crossing96/oncoscreening huggingface dataset:
Fungal microbiota signatures anticipate neoadjuvant immunochemotherapy outcomes in esophageal cancer.	BACKGROUND: Predicting neoadjuvant immunochemotherapy (NICT) response remains a critical challenge in esophageal squamous cell carcinoma (ESCC) management. While the gut bacteriome's role in immunotherapy has been established, the mycobiome's predictive potential remains largely unexplored. This study investigated whether gut fungal signatures could serve as reliable biomarkers for NICT response prediction in patients with ESCC. METHODS: We performed internal transcribed spacer 2 sequencing on 155 fecal samples from 68 patients with ESCC (pre-NICT and post-NICT) and 19 healthy controls. Patients were stratified by tumor regression grade scores. We analyzed mycobiome-immune marker correlations and developed multilayer perceptron (MLP) models using Boruta feature selection. Performance was validated in 37 independent pretreatment patients. Functional causality was confirmed using Candida_boidinii in syngeneic mouse experiments with anti-programmed cell death protein-1 (PD-1) therapy. RESULTS: Patients with ESCC exhibited significant mycobiome dysbiosis compared with healthy controls, characterized by reduced alpha diversity and enrichment of pathogenic fungi including s_Rhodotorula_minuta, s_Actinomucor_elegans, and s_Candida_zeylanoides. Baseline mycobiome profiles distinguished treatment responders from non-responders before therapy initiation. Responders demonstrated higher fungal diversity, more stable co-occurrence networks, and enrichment of beneficial taxa (s_Candida_boidinii, g_Meyerozyma, s_Meyerozyma_guilliermondii, s_Trichosporon_dermatis) that correlated with Th1-polarized immunity and elevated cytotoxic markers (interferon-γ, interleukin (IL)-12p70, IL-2). Non-responders harbored immunosuppressive fungi (s_Candida_albicans, s_Candida_parapsilosis, s_Candida_glabrata, g_Saccharomyces) associated with Th2 skewing and regulatory cytokines (IL-4, IL-10, IL-13). Functional analysis revealed responders exhibited enhanced catabolic pathways and phospholipase activities, while non-responders showed upregulated nucleotide biosynthesis. The MLP model achieved robust discriminative performance (genus-level: training area under the receiver operating characteristic curve (AUC) 98.0%, test AUC 82.9%; species-level: training AUC 87.1%, test AUC 87.4%). Candida_boidinii administration enhanced anti-PD-1 efficacy in mice, validating predicted metabolomic and immune changes. CONCLUSIONS: Baseline gut mycobiome signatures predict NICT response in ESCC with high accuracy. Experimental validation confirms functional causality, enabling precision medicine approaches for patient stratification and identifying therapeutic targets.	esophagus
MIF-expressing tumor cells mediate immunotherapeutic resistance in esophageal squamous cell carcinoma.	Background: Despite the use of immunotherapy in esophageal squamous cell carcinoma (ESCC), treatment failure occurs occasionally in patients, yet the underlying mechanisms remain poorly understood. Methods: We conducted large-scale single-cell RNA sequencing (scRNA-seq) data analysis, which integrated seven independent datasets from 192 ESCC patients to yield over 440,000 high-quality single cells, to systematically characterize the tumor microenvironment (TME) landscape during ESCC progression and immunotherapy response. Additionally, we performed high-resolution spatial transcriptomics (stRNA-seq) using the 10x Visium HD platform on paired pre- and post-treatment tissues from two patients (one immunotherapy responder and one non-responder), which enhanced the findings from the scRNA-seq data and mapped therapy-induced TME at the spatial level. Multiplex immunohistochemistry was employed based on seven patients to confirm distinct patterns of intercellular crosstalk underlying differential therapeutic outcomes. Results: In scRNA-seq data, we found that B lineage cells were reduced during ESCC progression but were enriched in immunotherapy-resistant patients. Further analysis of malignant ESCC cells suggested that immunotherapy resistance might be associated with a subpopulation of tumor cells exhibiting aberrantly elevated cholesterol biosynthesis. Cell communication analysis of scRNA-seq and stRNA-seq data collectively revealed that immunotherapy resistance was linked to cellular crosstalk between cholesterol-biosynthetic tumor cells and germinal center (GC) B cells within tertiary lymphoid structures. Notably, single-cell, spatial data, and multiplex immunohistochemistry demonstrated that cholesterol biosynthesis-associated ESCC cells express elevated levels of MIF. This disrupts GC reactions by competing with the CXCL12-CXCR4 signaling axis via MIF-CXCR4 interactions, thereby impairing B cell-mediated immunity. Conclusions: MIF(+) tumor cells in GCs may be a biomarker for predicting immunotherapy resistance in ESCC.	esophagus
