RESUMO
BACKGROUND AND AIMS: Peritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC. METHODS: We conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues, peritoneal metastases, and adjacent-normal peritoneal tissues. We employed whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM. RESULTS: Our analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared to liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis. CONCLUSION: Our study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes.
RESUMO
[This corrects the article DOI: 10.2196/46036.].
RESUMO
BACKGROUND: A plethora of weight management apps are available, but many individuals, especially those living with overweight and obesity, still struggle to achieve adequate weight loss. An emerging area in weight management is the support for one's self-regulation over momentary eating impulses. OBJECTIVE: This study aims to examine the feasibility and effectiveness of a novel artificial intelligence-assisted weight management app in improving eating behaviors in a Southeast Asian cohort. METHODS: A single-group pretest-posttest study was conducted. Participants completed the 1-week run-in period of a 12-week app-based weight management program called the Eating Trigger-Response Inhibition Program (eTRIP). This self-monitoring system was built upon 3 main components, namely, (1) chatbot-based check-ins on eating lapse triggers, (2) food-based computer vision image recognition (system built based on local food items), and (3) automated time-based nudges and meal stopwatch. At every mealtime, participants were prompted to take a picture of their food items, which were identified by a computer vision image recognition technology, thereby triggering a set of chatbot-initiated questions on eating triggers such as who the users were eating with. Paired 2-sided t tests were used to compare the differences in the psychobehavioral constructs before and after the 7-day program, including overeating habits, snacking habits, consideration of future consequences, self-regulation of eating behaviors, anxiety, depression, and physical activity. Qualitative feedback were analyzed by content analysis according to 4 steps, namely, decontextualization, recontextualization, categorization, and compilation. RESULTS: The mean age, self-reported BMI, and waist circumference of the participants were 31.25 (SD 9.98) years, 28.86 (SD 7.02) kg/m2, and 92.60 (SD 18.24) cm, respectively. There were significant improvements in all the 7 psychobehavioral constructs, except for anxiety. After adjusting for multiple comparisons, statistically significant improvements were found for overeating habits (mean -0.32, SD 1.16; P<.001), snacking habits (mean -0.22, SD 1.12; P<.002), self-regulation of eating behavior (mean 0.08, SD 0.49; P=.007), depression (mean -0.12, SD 0.74; P=.007), and physical activity (mean 1288.60, SD 3055.20 metabolic equivalent task-min/day; P<.001). Forty-one participants reported skipping at least 1 meal (ie, breakfast, lunch, or dinner), summing to 578 (67.1%) of the 862 meals skipped. Of the 230 participants, 80 (34.8%) provided textual feedback that indicated satisfactory user experience with eTRIP. Four themes emerged, namely, (1) becoming more mindful of self-monitoring, (2) personalized reminders with prompts and chatbot, (3) food logging with image recognition, and (4) engaging with a simple, easy, and appealing user interface. The attrition rate was 8.4% (21/251). CONCLUSIONS: eTRIP is a feasible and effective weight management program to be tested in a larger population for its effectiveness and sustainability as a personalized weight management program for people with overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT04833803; https://classic.clinicaltrials.gov/ct2/show/NCT04833803.
