RESUMEN
N6-Methyladenosine (m6A) modification and its regulators play critical roles in human cancers, but their functions and regulatory mechanisms in adenocarcinoma of the esophagogastric junction (AEG) remain unclear. Here, we identified that IGF2BP3 is the most significantly up-regulated m6A regulator in AEG tumors versus paired normal adjacent tissues from the expression profile of m6A regulators in a large cohort of AEG patients. Silencing IGF2BP3 inhibits AEG progression in vitro and in vivo. By profiling transcriptome-wide targets of IGF2BP3 and the m6A methylome in AEG, we found that IGF2BP3-mediated stabilization and enhanced expression of m6A-modified targets, including targets of the cell cycle pathway, such as CDC25A, CDK4, and E2F1, are critical for AEG progression. Mechanistically, the increased m6A modification of CDC25A accelerates the G1-S transition. Clinically, up-regulated IGF2BP3, METTL3, and CDC25A show a strong positive correlation in TCGA pan-cancer, including AEG. In conclusion, our study highlights the role of post-transcriptional regulation in modulating AEG tumor progression and elucidates the functional importance of the m6A/IGF2BP3/CDC25A axis in AEG cells.
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Adenocarcinoma , Adenosina , Ciclo Celular , Neoplasias Esofágicas , Proteínas de Unión al ARN , Fosfatasas cdc25 , Humanos , Fosfatasas cdc25/metabolismo , Fosfatasas cdc25/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenosina/análogos & derivados , Adenosina/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Animales , Unión Esofagogástrica/metabolismo , Unión Esofagogástrica/patología , Línea Celular Tumoral , Ratones , Regulación Neoplásica de la Expresión Génica , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Ratones Desnudos , Metiltransferasas/metabolismo , Metiltransferasas/genéticaRESUMEN
BACKGROUND: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC). METHODS: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II). RESULTS: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC. CONCLUSIONS: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.
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Anticuerpos Monoclonales Humanizados , Carcinoma Hepatocelular , Unión Esofagogástrica , Neoplasias Hepáticas , Neoplasias Gástricas , Humanos , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacología , Anciano , Persona de Mediana Edad , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Unión Esofagogástrica/patología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Anciano de 80 o más AñosRESUMEN
Letter to the Editor Regarding 'Impact of the number of therapy lines on survival in advanced gastric and esophagogastric adenocarcinoma - a real-world retrospective analysis from Croatia', published in Neoplasma 2024; 71: 201-208. https://doi.org/10.4149/neo_2024_231209N633.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Adenocarcinoma/patología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Estudios Retrospectivos , Unión Esofagogástrica/patologíaRESUMEN
Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Capecitabina , ADN Tumoral Circulante , Neoplasias Esofágicas , Oxaliplatino , Receptor ErbB-2 , Neoplasias Gástricas , Trastuzumab , Humanos , Trastuzumab/uso terapéutico , Trastuzumab/administración & dosificación , Capecitabina/administración & dosificación , Capecitabina/uso terapéutico , Femenino , Persona de Mediana Edad , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Anciano , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Masculino , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Adulto , Unión Esofagogástrica/patología , Resultado del Tratamiento , Supervivencia sin ProgresiónRESUMEN
Background: Immune checkpoint inhibitor (ICI) plus chemotherapy is effective in advanced gastric or gastroesophageal junction (G/GEJ) cancer. This study aims to evaluate the clinical effect of first-line immunotherapy in combination with chemotherapy for advanced G/GEJ cancer. Methods: PubMed, Web of Science, Embase and Cochrane databases were systematically searched from the inception of the databases to December 2021. Randomized trials comparing ICI plus chemotherapy with chemotherapy in first-line treatment for advanced G/GEJ cancer were included. The outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Analyses were performed in Stata 14.0 software. The study protocol was registered with PROSPERO, number CRD42022300907. Results: Five trials were included for analysis, involving 2, 814 patients. ICI plus chemotherapy can significantly improve OS (hazards ratio [HR], 0.86; 95% CI 0.78-0.94; P = .002), PFS (HR, 0.79; 95% CI 0.63-0.99; P ï¼ .001) and ORR (relative ratio [RR], 1.20; 95% CI 1.11-1.30; P < .001). In safety analyses, there were no significant differences in incidence of all AEs, treatment-related adverse event (TRAE), TRAE of grade 3 or higher, serious TRAE and TRAE leading to death between two arms (P > .05). Conclusions: ICI plus chemotherapy is more effective first-line treatment for advanced G/GEJ cancer in contrast to chemotherapy regrading to improving OS, PFS and ORR, without increasing TRAE risk. This study will redefine the role of ICI in combination with chemotherapy in the first-line setting for G/GEJ cancer, and provide reference for clinical treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas , Unión Esofagogástrica , Inhibidores de Puntos de Control Inmunológico , Neoplasias Gástricas , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Unión Esofagogástrica/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/mortalidad , Resultado del Tratamiento , Estadificación de NeoplasiasRESUMEN