Epidemiology of Barrett's Esophagus and Esophageal Adenocarcinoma.	Barrett's esophagus (BE) is an acquired condition resulting from chronic gastroesophageal reflux disease (GERD) and is the precursor to esophageal adenocarcinoma (EAC). In North America, the incidence of EAC increased markedly between 1970 to 2005. Despite increased efforts to screen and follow BE patients with the goal of preventing or detecting EAC early, most EAC cases present with advanced disease. Observational studies have identified increasing age, male sex, white race, GERD, abdominal obesity, cigarette smoking, and lack of infection with Helicobacter pylori infection as the main risk factors for BE. This article summarizes the current epidemiology of BE and EAC.	esophagus
P4HA2 interacted with ATAD3A to modulate PINK1/parkin-dependent mitophagy and (125)I brachytherapy sensitization in esophageal carcinoma.	Interventional brachytherapy, such as iodine-125((125)I), has improved the survival of obstructive late-stage esophageal cancer patients. However, most patients experience radioresistance after (125)I brachytherapy. It is key to decipher the underlying mechanism of (125)I radioresistance. In this study, we identified an endoplasmic reticulum-associated protein, P4HA2, which is upregulated and mediates resistance to (125)I treatment. Mechanistically, P4HA2 enhances mitochondrial autophagy (mitophagy) via the PINK1/parkin pathway by binding to ATAD3A. Clinically, high expression of P4HA2 correlates with shorter overall survival and predicts poor prognosis with (125)I brachytherapy. Moreover, the expression of P4HA2 is epigenetically increased by IGF2BP2 in an m(6)A-dependent manner. Notably, targeting P4HA2 with siRNA-based biocompatible nanomedicines significantly sensitizes ESCC to (125)I brachytherapy. Collectively, our results show the molecular mechanism of mitophagy-mediated (125)I radioresistance, which provides a potential therapeutic target and combinatorial strategy. Schematic diagram of the role of P4HA2 in (125)I brachytherapy for tumors.	esophagus
Intraperitoneal CAR T-cell therapy for peritoneal carcinomatosis from gastroesophageal cancer: preclinical investigations to a phase I clinical trial (NCT06623396).	Peritoneal carcinomatosis is a frequent metastatic condition in gastroesophageal cancer and is associated with poor prognosis and limited therapeutic options. Here, we establish clinically relevant mouse models of peritoneal carcinomatosis to evaluate the efficacy of a second-generation mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Our model recapitulates key clinical features, including ascites, bowel obstruction, and an immunosuppressive tumor microenvironment characterized by tumor-cell programmed death-ligand 1 expression and elevated TGF-β levels in ascites. To overcome T-cell exhaustion, we engineered a CAR T-cell construct (M28z1XXPD1DNR) that incorporates a programmed cell death protein-1 decoy receptor lacking the intracellular signaling domain, which enhances functional persistence. We demonstrate that intraperitoneal (regional) administration of CAR T cells at low doses achieves superior antitumor efficacy, longer survival, and sustained functional persistence, compared with intravenous (systemic) administration. Of note, intraperitoneal treatment also exhibits potency against distant disease sites. These findings provide a strong rationale for clinical translation; we are now conducting a clinical trial (NCT06623396) to evaluate intraperitoneal administration of M28z1XXPD1DNR CAR T cells in patients with gastroesophageal cancer peritoneal carcinomatosis.	esophagus
Precision Medicine in Thoracic Surgery: Esophageal Cancer.	Esophageal cancer, ranking 18th in incidence and 14th in mortality in the United States, has a low 5-year survival rate of around 20%. The 2 main histologic subtypes are esophageal adenocarcinoma, prevalent in Western countries and linked to obesity and gastroesophageal reflux disease, and esophageal squamous cell carcinoma, more common worldwide and associated with lifestyle risk factors like tobacco and alcohol. Accurate staging using endoscopic ultrasound, computed tomography, and PET scans guides treatment decisions, with multimodal approaches including surgery, chemoradiotherapy, and systemic therapies. Ongoing research into molecular targets and immunotherapies promises further improvements in management and survival for esophageal cancer patients.	esophagus