Assuntos
Inteligência Artificial , Comportamento Alimentar , Aplicativos Móveis , Humanos , Comportamento Alimentar/psicologia , Adulto , Feminino , Masculino , Obesidade/psicologia , Obesidade/terapia , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Transhiatal esophagectomy (THE) avoids thoracotomy but sacrifices mediastinal lymphadenectomy. Mediastinoscopy-assisted transhiatal esophagectomy (MATHE) allows for visualisation and en-bloc dissection of mediastinal lymph nodes while retaining the benefits of THE. However, given its novel inception, there is a paucity of literature. This study aimed to conduct the first meta-analysis to explore the efficacy of MATHE and clarify its role in the future of esophagectomy. METHODS: Four databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched from inception to May 1, 2023. Studies were included if they reported outcomes for patients with esophageal cancer who underwent MATHE. Meta-analyses of proportions and pooled means were performed for the outcomes of intraoperative blood loss, lymph node (LN) harvest, mean hospital length of stay (LOS), mean operative time, R0 resection, conversion rates, 30-day mortality rate, 5-year OS, and surgical complications (anastomotic leak, cardiovascular [CVS] and pulmonary complications, chyle leak and recurrent laryngeal nerve palsy [RLN]). Sensitivity analyses were performed for outcomes with substantial statistical heterogeneity. RESULTS: The search yielded 223 articles; 28 studies and 1128 patients were included in our analysis. Meta-analyses of proportions yielded proportion rates: 30-day mortality (0 %, 95 %CI 0-0), 5-year OS (60.5 %, 95 %CI 47.6-72.7), R0 resection (100 %, 95 %CI 99.3-100), conversion rate (0.1 %, 95 %CI 0-1.2). Among surgical complications, RLN palsy (14.6 %, 95 %CI 9.5-20.4) were most observed, followed by pulmonary complications (11.3 %, 95 %CI 7-16.2), anastomotic leak (9.7 %, 95 %CI 6.8-12.8), CVS complications (2.3 %, 95 %CI 0.9-4.1) and chyle leak (0.02 %, 95 %CI 0-0.8). Meta-analysis of pooled means yielded means: LN harvest (18.6, 95 %CI 14.3-22.9), intraoperative blood loss (247.1 ml, 95 %CI 173.6-320.6), hospital LOS (18.1 days, 95 %CI 14.4-21.8), and operative time (301.5 min, 95 %CI 238.4-364.6). There was moderate-to-high statistical heterogeneity. Findings were robust to sensitivity analyses. CONCLUSION: MATHE is associated with encouraging post-operative mortality and complication rates, while allowing for radical mediastinal lymphadenectomy with reasonable lymph node harvest.
Assuntos
Neoplasias Esofágicas , Esofagectomia , Mediastinoscopia , Humanos , Esofagectomia/métodos , Esofagectomia/mortalidade , Mediastinoscopia/métodos , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Prognóstico , Excisão de Linfonodo/métodos , Complicações Pós-Operatórias/epidemiologiaRESUMO
CONTEXT: Polyphenols are plant-based compounds with potential anti-inflammatory, antioxidant, and anti-obesogenic properties. However, their effects on health outcomes remain unclear. OBJECTIVE: To evaluate the effects of polyphenols on anthropometric and cardiometabolic markers. DATA SOURCES: Six electronic databases-namely, EMBASE, CINAHL, PubMed, Scopus, The Cochrane Library (reviews only), and Web of Science-were searched for relevant systematic reviews with meta-analyses (SRMAs). DATA EXTRACTION: Three reviewers performed the data extraction via a data-extraction Microsoft Excel spreadsheet. DATA ANALYSIS: An umbrella review and meta-analysis of existing SRMAs was