Pub Date : 2026-01-14DOI: 10.1016/j.esmogo.2025.100271
C. Smolenschi , M. Rémond , M. Valéry , M. Brugel , M. Ducreux , A. Turpin , A. Boilève
Biliary tract cancer and pancreatic cancer are aggressive malignancies, typically diagnosed in patients >50 years of age. Lately, <50 years of age has been rising, presenting unique challenges and clinical features that distinguish them from late-onset cases.
Here, we review the clinical, biological, and molecular characteristics of early-onset biliary tract cancer and pancreatic cancer and compare them with their late-onset counterparts. We also examine treatment patterns, efficacy, and the potential role of targeted therapies, as well as the potential psychological and social effects on younger patients, with particular emphasis on fertility. We therefore offer insights into the unique challenges and therapeutic strategies in managing early-onset disease.
{"title":"Clinical and molecular characteristics of early-onset pancreatic and biliary cancers","authors":"C. Smolenschi , M. Rémond , M. Valéry , M. Brugel , M. Ducreux , A. Turpin , A. Boilève","doi":"10.1016/j.esmogo.2025.100271","DOIUrl":"10.1016/j.esmogo.2025.100271","url":null,"abstract":"<div><div>Biliary tract cancer and pancreatic cancer are aggressive malignancies, typically diagnosed in patients >50 years of age. Lately, <50 years of age has been rising, presenting unique challenges and clinical features that distinguish them from late-onset cases.</div><div>Here, we review the clinical, biological, and molecular characteristics of early-onset biliary tract cancer and pancreatic cancer and compare them with their late-onset counterparts. We also examine treatment patterns, efficacy, and the potential role of targeted therapies, as well as the potential psychological and social effects on younger patients, with particular emphasis on fertility. We therefore offer insights into the unique challenges and therapeutic strategies in managing early-onset disease.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100271"},"PeriodicalIF":0.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978116","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}
Pub Date : 2026-01-14DOI: 10.1016/j.esmogo.2025.100281
J.K. van Vulpen , M.C. Verwijs , F.K. Gommers , R.A.H. van Eijck van Heslinga , S. van Meer , C.J.R. Verstraete , J. Hagendoorn , M.G.E.H. Lam , N. Haj Mohammad , M.L.J. Smits , M.N.G.J.A. Braat , M.P.W. Intven , J. de Bruijne
Background
First-line treatment strategies for (very) early-stage hepatocellular carcinoma (HCC) include liver transplantation, surgical resection and thermal ablation. Stereotactic body radiotherapy (SBRT) has recently been included in the European Association for the Study of the Liver Clinical Practice Guidelines on the management of hepatocellular carcinoma as an alternative ablative strategy. We aimed to carry out a systematic review and meta-analysis on oncological outcomes and toxicity of SBRT focused on early-stage HCC treatment.
Materials and methods
We carried out a systematic literature search in PubMed, Embase, and the Cochrane Library from inception throughout October 2022. Studies of SBRT targeting treatment-naive (very) early-stage HCC (BCLC 0/A) patients were included.
Results
One prospective and 15 retrospective studies were included in this review. In aggregate, SBRT in 1249 patients resulted in a 1-, 2-, and 3-year local control rate of 94% (95% CI 92%-97%), 89% (95% CI 85%-93%), and 79% (95% CI 68%-90%), respectively. The pooled results of the 1-, 2-, and 3-year overall survival rate were 90% (95% CI 85%-94%), 75% (95% CI 63%-87%), and 59% (95% CI 45%-73%), respectively. Grade ≥3 toxicity was observed in 2% of patients (95% CI 0%-4%).
Conclusion
This systematic review and meta-analysis showed that SBRT is an effective and safe treatment modality for treatment-naive patients with early-stage HCC. The data support incorporation of SBRT as a treatment option in the treatment algorithms for (very) early-stage HCC.
