Journal of Gastrointestinal Cancer最新文献

{"title":"Novel Strategies for the Management of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Review.","authors":"Tang Haowen, Huo Yuhao, Cao Yinbiao, Meng Xiangfei, Yang Zhanyu, Lu Shichun","doi":"10.1007/s12029-026-01554-3","DOIUrl":"10.1007/s12029-026-01554-3","url":null,"abstract":"<p><p>Portal vein tumor thrombus (PVTT) occurs in more than half of patients with hepatocellular carcinoma (HCC) and is associated with markedly shortened survival and a poor prognosis. Historically, management relied mainly on locoregional therapies or upfront surgical resection, but outcomes remained unsatisfactory. In recent years, immune checkpoint inhibitors (ICIs) combined with antiangiogenic targeted therapy have substantially changed the systemic treatment landscape for advanced HCC and created new opportunities for patients with unresectable or borderline-resectable HCC with PVTT to undergo conversion therapy followed by sequential surgery (CT-S). This review summarizes conventional treatment strategies for HCC with PVTT; the biologic rationale and clinical evidence for the conversion therapy based on the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic targeted drugs; patient selection and response assessment for CT-S; surgical timing and perioperative management; modified techniques for portal vein management; imaging assessment. Available evidence suggests that CT-S may improve oncologic outcomes in carefully selected patients. However, the evidence is derived predominantly from single-arm studies, retrospective cohorts, and real-world investigations. Multicenter prospective studies are therefore required to define criteria for successful conversion, establish the optimal washout interval, clarify postoperative adjuvant strategies, and determine the generalizability of this approach.</p>","PeriodicalId":15895,"journal":{"name":"Journal of Gastrointestinal Cancer","volume":"57 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-Agnostic and Histology-Tuned Targeted Therapies in Gastrointestinal Cancers: NTRK and RET Fusions and the Evolving Role of Molecular Basket Strategies.","authors":"Tamotsu Sagawa, Masahiro Hirakawa, Hiroyuki Nagashima, Koshi Fujikawa","doi":"10.1007/s12029-026-01586-9","DOIUrl":"10.1007/s12029-026-01586-9","url":null,"abstract":"<p><p>Tumor-agnostic targeted therapy has expanded precision oncology by allowing selected molecular alterations to guide treatment across conventional organ boundaries. In gastrointestinal (GI) cancers, however, actionability is not uniformly independent of histology. This narrative review examines NTRK and RET fusions as paradigmatic tumor-agnostic targets and contrasts them with histology-tuned or GI-specific fusion-directed strategies, particularly NRG1 fusion-positive pancreatic adenocarcinoma and cholangiocarcinoma. Targeted PubMed/MEDLINE and regulatory-agency searches were updated through August 3, 2026. In the initial 55-patient larotrectinib analysis, ORR was 75% by independent review and 80% by investigator assessment; the subsequent expanded pooled analysis reported an investigator-assessed ORR of 79%. By contrast, the dedicated NAVIGATE GI cohort reported an independent-review ORR of 28% across GI cancers and 44% in colorectal cancer. These estimates derive from different cohorts and assessment methods and should not be interpreted as a formal cross-trial comparison. Mature TRIDENT-1 data support repotrectinib in both TRK inhibitor-naive and pretreated disease, including solvent-front mutations. Selpercatinib received traditional US approval in July 2026, whereas zenocutuzumab provides GI-specific options for NRG1 fusion-positive pancreatic and biliary cancers. We separate two dimensions of clinical portability: whether response magnitude is preserved across histologies and whether drug choice, combination, or treatment sequence must be modified for a specific tumor type. MSI-H/dMMR shows high magnitude portability with histology-specific positioning, whereas available dedicated GI data for NTRK fusion illustrate that a tumor-agnostic label does not guarantee a uniform effect size across histologies. Practical implementation requires quantitative prevalence estimates, appropriately selected DNA- and RNA-based testing, recognition of false-positive and false-negative pan-TRK immunohistochemistry, molecular tumor-board interpretation, timely access, and resistance-informed reprofiling. Tumor-agnostic approvals create opportunities, but GI-specific biology determines how reliably and when those opportunities should be used.