells start to decay into inanimate matter. Therefore, ischemia time before final tissue preservation is the most important determinant of the quality of a tissue collection. Here we show the impact of ischemia time on tumor and matching adjacent normal tissue samples for mRNAs in 1664, proteins in 1818, and phosphosites in 1800 cases (tumor and matching normal samples) of four solid tumor types (CRC, HCC, LUAD, and LUSC NSCLC subtypes). In CRC, ischemia times exceeding 15 min impacted 12.5% (mRNA), 25% (protein), and 50% (phosphosites) of differentially expressed molecules in tumor versus normal tissues. This hypoxia- and decay-induced dysregulation increased with longer ischemia times and was observed across tumor types. Interestingly, the proteomics analysis revealed that specimen ischemia time above 15 min is mostly associated with a dysregulation of proteins in the immune-response pathway and less so with metabolic processes. We conclude that ischemia time is a crucial quality parameter for tissue collections used for target discovery and validation in cancer research.

Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection has shown promise across various malignancies, yet limited data exist for renal cell carcinoma (RCC), a traditionally low-shedding tumor type. Whole-exome sequencing (WES)-based approaches often lack sufficient sensitivity for effective MRD surveillance in RCC. The prospective, multicenter MONSTAR-SCREEN-3 study evaluates an ultra-sensitive whole-genome sequencing (WGS)-based MRD assay in patients with resectable solid tumors undergoing curative-intent therapy. Here, we report preliminary results from patients with resectable RCC enrolled in the definitive cohort (target n=1, 100). Methods: Personalized ctDNA panels were generated using a WGS-based tumor-informed platform (Myriad Genetics), incorporating up to 1, 000 tumor-specific variants identified through WGS of matched tumor tissue. Serial plasma samples were collected at baseline, 1 month post-surgery, quarterly during the first year, and biannually thereafter for up to two years. Results: As of September 2025, 30 patients with resectable RCC were enrolled; MRD results were available for 54 samples from 16 patients. Median age was 68 years (range: 41-88), with male predominance (87.5%). Clinical staging distribution included Stage I (6.3%), Stage II (6.3%), and Stage III (87.5%). All patients underwent upfront radical nephrectomy. Personalized panel creation succeeded in 100% of patients (16/16), identifying a median of 4, 054 highly confident tumor-specific alterations per patient (range: 902-7712), yielding bespoke panels containing 518-1, 000 alterations. The assay demonstrated 100% baseline ctDNA detection (16/16), with 56.3% (9/16) detected at ultra-sensitive levels (tumor fraction <100 parts per million [ppm]; minimum detection: 12.0 ppm). Post-surgical MRD positivity rates were 13.3% (2/15) at 1 month, 15.4% (2/13) at 3 months, and 10.0% (1/10) at 6 months. Among 16 evaluable patients, one developed radiographic recurrence, with MRD detection preceding imaging by 4.4 months. Extended follow-up and comprehensive longitudinal ctDNA dynamics will be presented. Conclusions: The WGS-based personalized ctDNA assay achieved high technical feasibility in RCC, with over half of patients demonstrating baseline ctDNA detection below 100 ppm, highlighting the critical importance of ultra-sensitive platforms for low-shedding tumors like RCC. Early data suggest potential clinical utility for recurrence surveillance. Updated molecular correlates and clinical outcomes will be presented.