背景:(极)早期肝细胞癌(HCC)的一线治疗策略包括肝移植、手术切除和热消融。立体定向放射治疗(SBRT)最近被纳入欧洲肝脏临床实践研究协会关于肝细胞癌管理的指导方针,作为一种替代消融策略。我们的目的是对早期HCC治疗的SBRT的肿瘤预后和毒性进行系统回顾和荟萃分析。材料和方法从2022年10月开始,我们在PubMed、Embase和Cochrane图书馆进行了系统的文献检索。纳入了针对未接受治疗(极)早期HCC (BCLC 0/A)患者的SBRT研究。结果本综述纳入1项前瞻性研究和15项回顾性研究。总的来说,1249例SBRT患者的1年、2年和3年局部控制率分别为94% (95% CI 92%-97%)、89% (95% CI 85%-93%)和79% (95% CI 68%-90%)。1年、2年和3年总生存率的汇总结果分别为90% (95% CI 85%-94%)、75% (95% CI 63%-87%)和59% (95% CI 45%-73%)。在2%的患者中观察到≥3级毒性(95% CI 0%-4%)。结论本系统综述和荟萃分析显示,SBRT是一种有效且安全的治疗方式,适用于未接受治疗的早期HCC患者。数据支持将SBRT作为一种治疗方案纳入(非常)早期HCC的治疗算法。
{"title":"Stereotactic body radiotherapy in early-stage hepatocellular carcinoma: a systematic review and meta-analysis","authors":"J.K. van Vulpen , M.C. Verwijs , F.K. Gommers , R.A.H. van Eijck van Heslinga , S. van Meer , C.J.R. Verstraete , J. Hagendoorn , M.G.E.H. Lam , N. Haj Mohammad , M.L.J. Smits , M.N.G.J.A. Braat , M.P.W. Intven , J. de Bruijne","doi":"10.1016/j.esmogo.2025.100281","DOIUrl":"10.1016/j.esmogo.2025.100281","url":null,"abstract":"<div><h3>Background</h3><div>First-line treatment strategies for (very) early-stage hepatocellular carcinoma (HCC) include liver transplantation, surgical resection and thermal ablation. Stereotactic body radiotherapy (SBRT) has recently been included in the European Association for the Study of the Liver Clinical Practice Guidelines on the management of hepatocellular carcinoma as an alternative ablative strategy. We aimed to carry out a systematic review and meta-analysis on oncological outcomes and toxicity of SBRT focused on early-stage HCC treatment.</div></div><div><h3>Materials and methods</h3><div>We carried out a systematic literature search in PubMed, Embase, and the Cochrane Library from inception throughout October 2022. Studies of SBRT targeting treatment-naive (very) early-stage HCC (BCLC 0/A) patients were included.</div></div><div><h3>Results</h3><div>One prospective and 15 retrospective studies were included in this review. In aggregate, SBRT in 1249 patients resulted in a 1-, 2-, and 3-year local control rate of 94% (95% CI 92%-97%), 89% (95% CI 85%-93%), and 79% (95% CI 68%-90%), respectively. The pooled results of the 1-, 2-, and 3-year overall survival rate were 90% (95% CI 85%-94%), 75% (95% CI 63%-87%), and 59% (95% CI 45%-73%), respectively. Grade ≥3 toxicity was observed in 2% of patients (95% CI 0%-4%).</div></div><div><h3>Conclusion</h3><div>This systematic review and meta-analysis showed that SBRT is an effective and safe treatment modality for treatment-naive patients with early-stage HCC. The data support incorporation of SBRT as a treatment option in the treatment algorithms for (very) early-stage HCC.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100281"},"PeriodicalIF":0.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978117","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}
Pub Date : 2026-01-08DOI: 10.1016/j.esmogo.2025.100282
M.P.G. Camandaroba, S. Aguiar Jr., V. Souza e Silva, R.P. Riechelmann
Background
Squamous-cell carcinoma of the anal canal (SCCA) is a rare gastrointestinal malignancy, and its incidence is increasing among the aging population. This study aims to examine treatment efficacy and toxicity in elderly patients and to compare treatment outcomes between elderly and non-elderly patients to inform optimal management strategies for SCCA in older adults.