conducted. Eighteen SRMAs published from 2015 to 2023, representing 445 primary studies and 838 unique effect sizes, were identified. Meta-analyses were conducted using random-effects models with general inverse variance. Polyphenol-containing foods were found to significantly improve weight (-0.36 kg; 95% confidence interval [CI]: -0.62, 0.77 kg; P < 0.01, I2 = 64.9%), body mass index (-0.25 kg/m2; 95% CI: -0.34, -0.17 kg/m2; P < 0.001, I2 = 82.4%), waist circumference (-0.74 cm; 95% CI: -1.34, -0.15 cm; P < 0.01, I2 = 99.3%), low-density-lipoprotein cholesterol (-1.75 mg/dL; 95% CI: -2.56, -0.94; P < 0.001, I2 = 98.6%), total cholesterol (-1.23 mg/dL; 95% CI: -2.00, -0.46; P = 0.002, I2 = 94.6%), systolic blood pressure (-1.77 mmHg; 95% CI: -1.77, -0.93 mmHg; P < 0.001, I2 = 72.4%), diastolic blood pressure (-1.45 mmHg; 95% CI: -2.09, -0.80 mmHg; P < 0.001, I2 = 61.0%), fat percentage (-0.70%; 95% CI: -1.03, -0.36%; P < 0.001, I2 = 52.6%), fasting blood glucose (-0.18 mg/dL; 95% CI: -0.35, -0.01 mg/dL; P = 0.04, I2 = 62.0%), and C-reactive protein (CRP; including high-sensitivity-CRP [hs-CRP]) (-0.2972 mg/dL; 95% CI: -0.52, -0.08 mg/dL; P = 0.01, I2 = 87.9%). No significant changes were found for high-density-lipoprotein cholesterol (-0.12 mg/dL; 95% CI: -1.44, 0.69; P = 0.67, I2 = 89.4%) and triglycerides (-1.29 mg/dL; 95% CI: -2.74, 0.16; P = 0.08, I2 = 85.4%). Between-study heterogeneity could be explained by polyphenol subclass differences. CONCLUSION: The findings of this umbrella review support the beneficial effects of polyphenols on anthropometric and metabolic markers, but discretion is warranted to determine the clinical significance of the magnitude of the biomarker improvements. SYSTEMATIC REVIEW REGISTRATION: International Prospective Register of Systematic Reviews no. CRD42023420206.
RESUMO
BACKGROUND: Anastomotic leak (AL) in upper gastrointestinal (UGI) surgery continues to be a diagnostic challenge. We seek to identify clinical parameters that predict AL and examine the effectiveness of investigations in evaluating AL following UGI surgeries. METHODS: 592 patients underwent UGI surgeries with an anastomosis between January 2011 and January 2021. Data on patient characteristics, surgery, postoperative investigations and outcomes were prospectively collected and analysed. RESULTS: The overall occurrence of AL was 6.4 %. Tachycardia >120 BPM (OR 6.959, 95 % CI 1.856-26.100, p = 0.004) and leukocyte count >19 × 109/L (OR 3.327, 95 % CI 1.009-10.967, p = 0.048) were independent predictors of AL. On multivariate analysis, patients whose anastomosis was deemed high risk and had pre-emptive investigation done postoperatively to exclude a leak were less likely to require intervention and were more likely to be managed conservatively (66.7 % vs 14.3 %, p = 0.025). Methylene blue test, oral contrast study and Computed Tomography scan with intravenous and oral contrast had 50.0 %, 20.0 % and 9.1 % false negative results, while esophagogastroduodenoscopy had none. There was no misdiagnosed AL when more than 1 investigation (n = 15, 39.5 %) were performed. CONCLUSION: Our study demonstrates that the presence of a triad including desaturation, tachycardia and leucocytosis predicts for AL following UGI surgery and for confirmation of a leak, evaluation with 2 or more investigation is needed. A practice of evaluating high risk anastomosis prior to commencement of feeding decreased the need for surgical intervention and improves success of conservative treatment.