Purpose: We previously reported preliminary activity of regorafenib plus nivolumab (REGONIVO) or lenvatinib plus pembrolizumab (LENPEM) in advanced gastric cancer (AGC). Meanwhile, several studies demonstrated liver metastases are less responsive to immunotherapy. Patients and Methods: Combined efficacy outcomes with a longer follow-up in a phase Ib trial of REGONIVO and a phase II trial of LENPEM were examined in AGC with or without liver metastases (REGONIVO plus LENPEM cohort). We also investigated the efficacy of anti-PD-1 monotherapies (anti-PD-1 monotherapy cohort). A comparison of the immune microenvironment between gastric primary tumors and liver metastases was also conducted by multiplex IHC. Results: In the REGONIVO plus LENPEM cohort, with a median follow-up of 14.0 months, objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were 46%, 7.8 months, and 15.6 months in patients with liver metastases, while 69%, 6.9 months, and 15.5 months in those without. In the anti-PD-1 monotherapy cohort, with a median follow-up of 27.6 months, ORR, mPFS, and mOS were 9%, 1.4 months, and 6.4 months in patients with liver metastases, while 22%, 2.3 months, and 9.0 months in those without. Multiplex IHC revealed liver metastases were associated with an abundance of immune-suppressive cells, such as tumor-associated macrophages and regulatory T cells, with fewer CD8þ T cells compared with gastric primary tumors. Conclusions: Anti-PD-1 antibodies plus regorafenib or lenvatinib for AGC showed promising antitumor activity with a longer follow-up, irrespective of liver metastases status, despite a more immune-suppressive tumor microenvironment in liver metastases.

Background: Hematologic malignancies exhibit marked biological heterogeneity that is often insufficiently characterized by genomic profiling alone. Integrated multi-omics approaches are required to enable more accurate prognostic stratification, elucidate resistance mechanisms, and identify therapeutic vulnerabilities across lymphoma, leukemia, and plasma cell neoplasms. Methods: SCRUM-Japan MONSTAR3 is a nationwide, prospective, integrated multi-omics platform. The hematology cohort aims to enroll 400 patients with newly diagnosed or relapsed/refractory hematologic malignancies. Tumor specimens—including bone marrow aspirates/biopsies or lymph node tissues—are collected at diagnosis and at relapse. The multi-omics workflow encompasses whole-exome sequencing, whole-transcriptome sequencing, spatial transcriptomics, plasma proteomics, metabolomics, microbiome analysis, and tumor-informed measurable residual disease (MRD) monitoring. MRD is assessed using next-generation sequencing-based immunoglobulin heavy (IgH) and T-cell receptor (TCR) rearrangement analysis for lymphoid malignancies and whole-genome sequencing–based variant tracking for myeloid malignancies. Results: Patient enrollment began in December 2024, followed by nationwide multicenter activation in November 2025. Multi-omics analyses have been implemented in a stepwise manner. Early operational indicators, including biospecimen acquisition, data quality control, and initiation of molecular assays, demonstrate the feasibility of coordinated nationwide deployment of this complex platform. Conclusion: The MONSTAR3 hematology cohort represents the first nationwide integrated multi-omics initiative dedicated to hematologic malignancies. Its large scale, standardized biospecimen framework, and capacity to incorporate emerging technologies provide a robust infrastructure for molecular stratification, longitudinal disease monitoring, and hypothesis-driven interventional research, thereby advancing clinically actionable precision hematology.

Patients with both BRAF V600E mutations and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) have poor prognosis. Currently, there are no specifically targeted first-line treatment options indicated for patients with mCRC whose tumors harbor both molecular aberrations. Pembrolizumab is a checkpoint inhibitor approved for the treatment of MSI-H/dMMR mCRC, and the BRAF inhibitor encorafenib, in combination with cetuximab, is approved for previously treated BRAF V600E-mutant mCRC. Combination of pembrolizumab with encorafenib and cetuximab may synergistically enhance antitumor activity in patients with BRAF V600E-mutant, MSI-H/dMMR mCRC. SEAMARK is a randomized phase II study comparing the efficacy of the combination of pembrolizumab with encorafenib and cetuximab versus pembrolizumab alone in patients with previously untreated BRAF V600E-mutant, MSI-H/dMMR mCRC.

In 2023, Greaves et~al.\ constructed several sets of 57 equiangular lines in dimension 18. Using the concept of switching root introduced by Cao et~al.\ in 2021, these sets of equiangular lines are embedded in a lattice of rank 19 spanned by norm 3 vectors together with a switching root. We characterize this lattice as an overlattice of the root lattice $A_9\oplus A_9\oplus A_1$, and show that there are at least $246896$ sets of 57 equiangular lines in dimension $18$ arising in this way, up to isometry. Additionally, we prove that all of these sets of equiangular lines are strongly maximal. Here, a set of equiangular lines is said to be strongly maximal if there is no set of equiangular lines properly containing it even if the dimension of the underlying space is increased. Among these sets, there are ones with only six distinct Seidel eigenvalues.