BACKGROUND: First-line zolbetuximab plus chemotherapy (SPOTLIGHT, mFOLFOX6; GLOW, CAPOX) significantly improved progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy in patients with human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors were claudin 18 isoform 2-positive in the phase III SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies. We present patient-reported outcomes (PROs) from these studies. MATERIALS AND METHODS: Health-related quality of life (HRQoL) was measured in the full analysis sets using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Core Questionnaire (QLQ-C30) and Oesophago-Gastric Module (QLQ-OG25), Global Pain, and 5-level EQ-5D (EQ-5D-5L) questionnaires. Analyses focused on key PRO domains: global health status (GHS)/QoL, physical functioning, abdominal pain and discomfort, and nausea/vomiting. Least squares mean (LSM) changes from baseline and time to first definitive deterioration (TTDD) were evaluated combined across SPOTLIGHT and GLOW and for individual studies. Time to confirmed deterioration (TTCD) was evaluated independently for SPOTLIGHT and GLOW. RESULTS: The combined analysis set included 1072 patients (zolbetuximab plus chemotherapy, 537; placebo plus chemotherapy, 535). Compliance rates were similar between treatment arms. Similar trends were observed in the zolbetuximab versus placebo arms for LSM changes from baseline in key PRO domains, with no clinically meaningful deterioration. Nausea/vomiting worsened during the first few zolbetuximab cycles but later returned to baseline levels. Overall TTCD and TTDD results were similar between arms in both studies. CONCLUSIONS: Patients in SPOTLIGHT and GLOW maintained measured HRQoL relative to baseline when treated with first-line zolbetuximab added to chemotherapy. Zolbetuximab plus chemotherapy improved PFS and OS without negatively affecting HRQoL in key PRO domains compared with placebo plus chemotherapy.
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Unión Esofagogástrica , Calidad de Vida , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamiento farmacológico , Unión Esofagogástrica/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Masculino , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Neoplasias Esofágicas/tratamiento farmacológico , Anciano , Medición de Resultados Informados por el Paciente , Fluorouracilo/uso terapéutico , Adulto , Leucovorina/uso terapéutico , Encuestas y Cuestionarios , Compuestos Organoplatinos/uso terapéutico , ClaudinasRESUMEN
The z-line refers to the squamocolumnar junction which marks the transition between the normal stratified squamous epithelium of the distal esophagus and the columnar epithelium of the gastric cardia. An "irregular" z-line refers to an irregular appearing squamocolumnar junction characterized by the presence of columnar mucosa less than 1 cm in length that extends above the gastroesophageal junction. In contrast, Barrett's esophagus is diagnosed when columnar mucosa of at least 1 cm is seen in the distal esophagus extending above the gastroesophageal junction with biopsies demonstrating specialized intestinal metaplasia. Current guidelines recommend against taking routine biopsies from a normal or irregular z-line in the absence of visible abnormalities and advise against endoscopic surveillance in this patient population, in large part due to multiple studies demonstrating lack of progression to advanced neoplasia such as high-grade dysplasia or esophageal adenocarcinoma in patients with an irregular z-line. Despite these recommendations, a sizable number of patients without Barrett's esophagus undergo biopsies from the z-line and are subsequently recommended to have surveillance endoscopies. Furthermore, patients with an irregular z-line are often mislabelled as Barrett's esophagus resulting in significant downstream consequences including higher healthcare costs and reduced health-related quality of life. In this review, we highlight the importance of landmark identification of the distal esophagus and gastroesophageal junction at the time of endoscopy, share recommendations from current guidelines related to the z-line, examine rates of neoplastic progression in those with an irregular z-line, discuss consequences of routinely biopsying an irregular z-line, and highlight strategies on how to approach an irregular z-line if seen on endoscopy. A careful, high-quality endoscopic examination can help to identify visible abnormalities at the z-line, which, if present, should be targeted for biopsies to rule out dysplasia and neoplasia.
