Search Results (145)

Background: Anastomotic leak (AL) after esophagectomy remains a devastating complication. Indocyanine green (ICG) fluorescence angiography may mitigate this risk by enabling perfusion-guided anastomotic site selection. This study evaluates the feasibility of quantitative ICG angiography using the SPY-PHI QP^® system (Stryker AB, Malmö, Sweden) during gastric conduit reconstruction. Methods: Six patients undergoing esophagectomy (Ivor Lewis/McKeown) after neoadjuvant therapy were retrospectively identified. ICG angiography was performed intraoperatively, with perfusion at the gastric conduit quantified as a relative perfusion ratio (RPR) using the first duodenal segment as the reference (100%). Anastomotic sites were selected based on maximal RPR (threshold > 80%). Postoperative outcomes included AL incidence (radiological/clinical), complications (Clavien–Dindo), and 90-day mortality. Results: All patients (median age: 69 years) underwent successful perfusion assessment. Adenocarcinoma predominated (50%, 3/6), with most tumours at the gastroesophageal junction (Siewert II: 66%). Intraoperative RPR at anastomotic sites ranged from 80% to 100%. No anastomotic leaks occurred. Complications included Clavien–Dindo grade II (n = 3; respiratory infections) and grade IV (n = 2; reintubation). There was no 90-day mortality. Conclusions: Quantitative ICG angiography using the SPY-PHI QP^® system facilitated perfusion-guided anastomosis with no leaks observed. Standardising perfusion assessment based on an RPR threshold of >80% may enhance surgical safety, though larger studies are needed to validate these findings. Full article

Esophageal cancer (EC) is one of the most aggressive cancers of the digestive system, with two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Over four decades, the frequencies of EAC and Barrett’s esophagus (BE), the known precursor lesion for EAC, have sharply increased in North America and Europe. This is mainly due to lifestyle and risk factors such as gastroesophageal reflux disease (GERD), obesity, and smoking. BE development to EAC involves numerous molecular modifications, including genetic and epigenetic alterations. Epigenetic changes, such as aberrant DNA methylation, play a critical role in the pathogenesis and progression of BE. This review discusses how non-genetic risk factors contribute to DNA methylation changes driving the transformation from BE to EAC, providing insights into the potential of developing methylation-based biomarkers for early diagnosis, risk stratification, and therapeutic intervention. Full article

Esophageal cancer (EC) is a highly aggressive gastrointestinal malignancy, with a notable increase in incidence over recent decades, representing a significant global health burden. The main histological subtypes are esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), with the former being closely associated with gastroesophageal reflux disease, Barrett’s esophagus, and obesity, and its incidence continues to increase in Western populations. The rising incidence of EC, combined with poor survival rates, underscores the need for new therapeutic approaches. A deeper understanding of the molecular basis of this prevalent malignancy may open new avenues for optimal therapeutic strategies, with immunotherapy now central in several clinical trials. Understanding the interplay between the tumor microenvironment (TME) and disease progression is pivotal for managing this malignancy, which remains highly challenging. This review highlights the role of the TME in EAC progression and drug resistance, and recent therapeutic advances. Full article

Gastroesophageal cancer (GEC) represents a global health burden, with rising incidence and high mortality. Despite advancements in early detection and systemic therapies, outcomes remain poor, especially in advanced stages. Management requires a multidisciplinary, multimodal approach that integrates surgery, chemotherapy, radiotherapy, targeted agents, and immunotherapy, tailored by tumor histology, location, and molecular profile. For localized disease, perioperative chemotherapy or chemoradiotherapy is standard, with adjuvant immunotherapy now emerging in selected high-risk cases. In metastatic or unresectable settings, systemic therapy forms the backbone of treatment, with biomarker-driven regimens targeting HER2, PD-L1, MSI-H/dMMR, and CLDN18.2, offering improved outcomes. Novel agents and combinations, including bispecific antibodies, FGFR2 inhibitors, and immunotherapy-based strategies, are actively being explored in clinical trials. This review provides a comprehensive overview of the evolving therapeutic landscape of GEC. It emphasizes the growing role of precision medicine and the integration of emerging clinical data into practice. Full article