</p>","PeriodicalId":15895,"journal":{"name":"Journal of Gastrointestinal Cancer","volume":"57 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Barriers and Priorities for Immunotherapy Implementation in Advanced Gastric Cancer: Findings from a Two-Phase Qualitative Study.","authors":"Angela Ragonese, Mario Airoldi, Maria Costanza Aquilano, Graziana Arborea, Katia Bencardino, Federica Castri, Ferdinando De Vita, Claudio Lotesoriere, Iacopo Panarese, Paolo Pochettino, Maria Antonietta Satolli, Antonia Strippoli, Annamaria Valentini, Paolo Sciattella","doi":"10.1007/s12029-026-01557-0","DOIUrl":"10.1007/s12029-026-01557-0","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy has changed the therapeutic approach to advanced gastric cancer (AGC) and has shown survival benefits compared with standard chemotherapy. However, in clinical practice, its use remains heterogeneous. Differences in diagnostic pathways, organisational aspects, and regional settings may lead to delays in treatment access. This study aimed to analyse these issues and to describe possible shared strategies to improve the use of immunotherapy in AGC in Italy.</p><p><strong>Materials and methods: </strong>The analysis was performed in two steps. First, a focus group comprising 13 oncologists and pathologists from 5 national reference centres was organised to collect information on the use of immunotherapy biomarker tests and the main barriers encountered in daily practice. Based on the topics emerging from this discussion, a second step was conducted using a consensus questionnaire. The questionnaire was sent to a multidisciplinary group composed of 19 oncologists, pathologists, surgeons, pharmacists, and endoscopists.</p><p><strong>Results: </strong>Several common problems were reported during the focus group discussion. These included delays in biomarker testing, differences in pre-analytical procedures among centres, the absence of shared quality indicators, and difficulties in tracking tissue samples, especially when samples were sent from outside hospitals. In addition, limited interaction among different specialists was frequently mentioned. The results of the questionnaire indicated a high level of agreement on several proposed actions, such as the evaluation of regional differences, the use of organisational models already adopted in some Italian oncology networks, the introduction of new biomarkers together with dedicated training activities, and the use of digital tools to support the discussion of complex cases. All survey items reached the predefined consensus threshold.</p><p><strong>Conclusions: </strong>This study identified several organizational and diagnostic challenges affecting the implementation of immunotherapy in AGC. Participants highlighted a number of potential priorities for improvement, including optimization of diagnostic workflows, stronger multidisciplinary collaboration, and greater coordination across centres. These findings may inform future initiatives aimed at reducing variability in clinical practice and supporting equitable access to innovative treatments.</p>","PeriodicalId":15895,"journal":{"name":"Journal of Gastrointestinal Cancer","volume":"57 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intraoperative Systemic Chemotherapy in Stage II-III Appendiceal Adenocarcinoma: A National Cancer Database Analysis.","authors":"Michal Perets, Noam Kahana, Michael R Freund, Nir Horesh, Maher Al Khaldi, Zubair Bayat, Marylise Boutros, Sameh Hany Emile","doi":"10.1007/s12029-026-01587-8","DOIUrl":"10.1007/s12029-026-01587-8","url":null,"abstract":"<p><strong>Background: </strong>Appendiceal adenocarcinoma is a rare malignancy with a high risk of peritoneal recurrence, especially in locally advanced stages. While intraoperative systemic chemotherapy (ISC) is standard for metastatic disease, its role in non-metastatic Stage II-III patients remains controversial. This study aimed to evaluate the survival benefit of ISC in this population.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study using the National Cancer Database (2006-2022). Patients with clinical Stage II-III (T4, N0-2) appendiceal adenocarcinoma who underwent surgical resection were included. Overall survival (OS) was compared between patients who received ISC and controls using Kaplan-Meier statistics and multivariable Cox proportional hazard models.</p><p><strong>Results: </strong>A total of 616 patients were identified, 130 (21.1%) of whom received ISC. Patients receiving ISC were more often younger, treated at academic centers, and had mucinous histology. In the unadjusted analysis, ISC was associated with a significantly longer median OS (193.8 vs. 67.7 months, p < 0.001). This survival benefit was significant for Stage II disease (p = 0.007) but not for Stage III (p = 0.43). However, after adjusting for age, grade, clinical stage, and margin status in a multivariable model, ISC was not an independent predictor of improved OS (HR 0.87, 95% CI 0.52-1.47, p = 0.611). In a subgroup analysis of only patients with mucinous and signet-ring cell carcinoma revealed that ISC was independently associated with improved OS (HR: 0.184, 95%CI: 0.044-0.762, p = 0.020).