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Esófago de Barrett , Neoplasias Esofágicas , Humanos , Esófago de Barrett/patología , Esófago de Barrett/diagnóstico , Biopsia/métodos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/diagnóstico , Unión Esofagogástrica/patología , Esófago/patología , Adenocarcinoma/patología , Adenocarcinoma/diagnóstico , Cardias/patología , Esofagoscopía/métodosRESUMEN
Peroral endoscopic myotomy (POEM) is the preferred endoscopic modality for managing achalasia cardia. However, there are no recommendations on the role of POEM in nonachalasia esophageal dysmotility disorders (NAEMD), including esophagogastric junction outflow obstruction (EGJOO), distal esophageal spasm (DES), and hypercontractile esophagus (HE). The present systematic review and meta-analysis aimed to assess the safety and efficacy of POEM in the treatment of NAEMD. MEDLINE, Embase, and Scopus were searched from inception to August 2023 for studies analyzing the outcome of POEM in NAEMD. Clinical success and adverse events were the main outcomes assessed. The event rates and their 95% confidence interval were calculated using a random effects model. A total of 11 studies with 271 patients were included in the final analysis. The pooled clinical success rate with POEM in NAEMD was 86.9% (82.9-90.9). On subgroup analysis, the pooled clinical success rates of POEM in DES and EGJOO were 97.8% (90.9-100.0) and 92.7% (86.3-95.1), which were significantly higher than in HE 81.2% (73.5-88.8). Data from limited studies showed that the pooled rate of improvement in dysphagia and chest pain was 88.5% (83.0-93.9) and 87.4% (80.5-94.4). The pooled incidence of overall AEs and serious AEs was 12.6% (5.7-19.5) and 0.3% (0.0-1.9), respectively. On follow-up, the pooled incidence of new-onset heartburn was 18.7% (11.1-26.2). POEM is a safe and efficacious treatment modality for the management of NAEMD with a lower clinical success in patients with HE. Further large-scale studies are required to validate the findings of the present analysis.
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Trastornos de la Motilidad Esofágica , Miotomía , Humanos , Trastornos de la Motilidad Esofágica/cirugía , Trastornos de la Motilidad Esofágica/complicaciones , Miotomía/métodos , Miotomía/efectos adversos , Resultado del Tratamiento , Masculino , Femenino , Persona de Mediana Edad , Esofagoscopía/métodos , Esofagoscopía/efectos adversos , Adulto , Espasmo Esofágico Difuso/cirugía , Espasmo Esofágico Difuso/complicaciones , Cirugía Endoscópica por Orificios Naturales/métodos , Cirugía Endoscópica por Orificios Naturales/efectos adversos , Anciano , Unión Esofagogástrica/cirugíaRESUMEN
BACKGROUND: A minority of patients with MSS tumors present a high tumor mutation burden (TMB) without underlying MMR defects. METHODS: Publicly available genomic series were assessed for identification of patients with MSS gastric gastroesophageal junction, and esophageal adenocarcinomas and a high TMB, defined as more than 10 mutations per Mb. These were compared with MSS cancers and a low TMB for genetic alterations and for survival outcomes. RESULTS: Patients with MSS cancers with high TMB in the MSK series were older but did not differ in other clinicopathologic parameters compared with MSS patients with low TMB. Mutations in tumor suppressors TP53 and APC and oncogenes KRAS and ERBB4 as well as amplifications of ERBB2 were more prevalent in the high TMB group of MSS cancers. Mutations in DDR associated genes, in epigenetic modifiers and in genes associated with immune response were more prevalent in the hIgh TMB group patients. However, high TMB was not associated with an improved survival in MSS gastric/gastroesophageal junction/esophageal adenocarcinomas (Log Rank p = 0.5). CONCLUSION: MSS Gastric/gastroesophageal junction/esophageal adenocarcinomas with TMB above 10 mutations per Mb possess a genomic landscape with increased alteration frequencies in common gastroesophageal cancer genes and pathways.