Gastrointestinal cancers, including gastric, gastroesophageal junction, pancreatic, and biliary tract cancers, remain associated with poor outcomes due to late diagnosis and limited effective treatment options. Claudin-18.2 (CLDN18.2), a tight junction protein primarily found in the gastric epithelium and ectopically expressed in gastrointestinal tumors, has emerged as a promising therapeutic target across these diseases. This narrative review expands on existing discussions surrounding CLDN18.2-directed therapy in gastric and gastroesophageal cancer and provides a comprehensive, updated analysis of the rapidly evolving therapeutic landscape across multiple gastrointestinal malignancies, including pancreatic and biliary tract cancers. We summarize key developments following the approval of the monoclonal antibody zolbetuximab and critically evaluate emerging modalities, including bispecific antibodies, antibody–drug conjugates, and chimeric antigen receptor T-cell therapies, highlighting differences in mechanisms of action, efficacy, toxicity profiles, and mitigation strategies. We also discuss the clinical relevance of CLDN18.2 and PD-L1 co-expression, the rationale for pairing CLDN18.2-targeted therapy with immune checkpoint inhibitors, and early data supporting combination approaches. Additionally, we examine tumor heterogeneity, biomarker challenges, and emerging resistance mechanisms, alongside strategies to overcome them. Finally, we identify current limitations in the field, including inconsistent CLDN18.2 testing criteria, and outline prioritized future directions to optimize integration of CLDN18.2-directed therapies across gastrointestinal cancers. By looking beyond zolbetuximab and incorporating cross-platform comparison, immuno-oncology considerations, and multi-tumor context, this review provides a broad and forward-looking framework to guide clinical application and next-generation research in CLDN18.2-targeted therapy. Full article

Advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma remains a common and deadly form of cancer. Advances in G/GEJ cancer treatment have improved survival outcomes with the claudin-18.2 (CLDN18.2)-targeted agent, zolbetuximab, and immune checkpoint inhibitors (ICIs) targeting the PD-1 receptor. This article offers an evidence-informed opinion on considerations when selecting between these first-line treatments for G/GEJ adenocarcinoma in patients with HER2-negative disease that expresses CLDN18.2 and/or PD-L1, including the reliability of biomarker scoring and interpretation, overall survival (OS) rates, toxicity profiles, and logistical practicalities. Evidence from Phase III trials for zolbetuximab and ICIs suggest similar OS benefits of 14–18 months compared to chemotherapy alone, but there appears to be a gradient of benefit for ICIs with increasing PD-L1 combined positive score (CPS). There is high inter-observer variability in CPS scoring, particularly at lower thresholds. Zolbetuximab is associated with high rates of nausea and vomiting during the initial infusion, whereas ICIs are associated with risk of later-onset immune-related toxicities that can be fatal in rare cases. In considering the available evidence, our opinion is that zolbetuximab is a reasonable option for initial targeted treatment in HER2-/CLDN18.2-positive advanced G/GEJ when PD-L1 CPS score is <10 based on the reliability of biomarker testing, comparable OS, and avoidance of potentially irreversible ICI-induced immune toxicity. Full article

The role of circulating tumor DNA (ctDNA) in gastroesophageal adenocarcinoma (GEA) has expanded in recent years. In resectable disease, postoperative ctDNA is able to detect patients at highest risk of recurrence months before scans. Tumor-informed assays provide the best sensitivity and emerging methylation assays are useful when tissue is scarce. In metastatic GEA, baseline ctDNA burden correlates with prognosis, and a decrease in ctDNA level after treatment initiation reflects therapeutic response. It can also uncover actionable targets, including ERBB2, FGFR2, and MSI-H, and detect resistance that can arise after starting treatment. Limitations include variable assay performance, low shedding in some tumors, clonal hematopoiesis confounding, and a lack of randomized data showing that ctDNA-guided changes improve outcomes. Ongoing trials are testing MRD-guided escalation/de-escalation and ctDNA-directed biomarker therapy. In this review, we evaluate the role of ctDNA in GEA cancers over recent years. Full article

