Activation of TGFB during and after RT suppresses lymphocytes.

BACKGROUND:Squamous cell carcinoma antigen (SCC-Ag) and carcinoembryonic antigen (CEA) are routinely monitored after definitive chemoradiotherapy (dCRT) for esophageal squamous cell carcinoma (ESCC) in Japan, but their clinical significance remains unclear. METHODS:We analyzed data from patients with resectable ESCC treated with dCRT in the JCOG0502 and JCOG0909 trials, who underwent intensive protocolized surveillance with computed tomography (CT), esophagogastroduodenoscopy (EGD), SCC-Ag, and CEA. Tumor marker positivity was defined as exceeding the cut-off value at least once, at two consecutive measurements, or at three consecutive measurements during follow-up. Sensitivity and specificity were calculated for SCC-Ag and CEA at 0.1-ng/mL increments to determine whether any cut-off met the predefined performance criteria (sensitivity ≥60% and specificity ≥70%). RESULTS:This study included 239 patients (stage I/II/III = 147/58/34 [UICC 6th edition]), among whom 38% (91/239) experienced disease progression or recurrence. The median baseline SCC-Ag and CEA levels were 1.0 ng/mL (interquartile range [IQR], 0.8-1.5) and 2.3 ng/mL (IQR, 1.6-3.6), respectively, with a median of 16 measurements each (IQR, 8-19 for SCC-Ag; 8-20 for CEA). The highest specificities with sensitivity ≥60% were 19.6% for SCC-Ag (cut-off, 1.5 ng/mL) and 20.3% for CEA (cut-off, 2.2 ng/mL), but neither met the predefined criteria. CONCLUSIONS:In this pooled cohort of patients with resectable ESCC who underwent dCRT and intensive protocolized CT and EGD surveillance, routine SCC-Ag and CEA monitoring showed limited incremental diagnostic value. The relevance of these findings to higher-risk cohorts and less intensive surveillance settings warrants further study.

Salivary gland cancer is a rare heterogeneous group of neoplasms with complex histopathologic patterns, including carcinoma with squamous differentiation, for which surgery is the standard treatment. However, further research is essential for developing new therapies. Head and neck squamous cell carcinoma is positive for p63 and negative for the bicellular tight junction protein cingulin (CGN). p63 plays a key role in cancer progression such as cell proliferation, migration, apoptosis, and squamous differentiation. To understand the roles of p63 in salivary duct adenocarcinoma, we investigated the malignancy by using overexpression of deltaNp63 in p63-negative salivary duct adenocarcinoma cells PGC2E derived from parotid gland duct adenocarcinoma. By transfection with deltaNp63, the PGC2E cells exhibited increased nuclear p63 expression and reduced CGN levels at the membrane. Overexpression of deltaNp63 disrupted epithelial polarity and epithelial permeability barriers, promoted cell proliferation and migration, and enhanced cellular metabolism. Treatment with inhibitors of histone deacetylase and nuclear factor kappa B, and antibodies to tumor necrosis factor-α and tricellular tight junction protein lipolysis-stimulated lipoprotein receptor induced apoptosis in PGC2E cells. However, overexpression of deltaNp63 prevented the induced apoptosis. These findings suggest that p63 contributes to cancer malignancy and the complex phenotype, and it may be possible to develop a novel treatment via p63.

Abstract Topic Esophageal Cancer: Adjuvant and Neo-Adjuvant Therapies Background In esophageal squamous cell carcinoma (ESCC), the importance of endoscopic assessment of tumor response after neoadjuvant chemotherapy has been reported. The Japanese Classification of Esophageal Cancer has introduced a new endoscopic sub-classification, “Remarkable response (RR),” but its clinical significance has not been fully clarified. Methods We retrospectively analyzed patients with resectable locally advanced ESCC (cT2–3/N0–3/M0–1, UICC-TNM 8th edition) who received ≥1 cycle of neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) therapy followed by surgery between 2015 and 2020 at our institution. Patients enrolled in JCOG1109, those without evaluable endoscopic images, those with >56 days from DCF completion to surgery, or those without R0 resection were excluded. Two endoscopists retrospectively evaluated pre- and post-treatment endoscopic images and classified cases into three groups: 1) non-CR/non-PD (RR), 2) non-CR/non-PD (non-RR) and 3) PD. Recurrence-free survival (RFS), overall survival (OS), and the proportion of histological responders (grade 2–3: moderately or markedly effective) were assessed. Results A total of 114 patients were included (median age 66.5 years, 91 mens). Endoscopic evaluation classified 63 patients as RR and 51 patients as non-RR, with no patients classified as PD. During a median follow-up of 42.6 months, 3-year RFS rates were 62.2% in the RR group and 49.0% in the non-RR group (P=0.098). Three-year OS rates were significantly higher in the RR group than in the non-RR group (76.9% vs. 53.0%, P=0.026). Histological responders (grade 2–3) was observed in 71.4% (45/63) of RR cases compared with 9.8% (5/51) of non-RR cases. Conclusion Endoscopic sub-classification “RR (Remarkable response)” may be useful for prognostic stratification and predicting histological response after neoadjuvant DCF therapy. We are planning multicenter studies with larger cohorts that include other treatment regimens, as well as chemoradiotherapy to further evaluate the clinical significance of RR.