Patients and methods
This retrospective study evaluates clinical outcomes in elderly (≥70 years) versus non-elderly (<70 years) patients with localized SCCA treated with definitive chemoradiotherapy or radiotherapy alone. The primary endpoints were overall survival (OS) and disease-free survival (DFS), whereas secondary endpoints were cancer-specific survival (CSS), complete response rates and grade 3 or 4 toxicity profiles. Statistical analyses were conducted using descriptive statistics, Kaplan–Meier methods, and Cox proportional hazards models.
Results
The study analyzed 269 patients. Elderly patients had a median age of 77.3 (range 70-83) years and presented with a higher burden of comorbidities and a lower prevalence of human immunodeficiency virus. No significant differences in treatment types or toxicity rates were observed between the groups. The median DFS for elderly patients was 103 months versus 128 months for non-elderly patients (P = 0.43). CSS rates were comparable, showing a rate of 83% at five years for the elderly compared with 85% for non-elderly patients (P = 0.74). Cox regression analyses revealed that cancer stage and treatment completion were significant predictors of DFS and OS.
Conclusion
This study highlights that while elderly patients with SCCA experience similar survival outcomes to their younger counterparts, age-related factors and comorbidities require careful management to optimize treatment efficacy while minimizing toxicity.
{"title":"The outcomes of elderly patients with localized squamous-cell carcinoma of the anal canal treated with chemoradiation","authors":"M.P.G. Camandaroba, S. Aguiar Jr., V. Souza e Silva, R.P. Riechelmann","doi":"10.1016/j.esmogo.2025.100282","DOIUrl":"10.1016/j.esmogo.2025.100282","url":null,"abstract":"<div><h3>Background</h3><div>Squamous-cell carcinoma of the anal canal (SCCA) is a rare gastrointestinal malignancy, and its incidence is increasing among the aging population. This study aims to examine treatment efficacy and toxicity in elderly patients and to compare treatment outcomes between elderly and non-elderly patients to inform optimal management strategies for SCCA in older adults.</div></div><div><h3>Patients and methods</h3><div>This retrospective study evaluates clinical outcomes in elderly (≥70 years) versus non-elderly (<70 years) patients with localized SCCA treated with definitive chemoradiotherapy or radiotherapy alone. The primary endpoints were overall survival (OS) and disease-free survival (DFS), whereas secondary endpoints were cancer-specific survival (CSS), complete response rates and grade 3 or 4 toxicity profiles. Statistical analyses were conducted using descriptive statistics, Kaplan–Meier methods, and Cox proportional hazards models.</div></div><div><h3>Results</h3><div>The study analyzed 269 patients. Elderly patients had a median age of 77.3 (range 70-83) years and presented with a higher burden of comorbidities and a lower prevalence of human immunodeficiency virus. No significant differences in treatment types or toxicity rates were observed between the groups. The median DFS for elderly patients was 103 months versus 128 months for non-elderly patients (<em>P</em> = 0.43). CSS rates were comparable, showing a rate of 83% at five years for the elderly compared with 85% for non-elderly patients (<em>P</em> = 0.74). Cox regression analyses revealed that cancer stage and treatment completion were significant predictors of DFS and OS.</div></div><div><h3>Conclusion</h3><div>This study highlights that while elderly patients with SCCA experience similar survival outcomes to their younger counterparts, age-related factors and comorbidities require careful management to optimize treatment efficacy while minimizing toxicity.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100282"},"PeriodicalIF":0.0,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926897","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}
Pub Date : 2026-01-06DOI: 10.1016/j.esmogo.2025.100279
A. Gandini , V. Martelli , L. Belgioia , S. Puglisi , M. Cremante , V. Murianni , A. Damassi , C. Pirrone , F. Catalano , M. Grassi , L. Trevisan , S. Vagge , V. Andretta , S. Mammoliti , D. Comandini , G. Fornarini , A. Pessino , A. Pastorino , S. Sciallero , A. Puccini , A.F. Sobrero
Pub Date : 2026-01-06DOI: 10.1016/j.esmogo.2025.100280
Y. Sekiguchi , K. Shibuya , S. Tomogane , Y. Miyasaka , S. Kakizaki , M. Okamoto , K. Araki , K. Shirabe , T. Ohno
Background
Transarterial chemoembolization (TACE) or embolization (TAE) for hepatocellular carcinoma (HCC) is often followed by an incomplete response or local recurrence, necessitating effective salvage therapies. Carbon-ion radiotherapy (CIRT) offers potential radiobiological advantages for treating TACE-refractory tumors. This study aimed to evaluate the efficacy and safety of CIRT for residual or recurrent HCC after TACE/TAE.