Assuntos
Fístula Anastomótica , Procedimentos Cirúrgicos do Sistema Digestório , Humanos , Fístula Anastomótica/diagnóstico , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Estudos Retrospectivos , Anastomose Cirúrgica/efeitos adversos , Taquicardia/diagnóstico , Taquicardia/epidemiologia , Taquicardia/etiologiaRESUMO
BACKGROUND: Mucosal gastric atrophy and intestinal metaplasia (IM) increase the risk for the development of gastric cancer (GC) as they represent a field for development of dysplasia and intestinal-type gastric adenocarcinoma. METHODS: We have investigated the expression of two dysplasia markers, CEACAM5 and TROP2, in human antral IM and gastric tumors to assess their potential as molecular markers. RESULTS: In the normal antral mucosa, weak CEACAM5 and TROP2 expression was only observed in the foveolar epithelium, while inflamed antrum exhibited increased expression of both markers. Complete IM exhibited weak CEACAM5 expression at the apical surface, but no basolateral TROP2 expression. On the other hand, incomplete IM demonstrated high levels of both CEACAM5 and TROP2 expression. Notably, incomplete IM with dysplastic morphology (dysplastic incomplete IM) exhibited higher levels of CEACAM5 and TROP2 expression compared to incomplete IM without dysplastic features (simple incomplete IM). In addition, dysplastic incomplete IM showed diminished SOX2 and elevated CDX2 expression compared to simple incomplete IM. CEACAM5 and TROP2 positivity in incomplete IM was similar to that of gastric adenomas and GC. Significant association was found between CEACAM5 and TROP2 positivity and histology of GC. CONCLUSIONS: These findings support the concept that incomplete IM is more likely associated with GC development. Overall, our study provides evidence of the heterogeneity of gastric IM and the distinct expression profiles of CEACAM5 and TROP2 in dysplastic incomplete IM. Our findings support the potential use of CEACAM5 and TROP2 as molecular markers for identifying individuals with a higher risk of GC development in the context of incomplete IM.
Assuntos
Lesões Pré-Cancerosas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Mucosa Gástrica/patologia , Lesões Pré-Cancerosas/patologia , Metaplasia , Antígeno Carcinoembrionário , Proteínas Ligadas por GPI/metabolismoRESUMO
Gastric cancer metastasis is a major cause of mortality worldwide. Inhibition of RUNX3 in gastric cancer cell lines reduced migration, invasion, and anchorage-independent growth in vitro. Following splenic inoculation, CRISPR-mediated RUNX3-knockout HGC-27 cells show suppression of xenograft growth and liver metastasis. We interrogated the potential of RUNX3 as a metastasis driver in gastric cancer by profiling its target genes. Transcriptomic analysis revealed strong involvement of RUNX3 in the regulation of multiple developmental pathways, consistent with the notion that Runt domain transcription factor (RUNX) family genes are master regulators of development. RUNX3 promoted "cell migration" and "extracellular matrix" programs, which are necessary for metastasis. Of note, we found pro-metastatic genes WNT5A, CD44, and VIM among the top differentially expressed genes in RUNX3 knockout versus control cells. Chromatin immunoprecipitation sequencing and HiChIP analyses revealed that RUNX3 bound to the enhancers and promoters of these genes, suggesting that they are under direct transcriptional control by RUNX3. We show that RUNX3 promoted metastasis in part through its upregulation of WNT5A to promote migration, invasion, and anchorage-independent growth in various malignancies. Our study therefore reveals the RUNX3-WNT5A axis as a key targetable mechanism for gastric cancer metastasis. SIGNIFICANCE: Subversion of RUNX3 developmental gene targets to metastasis program indicates the oncogenic nature of inappropriate RUNX3 regulation in gastric cancer.
Assuntos
Neoplasias Gástricas , Humanos , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Genes Controladores do Desenvolvimento , Neoplasias Gástricas/genética , Regulação para Cima/genéticaRESUMO
Objectives: To monitor the results of PIPAC directed therapy based on data from the International Society for the Study of the Pleura and Peritoneum (ISSPP) PIPAC database. Methods: Analysis of data from patients entered between June 15th, 2020, and February 28th, 2023. Results: Twelve centers reported 2,456 PIPAC procedures in 809 patients (median 2, range 1-18) with peritoneal metastasis (PM) from different primary tumors. Approximately 90â¯% had systemic chemotherapy prior to PIPAC. Twenty-eight percent were treated in prospective protocols. Overall non-access rate was 3.5â¯%. Concomitant surgical procedures were performed during PIPAC in 1.6â¯% of the patients. Median length of stay was 2 days. A total of 95 surgical complications were recorded, but only 22â¯% of these were graded ≥3b. Seventeen-hundred-and-three adverse events were noted, and 8â¯% were classified ≥3. The rate of complete or major histological response (peritoneal regression grade score, PRGS≤2) increased between the first and the third PIPAC in the group of patients who were evaluated by PRGS, and a PRGS ≤2 or a reduction of the mean PRGS of at least 1 between first and third PIPAC were observed in 80â¯%. Disease progression (50â¯%) or technical issues (19â¯%) were the most important reasons for stopping PIPAC treatment. Median overall survival from first PIPAC directed treatment varied from 10.7 months (CI 8.7-12.5) in gastric cancer to 27.1 months (16.4-50.5) in mesothelioma. Conclusions: The ISSPP PIPAC database provides substantial real-world data supporting the use of PIPAC directed therapy in patients with PM from different primary tumors.