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Adenocarcinoma , Neoplasias Esofágicas , Unión Esofagogástrica , Inestabilidad de Microsatélites , Mutación , Neoplasias Gástricas , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Unión Esofagogástrica/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Endoluminal Functional Lumen Imaging Probe (EndoFLIP) is a device that measures gastro-esophageal junction (GEJ) distensibility. However, it is not demonstrated that GEJ distensibility increases proportionally with varying gastric myotomy length in peroral endoscopic myotomy (POEM). This study aimed to investigate the association between gastric myotomy length in POEM and intraoperative EndoFLIP findings. METHODS: This single-center, retrospective cohort study included patients who underwent POEM with intraoperative EndoFLIP from December 2019 to January 2023. Using EndoFLIP, minimal balloon diameter and its distensibility index (DI) were measured pre- and post-myotomy. Primary and secondary outcomes were the post-myotomy EndoFLIP findings at 30 ml and 40 ml volume fills. RESULTS: The study included 44 patients (mean age 53.1 years, 50% female). Chicago classification included achalasia type I (39%), II (41%), III (9%), hypercontractile esophagus (2%), and EGJOO (9%). The mean esophageal myotomy length was 7.5 ± 2.2 cm and gastric myotomy was 2.1 ± 0.6 cm. Simple linear regression analyses indicated that for each 1 cm increase in gastric myotomy length, the DI at 30 ml volume fill was estimated to increase by 2.0 mm2/mmHg (p < 0.05, R2 = 0.41), the minimal diameter at 30 ml volume fill was estimated to increase by 2.4 mm (p < 0.05, R2 = 0.48), and the minimal diameter at 40 ml volume fill was estimated to increase by 1.3 mm (p < 0.05, R2 = 0.09). CONCLUSIONS: This study demonstrates a significant linear relationship between gastric myotomy length and GEJ distensibility measured by EndoFLIP during POEM. These findings may be useful in clinical practice by enabling EndoFLIP to help calibrate a desired gastric myotomy length to achieve optimal DI and minimal diameter.
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Acalasia del Esófago , Unión Esofagogástrica , Miotomía , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Unión Esofagogástrica/cirugía , Unión Esofagogástrica/fisiopatología , Acalasia del Esófago/cirugía , Acalasia del Esófago/fisiopatología , Miotomía/métodos , Adulto , Anciano , Manometría/métodos , Resultado del TratamientoRESUMEN
PURPOSE: Programmed death-1 antibody plus chemotherapy has gained approval for the treatment for (human epidermal growth factor receptor 2 negative locally advanced or metastatic gastric or gastroesophageal junction cancer. This study aims to analyze the efficacy and safety of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis therapy in Chinese patients with advanced or metastatic gastric or gastroesophageal junction cancer in a real-world setting. METHODS: In total, 122 patients treated with anti-programmed death-1 antibody-based combination therapy between April 2019 and December 2021 were encompassed. Clinical outcomes and safety proï¬le were measured and analyzed. RESULTS: In the whole cohort, median overall survival was 17.2 months, median progression-free survival was 10.9 months, and median duration of response was 9.4 months. Notably, in the first-line patients, the median overall survival was not reached, median progression-free survival was 14.8 months, objective response rate was 68.4%. In the second-line group, median overall survival, median progression-free survival, median duration of response, and objective response rate were 10.9 months, 5.9 months, 4.5 months, and 41.5%, respectively. Treatment-related adverse events of any grade were observed in 28.2% of the overall cohort, primarily affecting the hematological and liver function. Grade 3 or 4 adverse events were mainly characterized by increased levels of aspartate aminotransferase, alanine aminotransferase, along with decreased lymphocyte and white blood cells, as well as anemia. CONCLUSIONS: Patients in our cohort experienced a clinical benefit from anti-programmed death-1 antibody-combined treatment in first-line treatment settings, with acceptable treatment-related adverse events. The benefit of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis treatment to the second-line patients should be further confirmed by large multi-center randomized, controlled clinical trials.
