Trending Topics in Gastroenterology | GastroAGI

Pemigatinib Outperforms Chemotherapy in FGFR2-Rearranged Cholangiocarcinoma : JCO | June 2026

Introduction: Cholangiocarcinoma is an aggressive biliary tract malignancy with limited treatment options and poor long-term outcomes. The discovery of fibroblast growth factor receptor 2 (FGFR2) rearrangements in a subset of patients has transformed the therapeutic landscape, enabling the development of precision-targeted therapies. Pemigatinib previously demonstrated meaningful activity in previously treated FGFR2-rearranged cholangiocarcinoma, leading to its approval in the second-line setting. Problem Statement: Although targeted therapy has shown promise after chemotherapy failure, it remained uncertain whether FGFR inhibition could provide superior outcomes when used as first-line treatment. Establishing the role of precision medicine earlier in the disease course is critical for improving outcomes in biomarker-selected patients with advanced cholangiocarcinoma. Summary: The phase 3 FIGHT-302 trial represents the largest randomized study of a targeted therapy conducted in patients with advanced cholangiocarcinoma harboring FGFR2 rearrangements. The trial demonstrated that first-line pemigatinib significantly prolonged progression-free survival compared with standard gemcitabine-cisplatin chemotherapy. Pemigatinib also produced substantially higher objective response rates and more durable tumor responses, highlighting the effectiveness of biomarker-driven therapy in this molecularly defined population. Although overall survival was similar between treatment groups, interpretation is influenced by the study design, which allowed patients progressing on chemotherapy to receive pemigatinib subsequently. Notably, patients who crossed over to pemigatinib continued to derive meaningful clinical benefit, further supporting the activity of FGFR inhibition. The safety profile of pemigatinib was consistent with previous studies, with no unexpected toxicities identified. These findings provide strong evidence that molecular profiling should be routinely incorporated into the management of cholangiocarcinoma to identify patients with actionable FGFR2 alterations. The study marks an important milestone in biliary tract cancer, demonstrating that targeted therapy can outperform conventional chemotherapy in the frontline setting for appropriately selected patients. Overall, FIGHT-302 reinforces FGFR2 rearrangement as a clinically actionable biomarker and supports pemigatinib as a major therapeutic option in the evolving era of precision oncology for cholangiocarcinoma.

Fasting Alone Does Not Stabilize Stomach Volume During Pancreatic SBRT Journal: Practical Radiation Oncology | June 2026

• Pancreatic stereotactic body radiotherapy (SBRT) requires highly precise treatment because the pancreas lies immediately adjacent to radiosensitive organs such as the stomach and duodenum. • Most centers instruct patients to fast before simulation and treatment, assuming that an empty stomach will reduce daily variation and improve treatment reproducibility. • This study evaluated whether a standardized 2-hour fasting protocol actually produces consistent stomach volumes during pancreatic SBRT. • Seventy-four patients undergoing pancreatic SBRT were analyzed with repeated imaging throughout treatment. • The results showed that fasting instructions alone were insufficient for many patients. • Approximately 58% of patients demonstrated substantial day-to-day stomach volume variability despite following identical fasting instructions. • Patients with larger stomach volumes at simulation were more likely to show significant variation during treatment. • A baseline stomach volume of approximately >200 cc identified patients at higher risk for inter-fraction variability. • Surprisingly, total stomach volume correlated poorly with the volume of stomach located near the treatment target. • This finding is clinically important because radiation toxicity depends primarily on the stomach immediately adjacent to the planning target volume rather than the total gastric volume. • Simply measuring overall stomach size may therefore be inadequate when assessing radiation risk. • The study challenges the common assumption that uniform fasting instructions guarantee reproducible anatomy during pancreatic radiation therapy. • Adaptive radiotherapy, image guidance, and individualized preparation strategies may remain necessary despite fasting protocols. • Baseline simulation imaging may help identify patients who require more intensive motion management or adaptive planning. • The findings are particularly relevant as pancreatic SBRT continues to expand and dose escalation strategies increasingly rely on precise organ-at-risk avoidance. Bottom line: A standard 2-hour fasting protocol does not reliably produce consistent stomach volumes during pancreatic SBRT. Patients with larger baseline stomach volumes are particularly prone to day-to-day variability, highlighting the need for individualized image-guided and adaptive treatment strategies.