Surgery and chemoradiotherapy (CRT) are standard options for clinical stage I esophageal squamous cell carcinoma (ESCC). JCOG0502, a multicenter, non-randomized, parallel-group comparison, demonstrated the non-inferiority of definitive CRT compared with surgery for overall survival (OS) in patients with cT1bN0M0 ESCC; however, institutional differences may influence outcomes. This study explored inter-institutional heterogeneity in survival and adverse events (AEs) among patients in JCOG0502. Among 379 enrolled patients, 364 were analyzed. Institutions enrolling ≥ 13 patients, corresponding to the median institutional trial enrollment, were classified as high-enrollment institutions (High), whereas those enrolling < 13 patients were classified as low-enrollment institutions (Low). Institutional trial enrollment was evaluated as an exploratory indicator, rather than as a direct measure of institutional case or procedural volume. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS) and AEs. In the surgery group, institutional trial enrollment volume was not significantly associated with OS (HR for High vs. Low, 0.73; 95

Respiratory syncytial virus (RSV) is a major cause of severe respiratory illness across the lifespan, particularly in infants and older adults. Nonetheless, effective antiviral therapies remain limited. Here, we performed a clinically guided, medium-throughput screening of approved drugs used in pediatric populations and identified sparfloxacin (SPFX), a fluoroquinolone antibiotic, as a mechanistically informative antiviral scaffold. SPFX showed antiviral activity against genetically distinct RSV clinical isolates in vitro, and suppressed RSV infection in a mechanistic mouse model in vivo. Mechanistically, our findings support a host–virus dual-target framework in which SPFX suppresses RSV replication through activity consistent with modulation of viral RNA polymerase function together with a pro-viral HSP70-associated host pathway. Using primary human pediatric airway epithelial cells, we identified SPFX-responsive host factors and observed suppression of HSP70 expression independent of infection. Together, these findings establish SPFX as a mechanistically informative antiviral scaffold and support a host–virus dual-target framework for future RSV therapeutic development. Sparfloxacin inhibits respiratory syncytial virus through dual targeting of the viral RNA polymerase and the host HSP70 pathway, providing a promising antiviral scaffold for future RSV therapeutic development.

KEGG pathway visualization of virus- and HLA-associated immune reactions.

Background Pertuzumab plus trastuzumab is an established treatment for HER2-positive metastatic colorectal cancer (mCRC). While efficacy and safety of the intravenous (IV) formulation have been established, data on the subcutaneous (SC) formulation remain limited. This study compared the safety and efficacy of IV and SC pertuzumab and trastuzumab. Methods We retrospectively compared the efficacy, safety, and treatment process time of IV and SC pertuzumab and trastuzumab in patients with HER2-positive mCRC. Results Thirty-six patients were included (17 received the IV formulation and 19 received the SC formulation). No patients switched formulations during the treatment period. The ORR was 26.3% in the SC group and 23.5% in the IV group, while the DCR was 73.7% and 70.6%, respectively. Regarding safety, the incidence of IRRs was numerically lower in the SC group than in the IV group (15.8% [3/19] and 47.1% [8/17], respectively; p = 0.070). Rash and pruritus occurred at similar frequencies between the IV and SC groups (11.8% [2/17] vs. 10.5% [2/19] and 5.9% [1/17] vs. 10.5% [2/19], respectively). Injection site reactions occurred only in the SC group (10.5% [2/19] vs. 0% [0/17]). The median treatment process time was 97.5 minutes in the SC group and 208.0 minutes in the IV group ( p < 0.001). Conclusions The SC formulation showed efficacy comparable to that of the IV formulation with a lower incidence of IRRs and a substantially shorter treatment process time. These findings suggest that the SC formulation is a feasible and convenient alternative to IV administration in clinical practice.