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Neoplasias Esofágicas , Unión Esofagogástrica , Receptor de Muerte Celular Programada 1 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Masculino , Femenino , Persona de Mediana Edad , Unión Esofagogástrica/patología , Unión Esofagogástrica/efectos de los fármacos , Anciano , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del Tratamiento , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Supervivencia sin Progresión , China , Pueblos del Este de AsiaRESUMEN
PURPOSE: To describe the global landscape of clinical research into interventions for gastroesophageal cancers (GECs), with examination of trial characteristics, geographic distribution of trial sites, and factors associated with trial termination. METHODS: We queried ClinicalTrials.gov to identify all completed or terminated phase III interventional studies investigating GECs (esophageal squamous cell carcinoma [ESCC], esophageal adenocarcinoma [EAC], gastroesophageal junctional [GEJ], and gastric adenocarcinoma). Data on all reported trial characteristics were extracted. Pearson's chi-square and Fisher's exact tests were used to compare differences in completed and terminated trials. Multivariate logistic regression evaluated predictors of termination. RESULTS: A total of 179 trials were identified; of these, 90% were therapeutic. Most included sites in Asia (61%) and Europe (32%); few included sites in Africa (4%). Thirty percent included sites in low- and middle-income countries (LMICs). Most (70%) focused on gastric or GEJ adenocarcinoma, 13% on EAC and ESCC, and 9% on ESCC alone. Sixteen percent (n = 29) of trials terminated prematurely. In multivariate analysis, study site number, location of recruitment sites, and patient population emerged as predictors of termination. Trials recruiting from US-based sites were more likely to terminate (odds ratio [OR], 7.22 [95% CI, 1.59 to 32.69]). Trials conducted exclusively in LMICs were less likely to terminate (OR, 0.04 [95% CI, 0.01 to 0.59] v conducted in high-income countries [HICs] alone). Studies on ESCC were more likely to terminate (OR, 17.74 [95% CI, 1.49 to 210.69]). CONCLUSION: Although 80% of GECs occur in LMICs, trial activity disproportionately occurs in HICs. Few trials focus on EAC/ESCC despite being highly fatal, highlighting an unmet need. Overall, this study highlights (1) a missed opportunity to recruit patients from high-incidence regions globally; and (2) a pressing need for increasing funding, infrastructure, and support for GEC trials in LMICs.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Adenocarcinoma/terapia , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Ensayos Clínicos Fase III como Asunto , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/epidemiología , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/epidemiología , Unión Esofagogástrica/patología , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/terapiaRESUMEN
Importance: The prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone. Objective: To assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes. Data Sources: Literature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023. Study Selection: Two blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach. Main Outcomes and Measures: Overall and disease-free survival, postoperative morbidity, and mortality. Results: The analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00]). Conclusions and Relevance: In this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.
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Adenocarcinoma , Quimioradioterapia , Neoplasias Esofágicas , Unión Esofagogástrica , Metaanálisis en Red , Neoplasias Gástricas , Humanos , Adenocarcinoma/terapia , Adenocarcinoma/mortalidad , Unión Esofagogástrica/patología , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/mortalidad , Quimioradioterapia/métodos , Neoplasias Gástricas/terapia , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/tratamiento farmacológico , Masculino , Cuidados Preoperatorios/métodos , Persona de Mediana Edad , Femenino , Anciano , Supervivencia sin EnfermedadRESUMEN
Standardized assessment of the gastroesophageal valve during endoscopy, attainable via the Hill classification, is important for clinical assessment and therapeutic decision making. The Hill classification is associated with the presence of hiatal hernia (HH), a common endoscopic finding connected to gastro-esophageal reflux disease. A novel efficient medical artificial intelligence (AI) training pipeline using active learning (AL) is designed. We identified 21,970 gastroscopic images as training data and used our AL to train a model for predicting the Hill classification and detecting HH. Performance of the AL and traditionally trained models were evaluated on an external expert-annotated image collection. The AL model achieved accuracy of 76%. A traditionally trained model with 125% more training data achieved 77% accuracy. Furthermore, the AL model achieved higher precision than the traditional one for rare classes, with 0.54 versus 0.39 (p < 0.05) for grade 3 and 0.72 versus 0.61 (p < 0.05) for grade 4. In detecting HH, the AL model achieved 94% accuracy, 0.72 precision and 0.74 recall. Our AL pipeline is more efficient than traditional methods in training AI for endoscopy.