The technology to grow single crystals of the required shape directly from a melt has been researched extensively and developed in various industries and research fields. In this study, a micro-pulling-down method and a Mo crucible were applied to the shape-controlled crystal growth of Y$_3$Al$_5$O$_{12}$:Ce (YAG:Ce). Three types of Mo crucibles with different die shapes were developed. Stable crystal growth in the same shape as the die was achieved, and scintillation properties that are comparable with those of the previously reported YAG:Ce were obtained.

The treatment strategies and prognoses of patients with metastatic colorectal cancer (CRC) differ according to the sidedness of the primary tumor. TP53 gain-of-function (GOF) and non-GOF variants have been reported to be differentially associated with prognosis by sidedness. We aimed to evaluate the sidedness-dependent prognostic impact of gene alterations in metastatic CRC. Patients enrolled between April 2017 and March 2019 were included in this study. Those excluded were individuals whose tumor tissues were obtained after chemotherapy and those who were enrolled in the study more than six months after starting first-line chemotherapy. Finally, we assessed 531 patients who underwent complete gene sequencing. The study revealed a significant difference in overall survival between individuals with left-sided CRC (n = 355) and right-sided colon cancer (CC) (n = 176) when considering the TP53 non-GOF variant, KRAS wild-type, NOTCH1 wild-type, NOTCH1 covariant, NOTCH3 sole variant, and MYC amplification. Multivariate analysis on each side revealed that the TP53 GOF and KRAS variants were independent poor prognostic factors for left-sided CRC (p = 0.03 and p < 0.01, respectively), and the TP53 non-GOF variant, BRAF V600E, and MYC amplification for right-sided CC (p < 0.05, p < 0.01, and p = 0.02, respectively). The NOTCH3 sole variant was an independent and favorable prognostic factor for left-sided CRC (p < 0.01). The prognostic significance of gene alterations differed between left-sided CRC and right-sided CC.

BACKGROUND: In Japan, standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC) includes preoperative chemotherapy with fluorouracil plus cisplatin followed by esophagectomy. However, its efficacy is unclear in patients with recurrent disease with < 6 months of chemotherapy-free interval (CFI) after preoperative chemotherapy followed by esophagectomy and in those with ≥ 6 months of CFI and poor pathological response to prior preoperative chemotherapy. METHOD: We retrospectively evaluated the efficacy of fluorouracil plus platinum in patients with recurrent ESCC who received preoperative chemotherapy followed by curative esophagectomy. RESULTS: Among 105 patients with recurrent ESCC after preoperative chemotherapy followed by esophagectomy, a total of 55 patients received fluorouracil plus platinum for recurrent disease. Patients with a CFI < 6 months (n = 20) had significantly shorter overall survival (OS) (median, 7.1 vs 14.5 months, P = 0.008) compared with those with a CFI ≥ 6 months (n = 35). Multivariate analysis showed that OS was worse in patients with a CFI < 6 months or a tumor regression grade (TRG) ≤ 1a. Furthermore, in patients with a CFI ≥ 6 months, TRG ≤ 1a was associated with significantly shorter OS (11.1 months vs. not reached, P = 0.001). CONCLUSION: Fluorouracil plus platinum was ineffective for recurrent ESCC in patients with a CFI < 6 months and in those with a CFI ≥ 6 months and a TRG ≤ 1a. Alternate regimens including nivolumab or pembrolizumab might be considered for the treatment for recurrence in these patients.