Patients and methods
We retrospectively analyzed 99 patients (106 lesions) treated with CIRT between 2010 and 2021. Eligible patients had residual or recurrent HCC after 52.8-60.0 Gy [relative biological effectiveness (RBE)] in 4 fractions, or 60.0 Gy (RBE) in 12 fractions for tumors near critical structures. Efficacy endpoints were local control (LC), overall survival (OS), and progression-free survival (PFS). Toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0, and liver function was monitored using Child–Pugh and albumin–bilirubin (ALBI) scores.
Results
At a median follow-up of 38 months, the 3-year OS, PFS, and LC rates were 70.3%, 34.8%, and 90.7%, respectively. On multivariate analysis, larger tumor size (≥3.5 cm) and poorer baseline liver function (modified ALBI grade ≥2b) were significant predictors of worse OS. The treatment was well tolerated; severe (grade ≥3) late toxicities were rare, including two cases of encephalopathy. There was no statistically significant deterioration in Child–Pugh or ALBI scores following treatment.
Conclusions
CIRT is a safe and effective salvage therapy for TACE-refractory HCC, offering excellent LC, favorable survival outcomes, and preserved liver function.
{"title":"Clinical outcomes of carbon-ion radiotherapy for residual or recurrent hepatocellular carcinoma after transarterial chemoembolization","authors":"Y. Sekiguchi , K. Shibuya , S. Tomogane , Y. Miyasaka , S. Kakizaki , M. Okamoto , K. Araki , K. Shirabe , T. Ohno","doi":"10.1016/j.esmogo.2025.100280","DOIUrl":"10.1016/j.esmogo.2025.100280","url":null,"abstract":"<div><h3>Background</h3><div>Transarterial chemoembolization (TACE) or embolization (TAE) for hepatocellular carcinoma (HCC) is often followed by an incomplete response or local recurrence, necessitating effective salvage therapies. Carbon-ion radiotherapy (CIRT) offers potential radiobiological advantages for treating TACE-refractory tumors. This study aimed to evaluate the efficacy and safety of CIRT for residual or recurrent HCC after TACE/TAE.</div></div><div><h3>Patients and methods</h3><div>We retrospectively analyzed 99 patients (106 lesions) treated with CIRT between 2010 and 2021. Eligible patients had residual or recurrent HCC after 52.8-60.0 Gy [relative biological effectiveness (RBE)] in 4 fractions, or 60.0 Gy (RBE) in 12 fractions for tumors near critical structures. Efficacy endpoints were local control (LC), overall survival (OS), and progression-free survival (PFS). Toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0, and liver function was monitored using Child–Pugh and albumin–bilirubin (ALBI) scores.</div></div><div><h3>Results</h3><div>At a median follow-up of 38 months, the 3-year OS, PFS, and LC rates were 70.3%, 34.8%, and 90.7%, respectively. On multivariate analysis, larger tumor size (≥3.5 cm) and poorer baseline liver function (modified ALBI grade ≥2b) were significant predictors of worse OS. The treatment was well tolerated; severe (grade ≥3) late toxicities were rare, including two cases of encephalopathy. There was no statistically significant deterioration in Child–Pugh or ALBI scores following treatment.</div></div><div><h3>Conclusions</h3><div>CIRT is a safe and effective salvage therapy for TACE-refractory HCC, offering excellent LC, favorable survival outcomes, and preserved liver function.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100280"},"PeriodicalIF":0.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926804","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}
Pub Date : 2026-01-06DOI: 10.1016/j.esmogo.2025.100283
P. Seda , R. Abbey , L. Peng , I. Ezeaku , S.T. Laroia , H. Aziz