DOTATATE PET and Poorly Differentiated Extrapulmonary NEC: JNM | June 2026

• Somatostatin receptor (SSTR) imaging with ⁶⁸Ga-DOTATATE PET is a cornerstone for well-differentiated neuroendocrine tumours, but its role in poorly differentiated neuroendocrine carcinoma (NEC) has remained uncertain. • Previous retrospective studies suggested that up to 40% of NECs might demonstrate strong somatostatin receptor expression, raising interest in peptide receptor radionuclide therapy (PRRT) for these patients. • This prospective study was designed to provide a more accurate assessment by evaluating an unselected cohort of metastatic extrapulmonary NEC patients. • Thirty patients with metastatic extrapulmonary NEC underwent ⁶⁸Ga-DOTATATE PET, and most also underwent ¹⁸F-FDG PET. • Primary tumour sites included pancreas, colorectum, uterus, and cancers of unknown primary origin. • Histologies included both small-cell and large-cell neuroendocrine carcinoma. • The key finding was that uniform, high-level somatostatin receptor expression was uncommon. • Only 13% of patients demonstrated strong, homogeneous DOTATATE uptake consistent with high SSTR expression. • The vast majority of tumors showed either: Absent SSTR expression Patchy/heterogeneous receptor expression Predominantly FDG-avid biology • These findings suggest that most poorly differentiated NECs retain aggressive glycolytic behaviour rather than the receptor-rich phenotype typically seen in well-differentiated NETs. • The study challenges previous reports that may have overestimated SSTR positivity because of selection bias or inclusion of tumours with lower Ki-67 indices. • Clinically, this means that routine DOTATATE PET scanning is unlikely to identify large numbers of poorly differentiated NEC patients suitable for PRRT. • However, a small subset of NEC patients may still demonstrate strong receptor expression and could remain candidates for receptor-targeted therapies. • Dual-tracer imaging with FDG PET and DOTATATE PET may be particularly useful when considering individualised treatment strategies. • The findings reinforce the biological distinction between well-differentiated NETs and poorly differentiated NECs. Bottom line: Strong and uniform somatostatin receptor expression is present in only a small minority of patients with metastatic extrapulmonary poorly differentiated NEC. Most NECs remain predominantly FDG-avid tumours, limiting the routine applicability of DOTATATE-based imaging and PRRT in this population.

Fasting Alone Does Not Stabilise Stomach Volume During Pancreatic SBRT: Practical Radiation Oncology | June 2026

• Pancreatic stereotactic body radiotherapy (SBRT) requires highly precise treatment because the pancreas lies immediately adjacent to radiosensitive organs such as the stomach and duodenum. • Most centres instruct patients to fast before simulation and treatment, assuming that an empty stomach will reduce daily variation and improve treatment reproducibility. • This study evaluated whether a standardised 2-hour fasting protocol actually produces consistent stomach volumes during pancreatic SBRT. • Seventy-four patients undergoing pancreatic SBRT were analysed with repeated imaging throughout treatment. • The results showed that fasting instructions alone were insufficient for many patients. • Approximately 58% of patients demonstrated substantial day-to-day stomach volume variability despite following identical fasting instructions. • Patients with larger stomach volumes at simulation were more likely to show significant variation during treatment. • A baseline stomach volume of approximately >200 cc identified patients at higher risk for inter-fraction variability. • Surprisingly, total stomach volume correlated poorly with the volume of stomach located near the treatment target. • This finding is clinically important because radiation toxicity depends primarily on the stomach immediately adjacent to the planning target volume rather than the total gastric volume. • Simply measuring overall stomach size may therefore be inadequate when assessing radiation risk. • The study challenges the common assumption that uniform fasting instructions guarantee reproducible anatomy during pancreatic radiation therapy. • Adaptive radiotherapy, image guidance, and individualised preparation strategies may remain necessary despite fasting protocols. • Baseline simulation imaging may help identify patients who require more intensive motion management or adaptive planning. • The findings are particularly relevant as pancreatic SBRT continues to expand and dose escalation strategies increasingly rely on precise organ-at-risk avoidance. Bottom line: A standard 2-hour fasting protocol does not reliably produce consistent stomach volumes during pancreatic SBRT. Patients with larger baseline stomach volumes are particularly prone to day-to-day variability, highlighting the need for individualised image-guided and adaptive treatment strategies.