Neutrinoless double beta decay (0v2b) has been investigated as a physical process that can provide evidence for the Majorana nature of neutrinos. The theoretical predictions of the 0v2b rate are subject to significant uncertainty, primarily due to nuclear matrix elements (NME). To reduce this uncertainty, experimental measurements of the half-lives of two-neutrino double beta decay (2v2b) in various nuclei are essential as a benchmark for NME calculations. The PIKACHU (Pure Inorganic scintillator experiment in KAmioka for CHallenging Underground sciences) project searches for the previously unobserved 2v2b decay of 160Gd, employing Ce-doped Gd3Ga3Al2O12 (GAGG) single crystals. In the Phase 1 experiment, we aim to improve the current lower limit on the 2v2b half-life of 160Gd by a prior study using a Ce-doped Gd2SiO5 (GSO) crystal. Ultimately, in Phase 2, the project seeks to achieve a sensitivity surpassing the theoretical prediction of 7.4 x 10^20 years, enabling the potential discovery of the 160Gd 2v2b decay. In this paper, we describe the development of background models based on GEANT4 simulations. The modeled backgrounds are contributions from uranium and thorium decay chains, 40K present in GAGG, and 40K gamma-rays from outside of GAGG. Additionally, we developed models for both 2v2b and 0v2b decay by implementing the theoretical kinematics of two-electron emission in double beta decay in the GEANT4 simulation. As a result, our background models successfully reproduced the measured background spectrum through fitting. By generating pseudo background spectra expected in Phase 1 and analyzing them with the combined background and 2v2b models, we evaluated the 2v2b sensitivity of Phase 1 to be 2.78 x 10^19 years (90% C.L.). This paper presents the development of these simulation models and the expected sensitivities for both Phase 1 and Phase 2 based on the pseudo data analyses.

The present study proposes a novel and simple rheo-optical technique to investigate the relation between the rheology of complex fluids and their internal structural deformation under uniaxial extensional flow. The macroscale results of viscoelasticity from rheological measurements and microscale results of birefringence from optical measurements are combined to evaluate the microstructural deformation and orientation state inside the fluids under extensional stress. The proposed technique combines a liquid dripping method with a high-speed polarization camera to measure the extensional stress and flow-induced birefringence field simultaneously. In the liquid dripping method, temporal evolution images of the liquid filament diameter for fluids dripping from a nozzle are measured to obtain the extensional stress loading on the liquid filament. These images are captured with a high-speed polarization camera connected to a micro polarization element alley, enabling high-speed imaging of the birefringent field. Worm-like micellar solutions of cetyltrimethylammonium bromide (CTAB) and sodium salicylate (NaSal) with varying concentrations of CTAB and NaSal are employed as the measurement targets. Consequently, we successfully visualized temporally developing images of the birefringence field of uniaxially extending worm-like micellar solutions induced by the orientation of micelles toward the extensional direction. Furthermore, the proposed technique supports investigating the conditions for establishing the stress-optical rule, which is the linear relation between stress and birefringence for complex fluids. The stress-optical coefficient, a proportionality constant indicating the sensitivity of birefringence to stress, is analyzed from these measurements. The stress-optical coefficient under uniaxial extensional flow is confirmed to be comparable to that under shear flow.

Colorectal cancer (CRC) exhibits substantial molecular heterogeneity, yet detailed single-cell transcriptomic data from Japanese patients remain limited. Here, we performed single-cell RNA sequencing (scRNA-seq) on tumor tissues and adjacent normal tissues from four Japanese CRC patients to characterize malignant cell populations. We identified a common cancer-associated cell cluster observed across all four cases, characterized by high expression of the long noncoding RNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1). Further analysis revealed a marked decrease in Ras Association Domain Family Member 6 (RASSF6) expression within this cluster, despite clinical datasets reporting that elevated RASSF6 expression correlates with poor overall survival in Western cohorts. Reanalysis of publicly available bulk RNA-seq data from independent East Asian cohorts confirmed that RASSF6 expression was consistently reduced in tumor tissues compared with adjacent normal colon tissues, while KCNQ1OT1 expression showed no apparent differences across cohorts. Collectively, our single-cell analysis delineates a recurrent cancer-associated transcriptional state observed within this cohort and highlights distinct gene expression features that may be underappreciated by bulk or population-averaged analyses, underscoring the value of single-cell profiling for refining molecular interpretations of CRC.