Liver cancer, especially hepatocellular carcinoma (HCC), which accounts for ∼75%-85% of primary liver cancers, remains a major global health challenge. Because of its high incidence, late diagnosis, and limited curative options, local therapies have become increasingly popular for the multidisciplinary management of HCC, especially in early and intermediate Barcelona Clinic Liver Cancer stages or in medically inoperable patients. This review examines a landscape of local treatment modalities for HCC encompassing radiofrequency ablation, microwave ablation, cryoablation, irreversible electroporation, histotripsy, transarterial chemoembolization, transarterial radioembolization, and stereotactic body radiotherapy. We also highlight their respective advantages and disadvantages, compare their survival outcomes, and identify current gaps in the literature, including the need for further comparisons between safety profiles and efficacy, and the growing landscape that is using different local therapies in a sequential or combinatorial fashion. Emphasis is placed on treatment decisions tailored to tumor burden, liver function, and patient-specific considerations. Expanding access to advanced local therapies in resource-limited settings remains a global priority.
{"title":"A review of established and new developments in local therapies for liver cancer","authors":"P. Seda , R. Abbey , L. Peng , I. Ezeaku , S.T. Laroia , H. Aziz","doi":"10.1016/j.esmogo.2025.100283","DOIUrl":"10.1016/j.esmogo.2025.100283","url":null,"abstract":"<div><div>Liver cancer, especially hepatocellular carcinoma (HCC), which accounts for ∼75%-85% of primary liver cancers, remains a major global health challenge. Because of its high incidence, late diagnosis, and limited curative options, local therapies have become increasingly popular for the multidisciplinary management of HCC, especially in early and intermediate Barcelona Clinic Liver Cancer stages or in medically inoperable patients. This review examines a landscape of local treatment modalities for HCC encompassing radiofrequency ablation, microwave ablation, cryoablation, irreversible electroporation, histotripsy, transarterial chemoembolization, transarterial radioembolization, and stereotactic body radiotherapy. We also highlight their respective advantages and disadvantages, compare their survival outcomes, and identify current gaps in the literature, including the need for further comparisons between safety profiles and efficacy, and the growing landscape that is using different local therapies in a sequential or combinatorial fashion. Emphasis is placed on treatment decisions tailored to tumor burden, liver function, and patient-specific considerations. Expanding access to advanced local therapies in resource-limited settings remains a global priority.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100283"},"PeriodicalIF":0.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926898","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}
Pub Date : 2026-01-06DOI: 10.1016/j.esmogo.2025.100278
C.H. Maeng , A. Alkashash , A. Sy , H. Barnes , S. Bannon , C. Simms , M.R. Strickland , J.N. Glickman , S.J. Klempner
Background
Claudin-18 isoform 2 (CLDN18.2) is a validated therapeutic target in gastric cancer (GC) and gastroesophageal junction cancer (GEJ). The approved antibody zolbetuximab requires higher expression levels (≥75% of tumor cells with 2-3+ membranous staining), yet broader thresholds are increasingly explored. Data on clinicopathologic correlates and biomarker overlap at lower cut-offs remain limited.
Patients and methods
We retrospectively analyzed patients with esophageal cancer (EC), GEJ, or GC who underwent CLDN18.2 immunohistochemistry at a single high-volume center (2023-2025). CLDN18.2 positivity was defined using three thresholds: (i) stringent (75% threshold: ≥75% of tumor cells with 2-3+ staining); (ii) broader (H-score 25; ≥1+ intensity in ≥25% of cells); and (iii) the lowest (H-score 10; ≥1+ intensity in ≥10% of cells). Associations between CLDN18.2 and clinicopathologic variables, including histology and standard biomarkers [human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), and mismatch repair (MMR)], were assessed.