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Inteligencia Artificial , Humanos , Reflujo Gastroesofágico/diagnóstico , Hernia Hiatal/diagnóstico , Hernia Hiatal/diagnóstico por imagen , Gastroscopía/métodos , Unión Esofagogástrica/patología , Unión Esofagogástrica/diagnóstico por imagen , Aprendizaje Basado en Problemas/métodosRESUMEN
BACKGROUND: Limited data exist for global prevalence of claudin 18 isoform 2 (CLDN18.2) positivity and association of CLDN18.2 status with clinical and tumor characteristics in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. We report prevalence of CLDN18.2 positivity (phase 3; SPOTLIGHT, NCT03504397; GLOW, NCT03653507) and concordance of CLDN18.2 status between a subset of pair-matched tumor samples (phase 2, ILUSTRO, NCT03505320; phase 1, NCT03528629) from clinical studies of zolbetuximab. METHODS: Tumor samples from patients with LA unresectable or mG/GEJ adenocarcinoma were tested for CLDN18.2 status by immunohistochemistry. Human epidermal growth factor receptor 2 (HER2) expression was tested per central or local assessment. RESULTS: Across SPOTLIGHT and GLOW, the prevalence of CLDN18.2 positivity (≥ 75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 38.4%. Prevalence was similar in gastric versus GEJ adenocarcinoma samples and regardless of collection method (biopsy versus resection) or collection site (primary versus metastatic). CLDN18.2 positivity was most prevalent in patients with diffuse-type tumors. In ILUSTRO and the phase 1 study, concordance of CLDN18.2 positivity was 61.1% between archival (i.e., any time before treatment) and baseline (i.e., ≤ 3 months before first treatment) samples, and concordance of any CLDN18 staining (≥ 1% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 88.9%. CONCLUSIONS: CLDN18.2 was a highly prevalent biomarker in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma. CLDN18.2 positivity remained relatively stable over time in many patients. Biomarker testing for CLDN18.2 should be considered in standard clinical practice in these patients.
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Adenocarcinoma , Claudinas , Neoplasias Esofágicas , Unión Esofagogástrica , Neoplasias Gástricas , Humanos , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Unión Esofagogástrica/patología , Claudinas/metabolismo , Masculino , Femenino , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/metabolismo , Isoformas de Proteínas , Prevalencia , AdultoRESUMEN
OBJECTIVE: To investigate the significance of endoscopic grading (Hill's classification) of gastroesophageal flap valve (GEFV) in the examination of patients with gastroesophageal reflux disease (GERD). METHODS: One hundred and sixty-two patients undergoing gastroscopy in the Department of Gastroenterology, Xingyi People's Hospital between Apr. 2022 and Sept. 2022 were selected by convenient sampling, and data such as GEFV grade, and findings of esophageal high-resolution manometry (HRM) and esophageal 24-h pH/impedance reflux monitoring, and Los Angeles (LA) classification of reflux esophagitis (RE) were collected and compared. RESULTS: Statistically significant differences in age (F = 9.711, P < 0.001) and hiatal hernia (χ = 35.729, P < 0.001) were observed in patients with different GEFV grades. The resting LES pressures were 12.12 ± 2.79, 10.73 ± 2.68, 9.70 ± 2.29, and 8.20 ± 2.77 mmHg (F = 4.571, P < 0.001) and LES lengths were 3.30 ± 0.70, 3.16 ± 0.68, 2.35 ± 0.83, and 2.45 ± 0.62 (F = 3.789, P = 0.011), respectively, in patients with GEFV grades I-IV. DeMeester score (Z = 5.452, P < 0.001), AET4 (Z = 5.614, P < 0.001), acid reflux score (upright) (Z = 7.452, P < 0.001), weak acid reflux score (upright) (Z = 3.121, P = 0.038), liquid reflux score (upright) (Z = 3.321, P = 0.031), acid reflux score (supine) (Z = 6.462, P < 0.001), mixed reflux score (supine) (Z = 3.324, P = 0.031), gas reflux score (supine) (Z = 3.521, P = 0.024) were different in patients with different GEFV grades, with statistically significant differences. Pearson correlation analysis revealed a positive correlation between RE grade and LA classification of GERD (r = 0.662, P < 0.001), and the severity of RE increased gradually with the increase of the Hill grades of GEFV. CONCLUSION: The Hill grade of GEFV is related to age, hiatal hernia, LES pressure, and the consequent development and severity of acid reflux and RE. Evaluation of esophageal motility and reflux based on the Hill grade of GEFV is of significance for the diagnosis and treatment of GERD.