CCL5(hi) Macrophages Interact with CD8(+) T Cells and Potentiate Responsiveness to PD-1 Blockade Plus Chemotherapy in Esophageal Squamous Cell Carcinoma.	Immunotherapy has significantly transformed cancer therapy and reinvigorated research in cancer immunology. Several clinical trials have employed neoadjuvant immunochemotherapy (NIC) for advanced esophageal squamous cell carcinoma (ESCC), resulting in significant benefits for many patients. However, response rates remain limited, underscoring the need for more effective screening methods and novel therapeutic strategies. Tumor-associated macrophages (TAMs) have been shown to play a crucial role in tumor progression and impact the clinical outcomes of cancer patients. Nonetheless, it is worth noting that TAMs exhibit phenotypic and functional heterogeneity. In this study, a distinct population of CCL5(hi) macrophages is identified that plays a critical role in ESCC when treated with immunochemotherapy. Furthermore, insights are gained into the underlying mechanisms, revealing the existence of a feedback loop involving IFN-γ, CCL5(hi) macrophages, and CD8(+) T cells within the tumor microenvironment of ESCC undergoing immunochemotherapy. Specific signatures associated with CCL5(hi) macrophages are correlated with a better response to immunochemotherapy in patients with ESCC. Moreover, the in vivo experiments demonstrate that CCL5 supplementation enhances the effectiveness of immunochemotherapy. This research contributes to the optimization of patient stratification and provides a rationale for novel combinatorial approaches involving immunotherapy in the treatment of ESCC.	esophagus
Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial.	Perioperative treatment strategies for HER2-positive esophagogastric adenocarcinoma remain suboptimal. Here in the open-label, phase 2 IKF/AIO PHERFLOT trial, we evaluated the safety and efficacy of adding pembrolizumab and trastuzumab to FLOT chemotherapy in patients with localized HER2-positive esophagogastric adenocarcinoma. The primary endpoints are the pathological complete response rate and the 2-year disease-free survival rate. Secondary endpoints include the R0 resection rate, feasibility and safety. Exploratory endpoints include clinical efficacy in molecularly defined subgroups. In this prespecified interim analysis, given the limited median follow-up period of 14.8 months, only one of the primary endpoints, the pathological complete response rate, and selected secondary endpoints, including the R0 resection rate, feasibility and safety, are reported here. Among 31 enrolled patients, 30 proceeded to R0 resection, and one patient declined surgery without disease progression. The combination regimen resulted in grade ≥3 treatment-related serious adverse events in 48.4% of patients (15 out of 31) aligning with established toxicity profiles of the respective agents and no treatment-related deaths. After four cycles of therapy, the pathological complete response rate was 48.4% (95% confidence interval 30.2-66.9; 15 out of 31) in the intention-to-treat population, and the subtotal regression rate (TRG1b according to Becker classification) was 19.4% (95% confidence interval 7.5-37.5; 6 out of 31), resulting in a major pathological response rate of 67.7% (95% confidence interval 48.6-83.3; 21 out of 31). Responses tended to be enriched in tumors with strong HER2 expression (immunohistochemistry 3+), high PD-L1 combined positive scores and lower T stage, but were also observed in substantial fractions of HER2 immunohistochemistry 2+/ISH+, T3 or T4 and combined positive scores <10 tumors. These findings support the feasibility and antitumor activity of perioperative chemoimmunotherapy targeting HER2 and PD-1 and warrant further validation in randomized trials. ClinicalTrials.gov registration: NCT05504720 .	esophagus