Results
In total, 149 patients were included: 43 EC (28.9%), 46 GEJ (30.9%), and 60 GC (40.3%). CLDN18.2 positivity rates were 48.3%, 71.1%, and 73.8% at the 75%, H-score 25, and H-score 10 thresholds, respectively. CLDN18.2 positivity significantly correlated with tumor location, highest in GC and followed by GEJ and EC across thresholds. At the lowest cut-off, positivity was 85.0% in GC, 69.6% in GEJ, and 62.8% in EC (P = 0.030). Histological subtypes were also associated across thresholds: poorly cohesive carcinoma (PCC) demonstrated significantly higher positivity than non-PCC. No significant associations were found with HER2, PD-L1 combined positive score, or MMR. Triple positivity for CLDN18.2, HER2, and PD-L1 was rare (≤5.5%).
Conclusion
CLDN18.2 expression in upper gastrointestinal cancers was significantly associated with gastric origin and PCC histology, independent of HER2 and PD-L1 status. Broadening the threshold for positivity identified nearly three-quarters of patients as CLDN18.2 positive, underscoring the impact of selection cut points on trial eligibility. These findings highlight the potential to expand patient access to CLDN18.2-targeted therapies using lower thresholds.
{"title":"Clinicopathologic correlates of claudin 18.2 expression in esophagogastric cancer at multiple expression levels","authors":"C.H. Maeng , A. Alkashash , A. Sy , H. Barnes , S. Bannon , C. Simms , M.R. Strickland , J.N. Glickman , S.J. Klempner","doi":"10.1016/j.esmogo.2025.100278","DOIUrl":"10.1016/j.esmogo.2025.100278","url":null,"abstract":"<div><h3>Background</h3><div>Claudin-18 isoform 2 (CLDN18.2) is a validated therapeutic target in gastric cancer (GC) and gastroesophageal junction cancer (GEJ). The approved antibody zolbetuximab requires higher expression levels (≥75% of tumor cells with 2-3+ membranous staining), yet broader thresholds are increasingly explored. Data on clinicopathologic correlates and biomarker overlap at lower cut-offs remain limited.</div></div><div><h3>Patients and methods</h3><div>We retrospectively analyzed patients with esophageal cancer (EC), GEJ, or GC who underwent CLDN18.2 immunohistochemistry at a single high-volume center (2023-2025). CLDN18.2 positivity was defined using three thresholds: (i) stringent (<em>75% threshold</em>: ≥75% of tumor cells with 2-3+ staining); (ii) broader (<em>H-score 25</em>; ≥1+ intensity in ≥25% of cells); and (iii) the lowest (<em>H-score 10</em>; ≥1+ intensity in ≥10% of cells). Associations between CLDN18.2 and clinicopathologic variables, including histology and standard biomarkers [human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), and mismatch repair (MMR)], were assessed.</div></div><div><h3>Results</h3><div>In total, 149 patients were included: 43 EC (28.9%), 46 GEJ (30.9%), and 60 GC (40.3%). CLDN18.2 positivity rates were 48.3%, 71.1%, and 73.8% at the <em>75%</em>, <em>H-score 25</em>, and <em>H-score 10</em> thresholds, respectively. CLDN18.2 positivity significantly correlated with tumor location, highest in GC and followed by GEJ and EC across thresholds. At the lowest cut-off, positivity was 85.0% in GC, 69.6% in GEJ, and 62.8% in EC (<em>P</em> = 0.030). Histological subtypes were also associated across thresholds: poorly cohesive carcinoma (PCC) demonstrated significantly higher positivity than non-PCC. No significant associations were found with HER2, PD-L1 combined positive score, or MMR. Triple positivity for CLDN18.2, HER2, and PD-L1 was rare (≤5.5%).</div></div><div><h3>Conclusion</h3><div>CLDN18.2 expression in upper gastrointestinal cancers was significantly associated with gastric origin and PCC histology, independent of HER2 and PD-L1 status. Broadening the threshold for positivity identified nearly three-quarters of patients as CLDN18.2 positive, underscoring the impact of selection cut points on trial eligibility. These findings highlight the potential to expand patient access to CLDN18.2-targeted therapies using lower thresholds.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100278"},"PeriodicalIF":0.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926805","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}
Pub Date : 2025-12-15DOI: 10.1016/j.esmogo.2025.100274
B. Kimmel , S.T. Löhnert , F. Wedekink , M. Günther , S. Ormanns , I. Hartlapp , J. Siveke , G. Siegler , S. Boeck , H. Algül , U. Martens , F. Kullmann , T. Ettrich , S. Held , F. Anger , C.-T. Germer , V. Heinemann , J. Wischhusen , V. Kunzmann
Background
The prognostic and predictive role of growth differentiation factor-15 (GDF-15) in localized, non-metastatic pancreatic ductal adenocarcinoma (PDAC) has not yet been explored.