Multimodality Therapy Remains Key in Recurrent Rectal Cancer : Cancer | June 2026

Introduction: Locoregionally recurrent rectal cancer (LRRC) remains one of the most challenging scenarios in colorectal oncology. Recurrence within the pelvis is often associated with significant morbidity, impaired quality of life, and limited treatment options. Advances in surgery, radiation therapy, systemic therapy, and imaging have improved outcomes; however, optimal management requires careful integration of multiple treatment modalities and expertise across specialties. Problem Statement: The management of LRRC is highly individualized and influenced by prior treatments, anatomical location of recurrence, extent of disease, and resectability. Given the complexity of these cases, clinicians require evidence-based guidance to determine the most appropriate combination and sequencing of therapies while maximizing the chance of durable disease control. Summary: This American Radium Society Appropriate Use Criteria review provides comprehensive multidisciplinary guidance for the management of locoregionally recurrent rectal cancer. Drawing upon evidence from more than 100 studies and expert consensus, the document reinforces that achieving a margin-negative (R0) surgical resection remains the most important determinant of long-term survival and local disease control. The guidelines emphasize that successful surgery often depends on appropriate use of preoperative therapies, including systemic chemotherapy, radiation therapy, or combined-modality approaches, which can facilitate tumor downsizing and improve resectability. Treatment decisions should be tailored according to prior treatment exposure, recurrence location, and disease extent, highlighting the importance of individualized care planning. The review strongly advocates for management within experienced multidisciplinary teams involving colorectal surgeons, radiation oncologists, medical oncologists, radiologists, and gastroenterologists. While the recommendations do not fundamentally alter current treatment paradigms, they provide important validation of contemporary practice and underscore the continued value of combined-modality therapy in improving outcomes. Overall, the guidance supports a personalized, multidisciplinary strategy focused on maximizing the likelihood of complete resection while integrating systemic and local therapies to optimize survival and local control in patients with recurrent rectal cancer.

Nal-IRI Improves Second-Line Outcomes in Pancreatic Cancer : Pancreatology | June 2026

Introduction: Despite advances in systemic therapy, metastatic and recurrent pancreatic cancer remains associated with poor survival. Following progression on first-line gemcitabine-based chemotherapy, treatment options have historically been limited. The introduction of nanoliposomal irinotecan (nal-IRI) combined with 5-fluorouracil and leucovorin (5-FU/LV) represented an important therapeutic advance, demonstrating improved efficacy in clinical trials. However, whether this benefit translates into routine clinical practice has remained uncertain. Problem Statement: Clinical trial populations often differ from real-world patients encountered in daily oncology practice. Consequently, it is important to determine whether the availability of nal-IRI has meaningfully improved survival outcomes for patients with metastatic or recurrent pancreatic cancer outside controlled trial settings. Summary: This real-world study compared treatment outcomes in patients with metastatic or recurrent pancreatic cancer before and after the introduction of nal-IRI plus 5-FU/LV as a second-line treatment option. The investigators found that while overall survival from the start of first-line therapy remained largely unchanged, patients treated in the era following nal-IRI availability experienced significantly improved outcomes after progression on first-line treatment. Both progression-free survival and overall survival from initiation of second-line therapy were prolonged following the introduction of nal-IRI-based treatment. Furthermore, multivariable analysis identified treatment in the nal-IRI era as an independent predictor of improved second-line survival. These findings suggest that access to effective second-line therapy can meaningfully influence outcomes even in a disease with historically limited treatment options. Importantly, the survival benefits were achieved with an acceptable safety profile, supporting the feasibility of this regimen in routine practice. The study provides valuable real-world evidence confirming that the benefits observed in clinical trials can be translated into everyday clinical care. Overall, the results support nal-IRI plus 5-FU/LV as an important component of the treatment sequence for metastatic and recurrent pancreatic cancer and highlight the growing importance of effective second-line therapy in improving patient outcomes.