Background: Resectable gastric and gastroesophageal junction cancer (GC/GEJC) treatment patterns in the real-world are poorly described. This study described real-world perioperative treatment and outcomes for patients in the US with resectable GC/GEJC. Methods: Data from the Flatiron Health Enhanced Datamart were analyzed for adult patients diagnosed with resectable GC/GEJC between 1 January 2016 and 1 January 2023. The primary objective was to describe perioperative treatments (neoadjuvant only, adjuvant only, both). Secondary objectives included real-world event-free survival (rwEFS) and real-world overall survival (rwOS). Results: Data from 1717 patients (901/816 with GC/GEJC) were included. Median age of patients with GC/GEJC was 68.0/69.0 years, 62.4%/83.3% were male, and 97.3%/96.7% had adenocarcinoma, respectively. For GC/GEJC, 71.1%/47.9% underwent surgery, of which 15.6%/70.1% received neoadjuvant treatment only, 26.4%/5.6% received adjuvant treatment only, 25.0%/17.4% received both, and 33.1%/6.9% received no perioperative treatment, respectively. For GC, the most frequent neoadjuvant treatment was FLOT (43.0% neoadjuvant only; 53.8% both) and the most frequent adjuvant treatments were chemoradiotherapy (39.6% adjuvant only) and FLOT (43.1% both). For GEJC, chemoradiotherapy was the most frequent neoadjuvant (66.4% neoadjuvant only; 67.6% both) and adjuvant only (54.5%) treatment. When patients received both, the most frequent adjuvant treatment was nivolumab (45.6%). For GC/GEJC, median rwEFS (95% CI) was 29.1 (24.7–38.7)/20.8 (17.4–23.7) months for patients who had planned or cancelled surgery and 11.3 (9.6–13.5)/12.7 (11.6–15.4) months for patients without planned surgery. Median rwOS (95% CI) was 50.9 (43.7–62.4)/38.6 (31.4–47.2) months for patients who had planned or cancelled surgery and 15.4 (13.1–18.6)/21.0 (17.6–22.6) months for patients without planned surgery. Conclusions: Real-world data showed lower use of perioperative treatments for resectable GC/GEJC than expected. rwEFS and rwOS remain poor. Optimization of perioperative treatments is needed to improve long-term outcomes. Full article

Gastric and gastroesophageal junction (G/GEJ) adenocarcinomas remain among the most aggressive and lethal malignancies globally. Most patients are diagnosed at advanced stages and respond poorly to conventional chemotherapy, highlighting the urgent demand for more effective, novel treatment strategies such as monoclonal antibody therapies targeting drivers of tumor progression. This review examines the mechanisms, safety profiles, and clinical trial outcomes of three targeted agents—bemarituzumab, zolbetuximab, and ramucirumab—which inhibit tumor growth through the FGFR2b, CLDN18.2, and VEGFR2 pathways, respectively. We also compare traditional versus adaptive clinical trial designs, explore emerging challenges such as therapeutic resistance and treatment-related toxicities, and consider implications for personalized medicine. Collectively, these agents represent a paradigm shift from empiric chemotherapy toward biomarker-driven immunotherapy, with the potential to significantly improve survival and quality of life in patients with advanced G/GEJ cancers. Full article

