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Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Panel gene sequencing is an established diagnostic tool for precision oncology of solid tumors, but its utility for the treatment of cancers of the digestive system in clinical routine is less well documented., Methods: We retrospectively identified patients with advanced or metastatic gastrointestinal, pancreaticobiliary or hepatic cancers who received panel gene sequencing at a tertiary university hospital from 2015 to 2022. For these cases, we determined the spectrum of genetic alterations, clinicopathological parameters and treatment courses. Assessment of actionability of genetic alterations was based on the OncoKB database, cancer-specific ESMO treatment guidelines, and recommendations of the local molecular tumor board., Results: In total, 155 patients received panel gene sequencing using either the Oncomine Focus (62 cases), Comprehensive (91 cases) or Childhood Cancer Research Assay (2 cases). The mean age of patients was 61 years (range 24-90) and 37% were female. Most patients suffered from either colorectal cancer (53%) or cholangiocellular carcinoma (19%). 327 genetic alterations were discovered in 123 tumor samples, with an average number of 2.1 alterations per tumor. The most frequently altered genes were TP53, KRAS and PIK3CA. Actionable gene alterations were detected in 13.5-56.8% of tumors, according to ESMO guidelines or the OncoKB database, respectively. Thirteen patients were treated with targeted therapies based on identified molecular alterations, with a median progression-free survival of 8.8 months., Conclusions: Actionable genetic alterations are frequently detected by panel gene sequencing in patients with advanced cancers of the digestive tract, providing clinical benefit in selected cases. However, for the majority of identified actionable alterations, sufficient clinical evidence for targeted treatments is still lacking., (© 2024. The Author(s).)

Pancreatic acinar cell carcinoma (ACC) is a rare malignant disease that displays distinct differences to pancreatic ductal adenocarcinoma. Here, we report the case of a patient with ACC and underlying breast cancer susceptibility gene 2 (BRCA2) germline mutation that developed severe pancreatic panniculitis (PP) during the course of the disease. The patient received a multimodal therapy including surgery, systemic chemotherapy, and targeted therapy with the PARP inhibitor olaparib, resulting in an overall survival of 47 months. Findings from this case are compared to the current knowledge on management of ACC and paraneoplastic PP., Competing Interests: The authors have no conflicts of interest., (Copyright © 2021 by S. Karger AG, Basel.)

In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy, and these drugs have already become essential for the treatment of various noncurable tumors. However, monotherapy in advanced hepatocellular carcinoma (aHCC) failed to show statistically significant improvement.Recently, the combination of atezolizumab and bevacizumab demonstrated efficacy of combining ICI and VEGF inhibition, further substantiating previous data on synergistic mechanisms among respective substance classes.As TKI treatment is currently standard of care for aHCC, and ICIs are approved by the FDA and available in many areas of the world, numerous patients may have been treated with monotherapy of those drugs. However, it remains unclear if failure to monotherapy has an impact on combination therapy. We therefore report a patient well responding to combination therapy despite previous failures to TKI and ICI monotherapy., Competing Interests: Andreas Teufel received fees, travel expenses or project grants from the following companies: IPSEN, Roche, Lilly, Bayer, Esai., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Esophageal cancer is often marked by aggressive tumor growth and poor prognosis. Patient groups who benefit from perioperative therapy are not yet defined. The tumor microenvironment and circulating factors as possible predictors of response and prognosis gain interest. This study aimed to investigate cytokines in patients' serum and tumor tissue with regard to response and prognosis., Results: Median survival between SCC and AC was not different (published previously). Lower levels of CCL11 (Eotaxin-1) and CXCL10 (IP-10) in the tumor tissue were associated with a better prognosis (p = 0.022; p = 0.002). In the AC subgroup higher concentrations of TGF-β3 in serum and corresponding tumor tissue were associated with adverse prognosis (p = 0.035; p = 0.006). An association with histopathological response was found for IL-12(p70) and CXCL10 in patients' sera (p = 0.041; p = 0.032). The tissue levels of TGF-β1 and TGF-β2 were significantly lower in histopathological responders than in nonresponders (p = 0.033; p = 0.007). A similar trend was seen for TGF-β3, without statistical significance (p = 0.097)., Materials and Methods: Preoperative serum samples and corresponding tumor tissue (n = 54), only serum (n = 20) or only tissue (n = 4) were collected from patients undergoing surgery for cT3/4 esophageal squamous cell cancer (SCC) (n = 34) and adenocarcinoma (AC) (n = 44). All samples were taken after neoadjuvant treatment. All patients received perioperative chemo(radio)therapy. Cytokine levels of 17 different cytokines were measured by multiplex immunoassay and correlated with clinicopathological factors., Conclusions: Two chemokines (CCL11 and CXCL10) in posttherapeutic tumor tissue were associated with prognosis in patients with esophageal cancer, lower levels indicating a better prognosis. Lower levels of TGF-β were associated with better response and prognosis in patients with AC.