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Reflujo Gastroesofágico , Manometría , Humanos , Reflujo Gastroesofágico/fisiopatología , Masculino , Femenino , Persona de Mediana Edad , Manometría/métodos , Adulto , Anciano , Gastroscopía/métodos , Unión Esofagogástrica/fisiopatología , Unión Esofagogástrica/patología , Unión Esofagogástrica/cirugía , Monitorización del pH Esofágico , Hernia Hiatal/cirugía , Hernia Hiatal/complicaciones , Esfínter Esofágico Inferior/fisiopatologíaRESUMEN
OBJECTIVE: To conduct a systematic review and meta-analysis of case-control and cohort human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on esophageal cancer (EC), cancer of the gastroesophageal junction (GEJ), and gastric cancer (GC) in blood and tissue. BACKGROUND: Upper gastrointestinal cancers (UGC), predominantly EC, GEJ, and GC, are malignant tumour types with high morbidity and mortality rates. Numerous studies have focused on metabolomic profiling of UGC in recent years. In this systematic review and meta-analysis, we have provided a collective summary of previous findings on metabolites and metabolomic profiling associated with EC, GEJ and GC. METHODS: Following the PRISMA procedure, a systematic search of four databases (Embase, PubMed, MEDLINE, and Web of Science) for molecular epidemiologic studies on the metabolomic profiles of EC, GEJ and GC was conducted and registered at PROSPERO (CRD42023486631). The Newcastle-Ottawa Scale (NOS) was used to benchmark the risk of bias for case-controlled and cohort studies. QUADOMICS, an adaptation of the QUADAS-2 (Quality Assessment of Diagnostic Accuracy) tool, was used to rate diagnostic accuracy studies. Original articles comparing metabolite patterns between patients with and without UGC were included. Two investigators independently completed title and abstract screening, data extraction, and quality evaluation. Meta-analysis was conducted whenever possible. We used a random effects model to investigate the association between metabolite levels and UGC. RESULTS: A total of 66 original studies involving 7267 patients that met the required criteria were included for review. 169 metabolites were differentially distributed in patients with UGC compared to healthy patients among 44 GC, 9 GEJ, and 25 EC studies including metabolites involved in glycolysis, anaerobic respiration, tricarboxylic acid cycle, and lipid metabolism. Phosphatidylcholines, eicosanoids, and adenosine triphosphate were among the most frequently reported lipids and metabolites of cellular respiration, while BCAA, lysine, and asparagine were among the most commonly reported amino acids. Previously identified lipid metabolites included saturated and unsaturated free fatty acids and ketones. However, the key findings across studies have been inconsistent, possibly due to limited sample sizes and the majority being hospital-based case-control analyses lacking an independent replication group. CONCLUSION: Thus far, metabolomic studies have provided new opportunities for screening, etiological factors, and biomarkers for UGC, supporting the potential of applying metabolomic profiling in early cancer diagnosis. According to the results of our meta-analysis especially BCAA and TMAO as well as certain phosphatidylcholines should be implicated into the diagnostic procedure of patients with UGC. We envision that metabolomics will significantly enhance our understanding of the carcinogenesis and progression process of UGC and may eventually facilitate precise oncological and patient-tailored management of UGC.
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Metabolómica , Humanos , Metabolómica/métodos , Neoplasias Esofágicas/sangre , Neoplasias Esofágicas/metabolismo , Neoplasias Gástricas/sangre , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/diagnóstico , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Neoplasias Gastrointestinales/sangre , Neoplasias Gastrointestinales/metabolismo , Neoplasias Gastrointestinales/diagnóstico , Metaboloma/fisiología , Estudios de Casos y Controles , Unión Esofagogástrica/patología , Unión Esofagogástrica/metabolismoRESUMEN
BACKGROUND Although recurrence after surgery for esophagogastric junction (EGJ) adenocarcinoma frequently develops in the mediastinal and para-aortic lymph nodes (LN), distant LN recurrence in the mesocolon is rare. We report a rare case of ileocecal LN metastasis in the ascending mesocolon after radical surgery for an EGJ adenocarcinoma. CASE REPORT We performed subtotal esophagectomy with mediastinal and para-gastric LN dissection in a patient with an advanced EGJ adenocarcinoma. Clinicopathologically, the patient was diagnosed with type I EGJ adenocarcinoma based on Siewert's classification (pathological T3N1M0). One year after surgery, computed tomography showed enlarged lymph nodes around the ileocolic artery, and further examination was performed. Although positron emission tomography-computed tomography showed that the lesion had moderate uptake of fluorodeoxyglucose, we did not find the reason for the enlarged lymph nodes. Finally, laparoscopic ileocecal resection was performed for diagnostic and therapeutic purposes. Clinicopathological tests revealed that the specimen was a moderately differentiated adenocarcinoma, which was strongly suspected to be a metastasis of the EGJ adenocarcinoma. CONCLUSIONS We encountered a rare case of EGJ adenocarcinoma that spread to the ileocecal LN in the ascending mesocolon. To the best of our knowledge, this is the first such report in the literature to date. Laparoscopic ileocecal resection for metastasis to the ascending mesocolon seems reasonable as a local control.