Background: The role of CREBBP and EP300 mutations in hypermutation and immunotherapy response in gastroesophageal adenocarcinomas is poorly defined and needs further investigation. Methods: We conducted an in silico analysis of 12 publicly available studies (n = 1871; cBioPortal), stratifying samples by CREBBP/EP300 status to assess associations with TMB-High, MSI, co-mutation patterns, and mutation localization. Clinical validation was performed in an independent pan-cancer cohort treated with ICIs (n = 1610) and a gastric cancer cohort with WES data (n = 55). Results: Coding mutations in CREBBP and/or EP300 were significantly associated with TMB-high and MSI-high phenotypes (p < 0.001). All studied samples carrying coding mutations in both CREBBP and EP300 exhibited a TMB-high status. PTVs in functional HAT and bromodomain regions were exclusively associated with TMB-high. Incorporating CREBBP and/or EP300 mutation status improved identification of ultra-hypermutated tumors compared with single-gene biomarkers (p < 0.001). Clinically, these mutations predicted improved overall survival in the pan-cancer cohort (median OS 34 vs. 17 months; HR = 0.68, 95% CI 0.52–0.87, p = 0.0026), as well as in bladder (HR = 0.55, p = 0.0337) and gastrointestinal cancer cohorts (HR = 0.31, p = 0.0021) treated with ICIs. In the gastric cancer validation cohort, all tumors with PTVs demonstrated a partial response to anti-PD-1 therapy. Conclusions: We report CREBBP and EP300 coding mutations as novel potential surrogate biomarkers for hypermutation in gastroesophageal adenocarcinomas and demonstrate their association with favorable immunotherapy outcomes, supporting their potential clinical utility for patient stratification. Full article

Background/Objectives: Sugemalimab demonstrated clinical efficacy in the GEMSTONE-303 trial, but its cost-effectiveness remains unclear. This study aims to evaluate the cost-effectiveness of sugemalimab in combination with chemotherapy (CAPOX) as a first-line treatment for patients with advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, compared to chemotherapy alone, from the perspective of Taiwan’s healthcare payer. Methods: A partitioned survival model was developed to simulate outcomes over a 40-year time horizon, and model parameters were derived from GEMSTONE-303 and the wider literature. Health benefits were measured in quality-adjusted life-years (QALYs), and only direct medical costs were included, with both discounted at an annual rate of 3%. The willingness-to-pay threshold was set at three times the 2024 GDP per capita. Deterministic and probabilistic sensitivity analyses were conducted alongside scenario analyses. Results: Compared to capecitabine and oxaliplatin (CAPOX) alone, adding sugemalimab yielded an incremental gain of 0.39 QALYs at an additional cost of USD 47,020, resulting in an incremental net monetary benefit of −USD 7478. Conclusions: Sugemalimab plus CAPOX is not cost-effective for advanced or metastatic G/GEJ adenocarcinoma from the Taiwan payer’s perspective. Achieving cost-effectiveness would require a 20–30% price reduction for sugemalimab (to USD 1204–USD 1376 per 600 mg), assuming first-line therapy is administered for the median treatment duration observed in the GEMSTONE-303 trial. If reimbursement continued until disease progression, a reduction of approximately 68% would be required (USD 550 per 600 mg). Full article

Previous studies linked disadvantaged neighborhoods to poor cancer outcomes. The Neighborhood Deprivation Index (NDI) quantifies socioeconomic disadvantage, but its impact on gastroesophageal adenocarcinoma outcomes remains understudied. We conducted a retrospective analysis of 40,589 patients with esophageal or gastric adenocarcinoma from the SEER database (1996–2015), stratifying them by NDI: less disadvantaged (NDI < 60) and highly disadvantaged (NDI ≥ 60). Multivariate regression showed NDI ≥ 60 was independently associated with worse overall survival (OS) (HR 1.027, p = 0.017) and disease-specific survival (DSS) (HR 1.025, p = 0.04). Other predictors of poor OS and DSS included older age (≥60 years old), male sex, single marital status, lack of insurance, advanced stage/grade, and gastric tumor site. In contrast, Hispanic and non-Hispanic Black ethnicity, urban residence, and undergoing surgery were associated with better outcomes. Disadvantaged neighborhoods are linked to poorer survival in upper GI cancers, likely due to socioeconomic barriers. Addressing social determinants of health is crucial to reducing these disparities. Full article