Comprehensive overview of the scRNA-seq dataset and analysis from pretreatment to post-RT in esophageal cancer patients.

Abstract Neoadjuvant chemoradiotherapy (CRT) is standard for locally advanced rectal cancer (LARC), yet many patients retain residual disease. To resolve CRT-associated remodeling of the tumor microenvironment, we generated a multimodal spatial atlas from serial sections of paired pretreatment and post-treatment specimens from 24 patients using Xenium single-cell spatial transcriptomics and PhenoCycler multiplex proteomics, profiling 2.8 million cells; matched Visium HD datasets were generated on adjacent serial sections. Resistance was most strongly associated with fibroblast and myeloid programs adjacent to residual tumor. We identify a periostin ( POSTN )-expressing CAF subset selectively enriched around residual tumor cells in non-responders, displaying a myofibroblastic phenotype and activating extracellular matrix remodeling, noncanonical WNT signaling, and immunosuppressive pathways. Tumor cells neighboring POSTN + CAFs show consistent epithelial–mesenchymal transition signatures. Together, this atlas enables interrogation of CRT-induced spatial remodeling and nominates POSTN + CAFs as key mediators and targets of CRT resistance, with direct relevance to CRT-based combination strategies.

Identification of radiation-induced immune suppression signals through spatial transcriptomics.

426 Background: The prognosis for advanced gastroesophageal adenocarcinoma (GEA) remains poor, highlighting the urgent need for novel therapeutic options. MET-targeted agents including antibody-drug conjugates are under clinical investigation in GEA. However, the prevalence and prognostic impact of c-Met expression across different treatment regimens remain unclear. Understanding c-Met expression and its correlation with treatment regimens and other biomarkers is crucial for refining patient selection and guiding therapeutic strategy. Methods: We retrospectively analyzed 400 patients (pts) with advanced GEA receiving first-line therapy at our institution. Immunohistochemistry was performed for c-Met, HER2, PD-L1, CLDN18, and FGFR2. Pts were classified as c-Met high vs. low using a threshold of ≥50% with ≥2+ staining. We assessed correlations between c-Met high and other biomarkers, as well as survival outcomes by treatment regimen: chemotherapy alone (CTx, n = 173), combination with immune checkpoint inhibitors (ICI, n = 130), and combination with molecular targeted agents (MTA, n = 97). Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier method, log-rank test and Cox proportional hazards models. Exploratory genomic characterization by next-generation sequencing was performed in 177 pts; transcriptomic analysis in 88 pts. Results: High c-Met expression was detected in 11.3% of pts by membrane staining th Ultraview detection kit, showing significant association with PD-L1 positivity (CPS≥5) (P < 0.05) but not other protein biomarkers. c-Met high pts exhibited a trend of shorter PFS in the overall cohort (HR = 1.34; 95% CI: 0.96-1.88; P = 0.086), most pronounced in MTA group (HR = 1.73; 95% CI: 0.95-3.14; P = 0.069). Multivariate analysis confirmed c-Met high as an independent worse prognostic factor for PFS (HR = 1.52; 95% CI: 1.05-2.20; P = 0.025). OS did not differ significantly in the overall cohort (HR = 1.11; 95% CI: 0.77-1.62; P = 0.575) but was notably worse in CTx group for c-Met high pts (HR = 1.89; 95% CI: 1.02-3.52; P = 0.040). Multivariate analysis in CTx cohort supported c-Met as an independent predictor of poor OS (HR = 3.30; 95% CI: 1.48-7.3; P = 0.003). Genomic analysis identified MET amplification in 2.3% (4/177). Transcriptomic analysis revealed significant correlations between c-Met high and elevated MET RNA expression (c-Met high vs. low, median TPM: 800 vs. 113, P = 0.003). Conclusions: c-Met high expression was significantly associated with worse PFS in general, and poor OS in pts treated with chemotherapy alone. Further investigation is warranted to elucidate mechanisms underlying poor outcomes in c-Met high GEA pts as well as expression correlation with recently approved c-Met CDx assay, which may help inform ongoing MET-targeted treatment strategies.