Histopathological Profile of Gastrointestinal Cancer.	BACKGROUND: Gastrointestinal (GI) epithelial cancers are a leading cause of cancer-related deaths worldwide. The objective of this study was to analyse the epidemiology, symptomatology and histopathology of gastrointestinal epithelial malignancies in a GI pathology laboratory based in Kathmandu, Nepal. METHODS: An observational study was conducted to using the data collected from biopsy specimens, pathology reports, clinical information, and endoscopic reports of patients diagnosed from March, 2017 to December, 2018 in Samyak Pathology Lab (SPL), Kathmandu. Nonepithelial tumors were excluded. Data analysis was done using Microsoft Excel 365. RESULTS: Of 203 GI epithelial malignancies, there were 25 (12.3%) esophageal, 81 (39.9%) gastric, 29 (14.3%) duodenal/ampullary, and 68 (33.5%) colorectal carcinomas. Gastric cancer had a mean age of 59.7 years and a male-to-female (M: F) ratio of 2.4. Common symptoms included abdominal pain, nausea/vomiting, and weight loss. The mean age for esophageal cancer was 65.8 years and the M: F ratio was 2.6. Dysphagia was the commonest symptom. Duodenal cancer had a mean age of 57.2 years and an M: F ratio of 1.2. Among these, 17 were periampullary carcinomas, and obstructive jaundice was the most common symptom. For colorectal cancer, the mean age was 54 years, and the M: F ratio was 1.6. Common symptoms included per-rectal bleeding, abdominal pain, and altered bowel habits. CONCLUSIONS: Gastric cancer was the most common type of gastrointestinal (GI) epithelial cancer in this study, followed by colorectal, duodenal/ampullary, and esophageal cancer. There was a male predominance. The rise in colorectal carcinoma points to lifestyle changes as a contributing factor.	esophagus
Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial.	Dual inhibition of T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death protein 1 (PD-1) may enhance antitumor immunity in advanced gastroesophageal cancers. Here we report the EDGE-Gastric study, an ongoing, multicenter, international, phase 2 study with three cohorts, one in the first-line setting (cohort A) and two in the second-line or greater setting (cohorts B and C). Cohort A comprises four arms: two nonrandomized (A1 and A2) and two randomized (A3 and A4). In arm A1, presented here, dual blockade of TIGIT and PD-1 with domvanalimab (Fc-silent anti-TIGIT) and zimberelimab (anti-PD-1) plus oxaliplatin, leucovorin, fluorouracil (FOLFOX) was evaluated in patients with previously untreated advanced HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Among 41 treated patients, the confirmed objective response rate was 59% (90% confidence interval (CI) 44.5-71.6%), median progression-free survival was 12.9 months (90% CI 9.8-14.6 months) and median overall survival was 26.7 months (90% CI 18.4 months to not estimable (NE)). In patients with tumor area positivity ≥1% (PD-L1 positive) and tumor area positivity ≥5% (PD-L1 high), respectively, the objective response rate was 62% (90% CI 45.1-77.1%) and 69% (90% CI 45.2-86.8%), median progression-free survival was 13.2 months (90% CI 11.3-15.2 months) and 14.5 months (90% CI 11.3 months-NE), and median overall survival was 26.7 months (90% CI 19.5 months-NE) and not reached (90% CI 17.4 months-NE). Immune-related adverse events were reported in 27% of patients; the safety profile was consistent with that reported for anti-PD-1 plus platinum-based chemotherapy. Dual TIGIT and PD-1 blockade with domvanalimab and zimberelimab plus chemotherapy demonstrated encouraging efficacy, and the regimen is being evaluated in the phase 3 STAR-221 trial. ClinicalTrials.gov identifier: NCT05329766 .	esophagus
Helicobacter pylori Infection, Metabolomic Signature and Extra-gastric Cancer Risk: A Mediation and Mendelian Randomization Analysis.	Emerging evidence suggests that Helicobacter pylori (H. pylori) infection may contribute to extra-gastric malignancies, but the mechanisms are unclear. Using untargeted metabolomics data from two prospective Chinese cohorts, we constructed an H. pylori associated metabolomic signature in 1800 baseline participants and evaluated cancer risks using conditional logistic regression in 1:1 matched case-control studies for lung cancer (n = 352 pairs), colorectal cancer (CRC; n = 190 pairs), esophageal cancer (n = 146 pairs), and hepatocellular carcinoma (n = 163 pairs), with confounder adjustment and sex stratification. Mediation analysis was performed to evaluate the mediating effects of the metabolomic signature and specific plasma metabolites on the observed associations. Mendelian randomization (MR) analysis was conducted to evaluate causal relationships. H. pylori infection was significantly associated with an increased risk of CRC (OR = 1.80, 95% CI: 1.13-2.85), especially driven by males (OR = 3.01, 95% CI: 1.44-6.31), but not with other cancers. Additionally, the H. pylori infection-related metabolomic signature consisting of 26 