</p><p><strong>Conclusion: </strong>The findings of this large national cohort do not support the routine use of intraoperative chemotherapy in all patients with non-metastatic appendiceal cancer. However, intraoperative chemotherapy may be associated with an independent survival benefit in patients with mucinous and signet-ring cell carcinomas.</p>","PeriodicalId":15895,"journal":{"name":"Journal of Gastrointestinal Cancer","volume":"57 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of Claudin 18.2 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma: A Systematic Review and Meta-Analysis.","authors":"Fazal Elahi Khan, Rajendranandini Majumdar, Mohan Dodeja, Gabriel Amorim Moreira Alves, Amr Harby, Rida Siddiqui, Shahbaz Madappattuparambil","doi":"10.1007/s12029-026-01588-7","DOIUrl":"10.1007/s12029-026-01588-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Claudin 18 isoform 2 (CLDN18.2) has emerged as a clinically validated therapeutic target in gastric and gastroesophageal junction (GEJ) adenocarcinoma following the regulatory approval of zolbetuximab in combination with first-line chemotherapy. Accurate prevalence data at the clinically validated immunohistochemical threshold are essential for patient selection, healthcare resource planning, and treatment strategy. Reported prevalence estimates vary widely across studies due to differences in populations, methodologies, and immunohistochemical protocols. This systematic review and meta-analysis aimed to generate a robust pooled prevalence estimate of CLDN18.2 expression at the threshold used in pivotal phase III trials.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;PubMed, Embase, and the Cochrane Library were searched from database inception through March 12th, 2026. Studies reporting CLDN18.2 expression in gastric or gastroesophageal junction adenocarcinoma using the ≥ 75% moderate-to-strong membranous staining threshold were included. Prevalence proportions were pooled using a random-effects model with logit transformation and restricted maximum-likelihood estimation of between-study variance. Heterogeneity was assessed using the I² statistic and Cochran's Q test, and a 95% prediction interval was calculated. Pre-specified subgroup analyses assessed antibody clone and geographic region, with additional exploratory analyses according to disease setting and specimen type. Sensitivity analyses were performed to assess the robustness of the pooled estimate.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Twenty-two predominantly retrospective cohort studies comprising 12,173 patients were included. The pooled prevalence of CLDN18.2 positivity using a random-effects model was 33.99% (95% CI: 30.13%-38.07%; 95% prediction interval: approximately 18%-55%), with high between-study heterogeneity (I² = 92.4%). Subgroup analysis by antibody clone showed no statistically significant difference between studies using the 43-14 A clone (32.79%, 95% CI: 28.86%-36.97%) and those using other reported antibody clones (41.74%, 95% CI: 26.76%-58.42%; p = 0.281). One study with an unreported antibody clone was excluded from this subgroup analysis. Geographic subgroup analysis excluding the multinational Shitara et al. cohort demonstrated a non-significant trend toward higher prevalence in non-Asian populations (37.85%, 95% CI: 31.59%-44.54%) compared with Asian populations (32.10%, 95% CI: 27.28%-37.34%; p = 0.169). All three sensitivity analyses confirmed robustness of the pooled estimate. No significant evidence of publication bias was detected (Egger's test p = 0.56).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Approximately one-third of patients with gastric and GEJ adenocarcinoma express CLDN18.2 at the clinically validated ≥ 75% threshold. However, because the included studies encompassed heterogeneous disease settings and were predominantly HER2-unselected, the p","PeriodicalId":15895,"journal":{"name":"Journal of Gastrointestinal Cancer","volume":"57 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research Progress and Optimization Strategies of Bispecific Antibody Therapies for CLDN18.2-Positive Gastric Cancer.","authors":"Panpan Ji, Miaomiao Li, Jinyue Chen, Tingting Wen, Wanhong Chen, Jing Wang, Juan Li","doi":"10.1007/s12029-026-01584-x","DOIUrl":"10.1007/s12029-026-01584-x","url":null,"abstract":"<p><p>CLDN18.2 is specifically overexpressed in gastric cancer tissues and represents an important emerging therapeutic target in gastriccancer treatment. Bispecific antibodies (BsAbs), a class of antibody-based therapeutics capable of simultaneously targeting two antigensites, have recently entered clinical development for the treatment of CLDN18.2-positive gastric cancer. This review systematicallysummarizes