After a median study follow-up of 36.6 months, first-line pembrolizumab plus chemotherapy numerically improved overall survival (OS) and progression-free survival (PFS) versus placebo plus chemotherapy in Japanese participants with advanced esophageal cancer in the phase 3 KEYNOTE-590 study. The 5-year follow-up is presented. Participants with previously untreated advanced esophageal cancer were randomly assigned 1:1 to pembrolizumab 200 mg or placebo every 3 weeks up to 35 cycles plus chemotherapy (cisplatin 80 mg/m2 and 5-fluorouracil 800 mg/m2/day). Primary end points were OS and PFS per RECIST v1.1 by investigator; objective response rate (ORR) and safety were secondary. The data cutoff date was July 10, 2023. In total, 141 of 794... participants were enrolled in Japan. Median study follow-up was 60.6 months (range, 53.8–69.7). Median OS was 17.7 months (95

In the global phase 3 RATIONALE-306 study (NCT03783442), first-line tislelizumab plus chemotherapy showed significant overall survival (OS) benefit versus chemotherapy alone for unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC). We report post hoc results for the Japanese subgroup. Eligible Japanese patients were randomized (1:1) to tislelizumab 200 mg or placebo every 3 weeks plus chemotherapy (cisplatin plus fluoropyrimidine) and included in the Japanese analysis set. Endpoints included OS, progression-free survival (PFS), objective response rate (ORR), OS in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥ 10

RATIONALE-306 previously demonstrated improved overall survival (OS) in participants treated with tislelizumab plus chemotherapy versus those receiving placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma, with a minimum follow-up of approximately 15 months. Exploratory long-term efficacy, safety, and quality of life (QoL) analyses after 36.0 months’ minimum follow-up are reported here. Patients (649) were randomized 1:1 to tislelizumab 200 mg or placebo with investigator-chosen chemotherapy. Tislelizumab plus chemotherapy improves OS versus placebo plus chemotherapy in all patients (17.2 versus 10.6 months; hazard ratio, 0.70; 95% confidence interval, 0.59-0.80). At 3 years, 15.0% of patients treated with tislelizumab plus chemotherapy had not progressed versus 2.9% of those receiving placebo plus chemotherapy. No new safety signals have been identified. Median time to deterioration of physical functioning—a key QoL domain—has not been reached with tislelizumab plus chemotherapy versus 18.8 months with placebo plus chemotherapy. With longer follow-up, tislelizumab plus chemotherapy demonstrates long-lasting efficacy, tolerable safety, and favorable patient-reported outcomes, making it a suitable option for this patient population. ClinicalTrials.gov: NCT03783442. The RATIONALE-306 trial demonstrated improved overall survival in participants with advanced/metastatic esophageal squamous cell carcinoma treated with tislelizumab plus chemotherapy comparing with those who received placebo plus chemotherapy. Here they report its exploratory long-term efficacy/safety/quality of life analysis after 36.0 months follow-up.

Induction of CD8+ T cells induces IFNG pathway activation during RT.

Marker gene expression by lymphocytes.

BACKGROUND:To evaluate the dissemination and real-world implementation of recommendations from the 5th Edition of the Japanese Esophageal Cancer Practice Guidelines and to inform development of the upcoming 6th Edition, the Guideline Committee of the Japanese Esophageal Society conducted a nationwide Quality Indicator (QI) survey in Japan. METHODS:A nationwide, cross-sectional, web-based questionnaire survey was distributed to 381 certified institutions participating in the 2023 National Registry of Esophageal Cancer in Japan. Conducted in November 2024, the survey covered six domains-epidemiology, surgery, endoscopy, chemotherapy, radiation therapy, and pathology-reflecting key recommendations of the 5th Edition. Responses were summarized descriptively at the institutional level. RESULTS:Valid responses were obtained from 190 institutions (49.9%). Smoking cessation guidance was implemented in more than 90% of institutions, and over 90% also provided guidance on alcohol abstinence or moderation, although complete alcohol abstinence was less uniformly recommended. Minimally invasive, including robot-assisted, esophagectomy was adopted by over 90% of institutions. The proportion of institutions performing prophylactic cervical lymph node dissection varied by tumor location and stage, reflecting contemporary staging concepts. The DCF regimen was the predominant neoadjuvant therapy for stage II/III disease (94.7%), and immune checkpoint inhibitor-based chemotherapy was widely used for unresectable or recurrent disease. Advanced endoscopic diagnostic modalities, including magnifying and image-enhanced endoscopy, were widely adopted. CONCLUSIONS:This nationwide QI survey demonstrates broad adherence to guideline-based multidisciplinary management of esophageal cancer in Japan and provides an evidence base for refining recommendations in the 6th Edition of the Japanese Esophageal Cancer Practice Guidelines.