Helicobacter pylori (Hp), a widespread gastric pathogen, has long been studied for its role in upper gastrointestinal disorders. While its involvement in gastritis, peptic ulcer disease, and gastric cancer is well established, its impact on esophageal diseases remains an area of ongoing investigation. Nevertheless, some data indicate that Hp may be involved in the pathogenesis of gastroesophageal reflux disease–Barrett’s esophagus–esophageal adenocarcinoma sequence. Similarly, the Hp-related mast cell activation—an essential immunological event—may also play a crucial role in the progression from gastroesophageal reflux disease to Barrett’s esophagus and esophageal adenocarcinoma. The underlying mechanisms include immune modulation, cytokine cascades, and microbial interactions that collectively shape the esophageal microenvironment. This review provides an in-depth analysis of these pathways, highlighting the potential role of Hp-induced, mast cell-driven inflammation in esophageal disease progression and discussing emerging therapeutic strategies. Full article

Adenocarcinoma of the gastroesophageal junction (AEG) is an aggressive cancer with rising incidence and poor long-term survival despite multimodal treatment. Reliable preoperative prognostic markers are lacking. Methods: The study is based on data from a prospectively maintained institutional database, which was retrospectively analyzed. In total, 211 patients were analyzed who underwent curative resection for AEG to evaluate the association of SII and LVI and their combined prognostic value. Results: LVI was present in 45% of patients and was significantly associated with higher median SII values compared to patients without LVI (943 vs. 652; p < 0.001). Both high SII and the presence of LVI were independently associated with worse overall survival (p < 0.001 for both). In patients treated with primary surgery (65%), the combined presence of high SII and LVI identified a subgroup with particularly poor prognosis (pseudo-R² increased from 0.451 to 0.524; likelihood-ratio test p < 0.001). Among patients who received neoadjuvant therapy (NT) (35%), SII remained a strong prognostic factor (pseudo-R² = 0.432), while LVI alone was not statistically significant (p = 0.135), and its addition to the SII model did not improve prognostic performance (p = 0.377). Conclusions: The combined assessment of SII and LVI may improve prognostic stratification in AEG, especially in patients undergoing upfront surgery. These findings suggest that combined assessment of SII and LVI enhances prognostic stratification, particularly in patients treated with upfront surgery, and may aid personalized treatment and follow-up planning in AEG. To the best of our knowledge, this is the first study investigating the association of SII and LVI in AEG. Full article

Background and Aims: Gastroesophageal reflux disease (GERD) is the most common esophageal disorder worldwide and a progressive condition leading to Barrett’s esophagus and adenocarcinoma. Continuous medical therapy with proton pump inhibitors fails to restore the antireflux barrier and is unable to relieve symptoms in up to 40% of patients. A tailored and standardized antireflux surgical procedure may increase cure rates and meet patient expectations. Methods and Results: Antireflux surgery aims to reestablish the natural antireflux barrier, which includes the diaphragmatic crura, the lower esophageal sphincter (LES), and the angle of His along with the gastroesophageal flap valve. For decades, the Nissen total fundoplication has been the primary procedure and remains the gold standard for surgical treatment. Alternatives such as Toupet partial fundoplication, Dor partial fundoplication, and the magnetic sphincter augmentation (LINX™) procedure have been developed to mitigate side effects like dysphagia, gas-bloat syndrome, and the inability to belch or vomit. Recent clinical findings regarding a novel procedure, RefluxStop™, indicate that restoring the gastroesophageal flap valve, in conjunction with anterior fundoplication and a silicone device for stabilizing the LES beneath the diaphragm, can achieve lasting reflux control and enhance patient-reported outcomes. Conclusions: The planning of healthcare services and actionable strategies to improve equity and quality of treatment is critical to address the global burden of GERD. Modern laparoscopic surgery for GERD is safe and effective and should be performed in centers offering a complete diagnostic pathway and specific surgical techniques tailored to the individual GERD phenotype. Shared decision-making between the surgeon and the patient is essential for the choice of operation. A personalized approach can offer clinical benefits over total fundoplication and improve patient-reported outcomes. Full article