Early-Onset Cancers Rising Selectively in Spain : Ann Oncol | June 2026

Introduction: Concerns regarding increasing cancer incidence among adults younger than 50 years have gained global attention over the past decade. Reports from several countries have suggested a rise in early-onset cancers, particularly those affecting the gastrointestinal tract and other obesity-related malignancies. Understanding these trends is essential for guiding prevention strategies, public health policies, and future research into potential environmental and lifestyle drivers. Problem Statement: Although increasing rates of early-onset cancer have been reported internationally, population-based data from Southern Europe remain limited. It is unclear whether similar patterns are occurring in Spain and whether observed trends differ according to cancer type, age group, and sex. Summary: This large population-based study from the Spanish Network of Cancer Registries provides a comprehensive assessment of cancer incidence trends among adults aged 20–49 years over a 25-year period. The investigators found that changes in cancer incidence were highly heterogeneous rather than representing a universal increase across all cancer types. Notably, more rising trends were observed among women than men. Several cancers demonstrated increasing incidence, including pancreatic cancer and lymphomas in women, and kidney, thyroid, and Hodgkin lymphoma in men. Of particular relevance to gastroenterologists and oncologists, stomach, colon, and rectal cancers showed increasing incidence among the youngest adults, supporting growing concerns regarding early-onset gastrointestinal malignancies. In contrast, cancers strongly associated with tobacco exposure—including lung, laryngeal, bladder, and liver cancers—declined substantially in both sexes, reflecting the success of long-term tobacco control efforts. A key finding was that the increase in several obesity-associated cancers was largely confined to individuals aged 20–39 years, suggesting that changing metabolic and lifestyle factors may be contributing to cancer risk in younger generations. These observations reinforce the emerging global pattern linking obesity and metabolic dysfunction to rising early-onset cancer incidence. Overall, the study highlights the need for strengthened cancer prevention initiatives focused on modifiable lifestyle factors and emphasizes the importance of further research to clarify the biological and environmental mechanisms driving the increase in selected cancers among younger adults.

B-Cell Dysfunction Drives Immune Escape in iCCA : Gut | June 2026

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is one of the most aggressive primary liver malignancies, characterized by poor survival and limited therapeutic options. Although recent advances in immunotherapy have offered new treatment opportunities, response rates remain modest. A major obstacle is the highly complex and immunosuppressive tumor microenvironment, which limits effective antitumor immunity. While T-cell biology has been extensively studied in iCCA, the role of B lymphocytes within the tumor microenvironment remains incompletely understood. Problem Statement: B cells are increasingly recognized as important regulators of antitumor immunity, yet their functional significance in iCCA is unclear. Understanding how tumor-associated factors influence B-cell differentiation and activity may identify novel biomarkers of treatment response and uncover new therapeutic strategies to improve immunotherapy outcomes. Summary: This comprehensive translational study provides important insights into the role of B cells in the immune landscape of iCCA. The investigators demonstrated that B cells located in adjacent non-tumorous tissues frequently formed mature tertiary lymphoid structures (TLS), which were associated with more favorable clinical outcomes. In contrast, B cells infiltrating the tumor itself were scarce, immature, and exhibited impaired immune function with prominent immunosuppressive characteristics. Mechanistic analyses revealed that interactions with tumor cells and cancer-associated fibroblasts actively suppress B-cell maturation and effector activity. The cytokines IL-6 and TGF-β emerged as key mediators of this dysfunction, and simultaneous blockade of these pathways restored B-cell activation and differentiation in experimental models. Importantly, patients with higher levels of circulating BAFFR-positive B cells and expanded B-cell clonotypes experienced better responses to chemoimmunotherapy, suggesting potential predictive biomarkers for treatment selection. These findings highlight B cells as previously underappreciated contributors to immune regulation in iCCA and suggest that restoring B-cell function may enhance antitumor immunity. The study provides a strong rationale for developing therapeutic strategies aimed at reversing B-cell suppression and promoting mature TLS formation, potentially improving the effectiveness of immunotherapy in this difficult-to-treat malignancy.