metabolites (OR per standard deviation [SD] increment = 1.52, 95% CI: 1.03-2.25) and plasma metabolite methionine sulfone (OR per SD increment = 1.73, 95% CI: 1.16-2.58) were positively associated with CRC risk in males. Mediation analysis indicated partial mediation by the metabolomic signature (12.08%, 95% CI: 0.26-46.88%) and methionine sulfone (16.79%, 95% CI: 0.11-74.76%). MR analysis further supported a potentially causal association between methionine sulfone and CRC (OR = 1.08, 95% CI: 1.02-1.15). Collectively, these results implicate sex-specific metabolomic alterations, particularly involving methionine sulfone, in mediating the relationship between H. pylori infection and CRC risk in males. These insights advance understanding of CRC pathogenesis and may inform targeted prevention strategies.	esophagus
Tecotabart vedotin in Claudin 18.2-positive advanced gastric/gastroesophageal junction cancer: A Bayesian phase 1/2 clinical trial.	BACKGROUND: Tecotabart vedotin (LM-302) is a novel antibody-drug conjugate (ADC) targeting CLDN18.2, a promising therapeutic target in gastrointestinal cancers. This phase 1/2 study evaluated the safety, pharmacokinetics, immunogenicity, and preliminary anti-tumor activity of tecotabart vedotin in patients with advanced solid tumors, with a focus on CLDN18.2-positive gastric/gastroesophageal junction (G/GEJ) cancer. METHODS: This open-label, multicenter study utilized a Bayesian adaptive design. Phase 1 enrolled patients with advanced solid tumors; phase 2 focused on CLDN18.2-positive G/GEJ, pancreatic, biliary tract cancer, or gastrointestinal tumors with low to moderate CLDN18.2 expression. Tecotabart vedotin was administered at 0.2-2.8 mg/kg every 3 weeks (Q3W) or 1.8-2.0 mg/kg every 2 weeks (Q2W). Primary endpoints included dose-limiting toxicities (DLTs) and safety in phase 1, and objective response rate (ORR) in phase 2. Secondary endpoints included safety, pharmacokinetics, immunogenicity, and other anti-tumor activity outcomes. RESULTS: Overall, 153 patients received tecotabart vedotin (phase 1: 38; phase 2: 115). DLTs occurred in 5 patients at higher dose levels. The maximum tolerated dose was 2.4 mg/kg Q3W; recommended phase 2 doses were 1.8 mg/kg Q2W and 2.4 mg/kg Q3W. Among 52 evaluable patients with CLDN18.2-positive G/GEJ cancer receiving 1.8 mg/kg Q2W, ORR was 32.7 % (95 % confidence interval [CI] 20.3-47.1), with median progression-free survival of 4.9 months (95 % CI 2.7-6.9), and overall survival of 10.9 months (95 % CI 9.1-17.1). Adverse events were manageable and consistent with monomethyl auristatin E-based ADCs. CONCLUSIONS: Tecotabart vedotin demonstrated encouraging anti-tumor activity and manageable safety in CLDN18.2-positive G/GEJ cancer, supporting further clinical development in gastrointestinal malignancies.	esophagus
Comprehensive multi-omics analysis identifies transferrin receptor as a therapeutic target in esophageal cancer.	This study aimed to identify novel biomarkers for esophageal cancer (ESCA) through multi-omics approaches and to explore their roles in disease progression. We analyzed the cellular heterogeneity of ESCA samples using single-cell RNA sequencing data, and transcriptomic analysis revealed differentially expressed genes between ESCA and normal tissues. By integrating gene expression quantitative trait loci analysis with genome-wide association studies, we identified the key gene transferrin receptor (TFRC) as being associated with ESCA. Both pan-cancer and ESCA-specific analyses indicated that increased TFRC expression is linked to poor prognosis and drug metabolism. Additionally, high TFRC expression was associated with reduced immune cell infiltration and downregulation of immune checkpoint genes. Multiplexed immunofluorescence assays further revealed that elevated TFRC expression is associated with immune evasion, negatively correlating with CD8(+) T cell infiltration and positively correlating with M2 macrophage infiltration. Furthermore, our findings support a model in which TFRC modulates iron availability to influence the survival and activity of tumor cells, rather than primarily driving lipid peroxidation or ferroptosis. TFRC knockdown enhanced M1 macrophage polarization and CD8(+) T cell infiltration. The differential expression of TFRC in the tumor epithelium and stroma highlights its significant role in immune evasion. In conclusion, TFRC plays a critical role in the development of ESCA and its immune escape mechanisms, suggesting that it may serve as a potential target for cancer immunotherapy.	esophagus