the molecular designs, functional subtypes, and clinical development of CLDN18.2-related BsAbs, while analyzing currentchallenges and potential optimization strategies. Currently, CLDN18.2-related BsAbs that have entered clinical development mainlycomprise three categories: T-cell engagers, T-cell costimulators, and immune checkpoint-blocking BsAbs. These agents havedemonstrated preliminary antitumor activity in later-line monotherapy and first-line combination therapy settings, with generallymanageable safety profiles. Optimization of target combinations, precise patient selection, strategies to overcome efficacy limitations, and improved safety management represent important directions for enhancing the therapeutic value of BsAb-based approaches.</p>","PeriodicalId":15895,"journal":{"name":"Journal of Gastrointestinal Cancer","volume":"57 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemotherapy After Immune Checkpoint Inhibitor Exposure in Advanced Gastric Cancer: Clinical Evidence and Treatment Sequencing in the ICI Era.","authors":"Tamotsu Sagawa, Hiroyuki Nagashima, Koshi Fujikawa","doi":"10.1007/s12029-026-01575-y","DOIUrl":"10.1007/s12029-026-01575-y","url":null,"abstract":"<p><strong>Purpose: </strong>The incorporation of immune checkpoint inhibitors (ICIs) into first-line therapy has changed the treatment landscape of advanced gastric and gastroesophageal junction cancer. This review summarizes the clinical evidence for chemotherapy after prior ICI exposure, discusses potential biological mechanisms, and considers practical treatment sequencing in the ICI era.</p><p><strong>Methods: </strong>We conducted a targeted narrative review of PubMed/MEDLINE and major oncology congress proceedings through July 19, 2026. Original clinical studies reporting outcomes of systemic chemotherapy after prior ICI exposure in advanced gastric or gastroesophageal junction cancer were prioritized, with selected evidence from other tumor types and mechanistic studies included for context.</p><p><strong>Results: </strong>Retrospective and observational studies suggest that chemotherapy after anti-PD-1 therapy can retain clinically meaningful activity, although the evidence is heterogeneous and largely non-randomized. Taxane plus ramucirumab is the most extensively studied post-ICI regimen, but available data in the contemporary first-line-ICI setting do not establish superiority over other guideline-supported second-line options. Whether favorable outcomes reflect true immunologic chemosensitization, residual immune activation interacting with subsequent cytotoxic or anti-angiogenic therapy, or patient selection remains unresolved.</p><p><strong>Conclusion: </strong>Current evidence supports individualized selection among guideline-recommended second-line regimens, including taxane plus ramucirumab, single-agent taxane, and irinotecan, after first-line fluoropyrimidine/platinum plus ICI. Prospective post-ICI validation and biomarker-integrated studies are needed.</p>","PeriodicalId":15895,"journal":{"name":"Journal of Gastrointestinal Cancer","volume":"57 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Zolbetuximab: Next-Generation Targeting Strategies for CLDN18.2.","authors":"Tamotsu Sagawa, Hiroyuki Nagashima, Koshi Fujikawa","doi":"10.1007/s12029-026-01577-w","DOIUrl":"10.1007/s12029-026-01577-w","url":null,"abstract":"<p><strong>Purpose: </strong>Claudin 18 isoform 2 (CLDN18.2) has emerged as a clinically actionable target in gastric and gastroesophageal junction adenocarcinoma. Zolbetuximab plus chemotherapy established the first validated CLDN18.2-directed strategy, but also highlighted clinically important limitations: incomplete primary sensitivity, spatial and temporal heterogeneity of antigen expression, gastrointestinal toxicity, uncertain biomarker persistence after treatment, and the absence of an evidence-based sequence after progression. These limitations have accelerated development of antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies, T-cell engagers, and rational combinations with chemotherapy or immune checkpoint blockade.</p><p><strong>Methods: </strong>This review summarizes current evidence through July 2026, examines plausible mechanisms of resistance and biomarker evolution, and proposes a cautious, modality-specific framework for future clinical development.</p><p><strong>Results: </strong>Updated clinical data support proof of concept across multiple modalities. IBI343, an exatecan-based ADC, has shown antitumor activity with predominantly hematologic toxicity; vedotin-based ADCs demonstrate a different linker-payload profile with additional concern for microtubule-related cumulative toxicity. Randomized phase II data with satricabtagene autoleucel have established progression-free survival benefit over treatment of physician's choice in previously treated disease, although lymphodepletion-related cytopenias and cytokine-release syndrome require specialized infrastructure. Early studies of givastomig and IBI389 further support immune-engaging approaches.