RTOG 0848: Adjuvant Chemoradiotherapy Fails Overall, but Node-Negative Patients May get benifit: JCO| June 2026

• RTOG 0848 is one of the largest randomized phase III trials evaluating the role of adjuvant chemoradiotherapy after curative-intent resection of pancreatic head adenocarcinoma. • The study addressed a long-standing controversy in pancreatic cancer: does adding fluoropyrimidine-sensitized radiotherapy after adjuvant chemotherapy improve outcomes? • Patients first received adjuvant gemcitabine-based chemotherapy and, if disease-free after five cycles, were randomized to receive the sixth cycle alone or combined with chemoradiotherapy. • A total of 354 patients were randomized between chemotherapy alone and chemotherapy plus chemoradiotherapy. • The primary endpoint was overall survival, and the study was formally negative. • Median overall survival was similar between the two groups, and the addition of chemoradiotherapy did not significantly improve overall survival. • Disease-free survival showed a favorable trend with chemoradiotherapy, but this did not reach conventional statistical significance. • Importantly, adding radiotherapy did not increase grade 4 or grade 5 toxicities. • However, grade 3 toxicity was significantly higher in patients receiving chemoradiotherapy. • The most clinically relevant finding emerged from subgroup analysis based on lymph node status. • Patients with node-negative disease experienced significant improvements in both overall survival and disease-free survival when chemoradiotherapy was added. • In contrast, patients with node-positive disease did not derive a similar benefit. • These findings suggest that local disease control may be particularly important in node-negative pancreatic cancer, whereas systemic disease biology may dominate outcomes in node-positive patients. • The trial was conducted in the gemcitabine era, before widespread use of modern regimens such as modified FOLFIRINOX and gemcitabine-capecitabine. • Therefore, the applicability of these findings to contemporary practice remains uncertain and requires validation in the setting of modern systemic therapy. • The results may also support renewed interest in selective use of radiation therapy, particularly in biologically favorable patients with node-negative disease. Bottom line: RTOG 0848 did not demonstrate an overall survival benefit for routine addition of adjuvant chemoradiotherapy after pancreatic cancer resection. However, node-negative patients showed significant improvements in survival outcomes, suggesting that carefully selected patients may still benefit from radiation as part of multimodality treatment.

Underwater Endoscopy for Colorectal Neoplasia : Frontline Gastroenterol | Jun 2026

Introduction: Water-assisted and immersion-based endoscopic techniques are increasingly transforming the diagnosis and treatment of colorectal neoplasia. Unlike conventional gas insufflation, these approaches replace luminal gas with water or saline, creating a different optical and mechanical environment within the gastrointestinal tract. This can improve lesion visualisation, facilitate endoscopic resection, and enhance patient comfort. Over the past decade, underwater techniques have evolved from simple insertion methods to advanced therapeutic platforms for complex colorectal lesions. Problem Statement: Despite major advances in colonoscopy and endoscopic resection, challenges remain in optimizing adenoma detection, improving procedural comfort, and achieving safe and effective removal of complex colorectal neoplasms. Conventional techniques may be limited by suboptimal visualisation, difficult lesion access, and procedural complexity. There is growing interest in whether underwater and immersion-assisted approaches can overcome these limitations and improve both diagnostic and therapeutic outcomes. Summary: This review highlights the expanding role of underwater endoscopy across the spectrum of colorectal neoplasia management. Water-aided colonoscopy (WAC) has been associated with improved patient tolerance, enhanced bowel cleanliness, better adenoma detection, and smoother procedural performance. Underwater endoscopic mucosal resection (U-EMR) has emerged as an effective technique for colorectal lesion removal, offering efficient resection with favorable outcomes and reduced recurrence in selected cases. More recently, saline-immersion strategies such as the Saline-Immersion/Irrigation Technique (SITE) have been incorporated into endoscopic submucosal dissection (ESD). By creating a fluid-filled operative field, SITE may enhance visualisation, provide buoyancy-assisted tissue traction, improve electrosurgical performance, and potentially reduce thermal injury. Early experience suggests that SITE-ESD may simplify technically demanding dissections and improve procedural safety. Collectively, underwater endoscopy is evolving into a comprehensive platform for colorectal neoplasia management, with growing evidence supporting its integration into routine and advanced endoscopic practice. Further standardization and prospective studies will help define its optimal role in modern therapeutic endoscopy.