RESUMO
Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception.
Assuntos
Lesões Pré-Cancerosas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Estudos Prospectivos , Mucosa Gástrica/patologia , Genômica , Metaplasia/genética , Lesões Pré-Cancerosas/genéticaRESUMO
OBJECTIVES: Artificial intelligence (AI) uses deep learning functionalities that may enhance the detection of early gastric cancer during endoscopy. An AI-based endoscopic system for upper endoscopy was recently developed in Japan. We aim to validate this AI-based system in a Singaporean cohort. METHODS: There were 300 de-identified still images prepared from endoscopy video files obtained from subjects that underwent gastroscopy in National University Hospital (NUH). Five specialists and 6 non-specialists (trainees) from NUH were assigned to read and categorize the images into "neoplastic" or "non-neoplastic." Results were then compared with the readings performed by the endoscopic AI system. RESULTS: The mean accuracy, sensitivity, and specificity for the 11 endoscopists were 0.847, 0.525, and 0.872, respectively. These values for the AI-based system were 0.777, 0.591, and 0.791, respectively. While AI in general did not perform better than endoscopists on the whole, in the subgroup of high-grade dysplastic lesions, only 29.1% were picked up by the endoscopist rating, but 80% were classified as neoplastic by AI (P = 0.0011). The average diagnostic time was also faster in AI compared with endoscopists (677.1 s vs 42.02 s (P < 0.001). CONCLUSION: We demonstrated that an AI system developed in another health system was comparable in diagnostic accuracy in the evaluation of static images. AI systems are faster and not fatigable and may have a role in augmenting human diagnosis during endoscopy. With more advances in AI and larger studies to support its efficacy it would likely play a larger role in screening endoscopy in future.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico por imagem , Inteligência Artificial , Gastroscopia , Povo Asiático , FadigaRESUMO
Surgical resection is the mainstay treatment for resectable gastrointestinal stromal tumors (GISTs). However, resection in anatomically challenging locations, such as near the gastroesophageal junction, lesser curve and fundus, remain technically challenging. We herein report the outcomes of the largest series of patients who underwent single-incision transgastric resection of an intraluminal gastric GIST. Our reduced-port resection technique for intraluminal GISTs in these anatomically challenging locations involves a single incision in the left hypochondrium, deepened to access the gastric lumen, with the surgery completed in a transgastric manner. A total of 22 patients received surgery with this technique at the National University Hospital in Singapore from November 2012 to September 2020. The median operative time was 101 (range 50-253) min, with no conversions to open surgery, median lesion size 3.6 (range 1.8-8.2) cm and median postoperative length of stay 5 (range 1-13) days. There was no 30-day mortality and no recurrence during the follow-up period. Our laparoscopic approach for reduced-port transgastric excision of intraluminal GISTs allows for adequate surgical clearance, convenient extraction and secure gastrostomy closure with low morbidity.