Background: Antiangiogenic treatment is at the horizon in the palliative treatment of gastric cancer (GC), but data on proangiogenic biomarkers are still limited. The aim of this study was to analyze five proteins with a function in tumor angiogenesis: vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), follistatin, leptin, and platelet endothelial cell adhesion molecule 1 (CD31) in peripheral blood and corresponding tumor tissue., Material and Methods: From 2008-2010, tumor tissue (n = 76) and corresponding preoperative serum (n = 69) of patients with localized GC were collected; 45 had perioperative chemotherapy. Protein serum or tumor lysate levels of these factors were measured by an angiogenesis multiplex immunoassay and correlated with response and survival., Results: Serum Ang-2 had prognostic relevance in the whole study population (P = 0.027). In subgroup analysis, serum VEGF and Ang-2 had prognostic relevance in primarily resected patients (P = 0.028; P = 0.048) but no association was found in neoadjuvantly treated patients. Follistatin concentration in the tumor tissue was associated with prognosis in all patients (P = 0.019). Tumor VEGF concentrations were correlated with histopathologic response (P = 0.011), with patients showing >50% remaining tumor having higher VEGF concentrations. The tissue Ang-2/VEGF ratio was significantly correlated with both clinical and histopathologic response (P = 0.029, P = 0.009). Additionally, the level of leptin in the tissue was associated with clinical response: nonresponding patients had higher leptin levels than those of responding patients (P = 0.032)., Conclusions: Our results show the importance of angiogenetic factors in serum and tumor tissue in GC for prognosis and treatment response. Further trials in larger patient populations are warranted for a further evaluation of proangiogenetic factors as biomarkers in gastrointestinal cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Despite multimodal therapy esophageal cancer often presents with poor prognosis. To improve outcome, tumor angiogenesis and anti-angiogenic therapeutic agents have recently gained importance. However, patient subgroups who benefit from anti-angiogenic therapy are not yet defined. In this retrospective exploratory study we investigated 9 angiogenic factors in patients' serum and tissue samples with regard to their association with clinicopathological parameters, prognosis and response in patients with locally advanced preoperatively treated esophageal cancer., Methods: From 2007 to 2012 preoperative serum and corresponding tumor tissue (n = 54), only serum (n = 20) or only tumor tissue (n = 4) were collected from esophageal squamous cell carcinoma (SCC) (n = 34) and adenocarcinoma of the esophagogastric junction (AEG) (n = 44) staged cT3/4NanyM0/x after preoperative chemo(radio)therapy. Angiogenic cytokine levels in both tissue and serum were measured by multiplex immunoassay., Results: Median survival in all patients was 28.49 months. No significant difference was found in survival between SCC and AEG (p = 0.90). 26 patients were histopathological responders. Histopathological response was associated with prognosis (p = 0.05). Angiogenic factors were associated with the following clinicopathological factors: tumor tissue expression of Angiopoietin-2 and Follistatin was higher in SCC compared to AEG (p = 0.022 and p = 0.001). High HGF and Follistatin expression in the tumor tissue was associated with poor prognosis in all patients (p = 0.037 and p = 0.036). No association with prognosis was found in the patients' serum. Neither patients' serum nor tumor tissue showed an association between angiogenic factors and response to neoadjuvant therapy., Conclusion: Two angiogenic factors (HGF and Follistatin) in posttherapeutic tumor tissue are associated with prognosis in esophageal cancer patients. Biological differences of AEG and SCC with respect to angiogenesis were evident by the different expression of 2 angiogenic factors. Results are promising and should be pursued prospectively, optimally sequentially pre- and posttherapeutically.