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Adenocarcinoma , Neoplasias Esofágicas , Esofagectomía , Unión Esofagogástrica , Metástasis Linfática , Humanos , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Unión Esofagogástrica/patología , Unión Esofagogástrica/cirugía , Masculino , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Persona de Mediana Edad , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Recurrencia Local de Neoplasia/cirugía , AncianoRESUMEN
BACKGROUND: Fusobacterium nucleatum inhabits the oral cavity and affects the progression of gastrointestinal cancer. Our prior findings link F. nucleatum to poor prognosis in oesophageal squamous cell carcinoma via NF-κB pathway. However, its role in oesophagogastric junction and gastric adenocarcinoma remains unexplored. We investigated whether F. nucleatum influences these cancers, highlighting its potential impact. METHODS: Two cohorts of EGJ and gastric adenocarcinoma patients (438 from Japan, 380 from the USA) were studied. F. nucleatum presence was confirmed by qPCR, FISH, and staining. Patient overall survival (OS) was assessed based on F. nucleatum positivity. EGJ and gastric adenocarcinoma cell lines were exposed to F. nucleatum to study molecular and phenotypic effects, validated in xenograft mouse model. RESULTS: In both cohorts, F. nucleatum-positive EGJ or gastric adenocarcinoma patients had notably shorter OS. F. nucleatum positivity decreased in more acidic tumour environments. Cancer cell lines with F. nucleatum showed enhanced proliferation and NF-κB activation. The xenograft model indicated increased tumour growth and NF-κB activation in F. nucleatum-treated cells. Interestingly, co-occurrence of F. nucleatum and Helicobacter pylori, a known risk factor, was rare. CONCLUSIONS: F. nucleatum can induce the NF-κB pathway in EGJ and gastric adenocarcinomas, leading to tumour progression and poor prognosis.
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Adenocarcinoma , Neoplasias Esofágicas , Unión Esofagogástrica , Infecciones por Fusobacterium , Fusobacterium nucleatum , FN-kappa B , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Animales , Neoplasias Esofágicas/microbiología , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Ratones , Unión Esofagogástrica/patología , Unión Esofagogástrica/microbiología , Masculino , Femenino , Adenocarcinoma/microbiología , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , FN-kappa B/metabolismo , Línea Celular Tumoral , Infecciones por Fusobacterium/complicaciones , Infecciones por Fusobacterium/microbiología , Anciano , Persona de Mediana Edad , Pronóstico , Proliferación Celular , Microambiente Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Esophagogastric junction cancer (EJC) refers to malignant tumors that develop at the junction between the stomach and the esophagus. TUSC1 is a recently identified tumor suppressor gene known for its involvement in various types of cancer. The objective of this investigation was to elucidate the regulatory influence of DNA methylation on TUSC1 expression and its role in the progression of EJC. METHODS: Bioinformatics software was utilized to analyze the expression of TUSC1, enriched pathways, and highly methylated sites in the promoter region. TUSC1 expression in EJC was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot (WB), and immunohistochemistry. Methylation-specific PCR was employed to detect the methylation level of TUSC1. To analyze the effects of TUSC1 and 5-AZA-2 on tumor cell proliferation, migration, invasion, cell cycle, and apoptosis, several assays including CCK-8, colony formation, transwell, and flow cytometry were conducted. The expression of MDM2 was assessed using qRT-PCR and WB. WB detected the expression of p53, and p-p53, markers for EJC cell proliferation, epithelial-mesenchymal transition, and apoptosis. The role of TUSC1 in tumor occurrence in vivo was examined using a xenograft mouse model. RESULTS: TUSC1 expression was significantly downregulated in EJC. Overexpression of TUSC1 and treatment with 5-AZA-2 inhibited the malignant progression of EJC cells. In EJC, low methylation levels promoted the expression of TUSC1. Upregulation of TUSC1 suppressed the expression of MDM2 and activated the p53 signaling pathway. Inactivation of this pathway attenuated the inhibitory effect of TUSC1 overexpression on EJC cell proliferation, migration, invasion, and other behaviors. Animal experiments demonstrated that TUSC1 overexpression inhibited EJC tumor growth and metastasis in vivo. CONCLUSION: TUSC1 was commonly downregulated in EJC and regulated by methylation. It repressed the malignant progression of EJC tumors by mediating the p53 pathway, suggesting its potential as a diagnostic and therapeutic target for EJC.