</p><p><strong>Conclusion: </strong>Tissue immunohistochemistry remains the reference method for treatment selection; circulating tumor DNA cannot currently reproduce membranous protein intensity or spatial distribution, and liquid-biopsy approaches for CLDN18.2 reassessment remain investigational.</p>","PeriodicalId":15895,"journal":{"name":"Journal of Gastrointestinal Cancer","volume":"57 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Advanced Lung Cancer Inflammation Index Is Not Independently Prognostic for Overall Survival in De Novo Metastatic Pancreatic Cancer: A Comparison with Established Inflammation- and Nutrition-based Scores.","authors":"Rıfat Furkan Aydın, Elif Berna Köksoy","doi":"10.1007/s12029-026-01585-w","DOIUrl":"10.1007/s12029-026-01585-w","url":null,"abstract":"<p><strong>Purpose: </strong>The Advanced Lung Cancer Inflammation Index (ALI) combines body mass index, serum albumin, and the neutrophil-to-lymphocyte ratio, but overlaps with many other prognostic scores in pancreatic ductal adenocarcinoma (PDAC). We evaluated whether ALI is independently prognostic in de novo metastatic PDAC and whether it adds information beyond performance status and established scores.</p><p><strong>Methods: </strong>In this single-centre retrospective cohort of patients with de novo metastatic PDAC diagnosed between 2019 and 2023, ALI was calculated at diagnosis. It was compared head-to-head with NLR, PNI, mGPS, CONUT, SII, PLR, LMR, and HALP using Harrell's concordance index (C-index), and its incremental value over a clinical model (ECOG performance status, CA 19 - 9, liver metastasis, age) was quantified with bootstrap internal validation.</p><p><strong>Results: </strong>Of 102 patients, 101 were analysable (47 deaths; median follow-up 14.3 months). Low ALI (≤ 26.4) was associated with shorter median overall survival than high ALI (10.6 vs. 21.8 months; hazard ratio 1.97; p = 0.025), but this was not independent after multivariable adjustment for performance status (adjusted hazard ratio 1.62, 95% CI 0.85-3.09; p = 0.144). Discrimination was modest (C-index 0.591) and did not exceed that of mGPS (0.630), LMR (0.608), or NLR (0.596); adding ALI to the clinical model did not improve discrimination (ΔC-index - 0.001). A worst-case analysis for loss to follow-up was the only specification in which ALI remained independent.</p><p><strong>Conclusion: </strong>In de novo metastatic PDAC, ALI is not independently prognostic after adjustment for performance status and offers no discriminative advantage over simpler, established inflammation-based scores.</p>","PeriodicalId":15895,"journal":{"name":"Journal of Gastrointestinal Cancer","volume":"57 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging Therapeutic Strategies for Non-G12C KRAS Mutations in Colorectal Cancer: Focusing on G12D and G12V.","authors":"Tamotsu Sagawa, Masahiro Hirakawa, Hiroyuki Nagashima, Koshi Fujikawa","doi":"10.1007/s12029-026-01579-8","DOIUrl":"10.1007/s12029-026-01579-8","url":null,"abstract":"<p><strong>Purpose: </strong>KRAS mutations are present in approximately 40-45% of colorectal cancers (CRC), but currently approved KRAS-directed therapies address only the small G12C subset. G12D and G12V account for a much larger proportion of KRAS-mutant CRC and remain major unmet therapeutic targets. This review summarizes emerging strategies for non-G12C KRAS-mutant CRC.</p><p><strong>Methods: </strong>Current preclinical, translational, and early clinical evidence was narratively synthesized, focusing on allele-specific G12D and G12V inhibitors, pan-RAS approaches, upstream SOS1/SHP2 co-targeting, anti-EGFR combinations, immune-based strategies, and tissue and circulating tumor DNA profiling.</p><p><strong>Results: </strong>The development of MRTX1133, zoldonrasib (RMC-9805), VS-7375, RMC-5127, and daraxonrasib (RMC-6236) demonstrates that direct targeting of previously undruggable KRAS alleles is becoming clinically feasible. In CRC, however, EGFR-mediated feedback reactivation of wild-type RAS remains a central resistance mechanism, making anti-EGFR combination strategies particularly important.Tissue and circulating tumor DNA profiling may support patient selection, monitoring of clonal evolution, and characterization of acquired resistance.</p><p><strong>Conclusion: </strong>The non-G12C KRAS era is beginning, but durable benefit in CRC will likely require rational combinations tailored to allele, lineage, and resistance biology.</p>","PeriodicalId":15895,"journal":{"name":"Journal of Gastrointestinal Cancer","volume":"57 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}