Assuntos
Tumores do Estroma Gastrointestinal , Laparoscopia , Neoplasias Gástricas , Ferida Cirúrgica , Humanos , Resultado do Tratamento , Laparoscopia/métodos , Tumores do Estroma Gastrointestinal/cirurgia , Tumores do Estroma Gastrointestinal/patologia , Gastrectomia/métodos , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Estudos RetrospectivosRESUMO
INTRODUCTION: Computer-aided diagnosis (CADx) of polyp histology could support endoscopists in clinical decision-making. However, this has not been validated in a real-world setting. METHODS: We performed a prospective, multicenter study comparing CADx and endoscopist predictions of polyp histology in real-time colonoscopy. Optical diagnosis based on visual inspection of polyps was made by experienced endoscopists. After this, the automated output from the CADx support tool was recorded. All imaged polyps were resected for histological assessment. Primary outcome was difference in diagnostic performance between CADx and endoscopist prediction of polyp histology. Subgroup analysis was performed for polyp size, bowel preparation, difficulty of location of the polyps, and endoscopist experience. RESULTS: A total of 661 eligible polyps were resected in 320 patients aged ≥40 years between March 2021 and July 2022. CADx had an overall accuracy of 71.6% (95% confidence interval [CI] 68.0-75.0), compared with 75.2% (95% CI 71.7-78.4) for endoscopists ( P = 0.023). The sensitivity of CADx for neoplastic polyps was 61.8% (95% CI 56.9-66.5), compared with 70.3% (95% CI 65.7-74.7) for endoscopists ( P < 0.001). The interobserver agreement between CADx and endoscopist predictions of polyp histology was moderate (83.1% agreement, κ 0.661). When there was concordance between CADx and endoscopist predictions, the accuracy increased to 78.1%. DISCUSSION: The overall diagnostic accuracy and sensitivity for neoplastic polyps was higher in experienced endoscopists compared with CADx predictions, with moderate interobserver agreement. Concordance in predictions increased this diagnostic accuracy. Further research is required to improve the performance of CADx and to establish its role in clinical practice.
Assuntos
Pólipos do Colo , Neoplasias Colorretais , Humanos , Pólipos do Colo/diagnóstico , Pólipos do Colo/patologia , Estudos Prospectivos , Valor Preditivo dos Testes , Colonoscopia/métodos , Computadores , Neoplasias Colorretais/patologia , Imagem de Banda Estreita/métodosAssuntos
Neoplasias Colorretais , Hipertermia Induzida , Neoplasias Peritoneais , Humanos , Neoplasias Peritoneais/secundário , Peritônio/cirurgia , Peritônio/patologia , Neoplasias Colorretais/patologia , Procedimentos Cirúrgicos de Citorredução , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia CombinadaRESUMO
OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A-specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss. DESIGN: Genomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A-mutated GCs were analysed to examine tumour microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A-mutated GCs were converged at the genomic, single-cell and epigenomic level, and targeted by pharmacological inhibition. RESULTS: We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven proinflammatory tumour microenvironment. ARID1A-depletion caused loss of H3K27ac activation signals at ARID1A-occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2. Promoter activation in ARID1A-mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A-genomic status. CONCLUSION: Our results suggest a therapeutic strategy for ARID1A-mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes.
Assuntos
Neoplasias Gástricas , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/patologia , Proteínas Nucleares/genética , Epigenômica , Mutação , Microambiente Tumoral/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ciclo Celular/genéticaRESUMO
Gastric cancer is among the most common malignancies worldwide, characterized by geographical, epidemiological and histological heterogeneity. Here, we report an extensive, multiancestral landscape of driver events in gastric cancer, involving 1,335 cases. Seventy-seven significantly mutated genes (SMGs) were identified, including ARHGAP5 and TRIM49C. We also identified subtype-specific drivers, including PIGR and SOX9, which were enriched in the diffuse subtype of the disease. SMGs also varied according to Epstein-Barr virus infection status and ancestry. Non-protein-truncating CDH1 mutations, which are characterized by in-frame splicing alterations, targeted localized extracellular domains and uniquely occurred in sporadic diffuse-type cases. In patients with gastric cancer with East Asian ancestry, our data suggested a link between alcohol consumption or metabolism and the development of RHOA mutations. Moreover, mutations with potential roles in immune evasion were identified. Overall, these data provide comprehensive insights into the molecular landscape of gastric cancer across various subtypes and ancestries.
Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Transcriptoma , Herpesvirus Humano 4/genética , GenômicaRESUMO
BACKGROUND: We evaluated the relevance of PD-1+CD8+ T-cells in gastric cancer (GC) including prognostic significance, association with chemotherapy and immunotherapy sensitivity and correlations with the tumor microenvironment (TME). METHODS: Discovery cohort: GC samples were evaluated for AE1/3, CD8, PD-1, Ki-67 and Granzyme-B expression with fluorescence-based multiplex immunohistochemistry (mIHC). Validation cohorts: we analyzed bulk RNAseq GC datasets from TCGA, the "3G" chemotherapy trial and an immunotherapy phase 2 trial. The cox proportional hazards model was used to identify factors that influenced overall survival (OS). To study the TME, we analyzed single-cell RNAseq performed on GCs. RESULTS: In the discovery cohort of 350 GCs, increased PD-1 expression of CD8 T-cells was prognostic for OS (HR 0.822, p = 0.042). PD-1 expression in CD8 T-cells highly correlated with cytolytic [Granzyme-B+] (r = 0.714, p < 0.001) and proliferative [Ki-67+] (r = 0.798, p < 0.001) activity. Analysis of bulk RNAseq datasets showed tumors with high PD-1 and CD8A expression levels had improved OS when treated with immunotherapy (HR 0.117, p = 0.036) and chemotherapy (HR 0.475, p = 0.017). Analysis of an scRNAseq dataset of 152,423 cells from 40 GCs revealed that T-cell and NK-cell proportions were higher (24% vs 18% and 19% vs 15%, p < 0.0001), while macrophage proportions were lower (7% vs 11%, p < 0.0001) in CD8PD-1high compared to CD8PD-1low tumors. CONCLUSION: This is one of the largest GC cohorts of mIHC combined with analysis of multiple datasets providing orthogonal validation of the clinical relevance of PD-1+CD8+ T-cells being associated with improved OS. CD8PD-1high tumors have distinct features of an immunologically active, T-cell inflamed TME.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias Gástricas , Humanos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Granzimas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/metabolismo , Relevância Clínica , Antígeno Ki-67/metabolismo , Linfócitos do Interstício Tumoral/patologia , Prognóstico , Microambiente Tumoral , Antígeno B7-H1/metabolismoRESUMO
PURPOSE: Colon conduit is an alternative to a gastric conduit for esophagectomy in patients that stomach is not available. Surgical technique is complex and has a high risk of morbidities and mortality. Outcomes of patients are still lacking in the literature, thus aims of this study are to evaluate the safety, feasibility and long-term functional outcomes of patients who underwent esophagectomy for cancer with colon conduit via retrosternal route. METHODS: Twenty-six patients underwent operation between August 2016 and June 2021 for malignancies. Minimally invasive esophagectomy and laparotomy were performed in accordance with the 2017 Japan Esophageal Society's guidelines. Colonic interposition was used for esophageal replacement. Outcomes were technical success, complications assessed using Clavien-Dindo classification, and patient's quality of life (QOL) based on EORTC-QOL-OES18 questionnaire. RESULTS: Mean age was 56.0 ± 9.9 years and 21 patients (80.8%) were men. Mean operating time was 432 ± 66 min. Technical success was 100%. The average number of resected lymph nodes was 26 ± 14. Twelve patients (46.2%) experienced postoperative complications: 7/12 were classified as grade I-II, 3/12 as grade III, 1/12 as grade IV, and 1/12 as grade V (death). Patient's QOL improved during the follow-up period with median (25-75th percentiles) global EORTC-QOL-OES18 score was 29 (17-34); 13 (9-21), and 9 (6-16) at 3, 6, and 12 months, respectively. During the follow-up period, there were 4 late complications, 3 lymphatic recurrences, 5 distant metastases, and 6 deaths. CONCLUSIONS: Colon conduit via retrosternal route after esophagectomy is feasible, safe, and could provide acceptable long-term functional outcomes.