Patients and methods
During the prospective randomized phase II NEOLAP-1 (AIO-PAK-0113) trial for patients with therapy-naive locally advanced (borderline or unresectable) PDAC, blood (n = 131) and tumor tissue samples (n = 39) were collected. Using paired baseline and post-induction chemotherapy (ICT) samples, circulating GDF-15 (cGDF-15) levels were quantified by enzyme-linked immunosorbent assay, and local GDF-15 tumor expression (tGDF-15) was assessed by immunohistochemistry.
Results
Lower baseline cGDF-15 levels (≤0.8 ng/ml) were significantly associated with increased median overall survival [21.92 (95% CI 19.73-24.16) versus 12.68 [95% confidence interval (CI) 10.56-14.81] months, P < 0.001, and significantly higher secondary R0 resection rates (36.5% versus 13.9%, P = 0.0051). In contrast to CA 19-9, cGDF-15 levels significantly increased after ICT [median 1.0 ng/ml [interquartile range (IQR) 0.62-1.5 ng/ml] at baseline versus median 2.37 ng/ml (IQR 1.32-4.43 ng/ml) at week 16], especially after treatment using platinum-based agents. In initial tumor specimens, GDF-15 expression was rare and predominantly confined to tumor cells. tGDF-15 correlated with high cGDF-15 levels at baseline [median 1.8 ng/ml (1.13-2.34 ng/ml) in positive tumor specimens, versus 0.76 ng/ml (0.55-1.17 ng/ml) in negative tumor specimens; P = 0.0087]. Similarly to cGDF-15, tGDF-15 expression increased after ICT (from 10% to 41% positive tumor specimens).
Conclusions
High cGDF-15 levels at baseline are a negative prognostic and predictive biomarker in localized, non-metastatic PDAC. Considering that GDF-15 is further up-regulated by neoadjuvant multiagent chemotherapy, our data, together with recent findings on clinical effects of GDF-15, provide a strong rationale for upfront therapeutic GDF-15 blockade in localized PDAC.
{"title":"Growth differentiation factor-15 (GDF-15) in localized pancreatic adenocarcinoma treated with multiagent chemotherapy: a biomarker analysis from the NEOLAP trial (AIO-PAK-0113)","authors":"B. Kimmel , S.T. Löhnert , F. Wedekink , M. Günther , S. Ormanns , I. Hartlapp , J. Siveke , G. Siegler , S. Boeck , H. Algül , U. Martens , F. Kullmann , T. Ettrich , S. Held , F. Anger , C.-T. Germer , V. Heinemann , J. Wischhusen , V. Kunzmann","doi":"10.1016/j.esmogo.2025.100274","DOIUrl":"10.1016/j.esmogo.2025.100274","url":null,"abstract":"<div><h3>Background</h3><div>The prognostic and predictive role of growth differentiation factor-15 (GDF-15) in localized, non-metastatic pancreatic ductal adenocarcinoma (PDAC) has not yet been explored.</div></div><div><h3>Patients and methods</h3><div>During the prospective randomized phase II NEOLAP-1 (AIO-PAK-0113) trial for patients with therapy-naive locally advanced (borderline or unresectable) PDAC, blood (<em>n</em> = 131) and tumor tissue samples (<em>n</em> = 39) were collected. Using paired baseline and post-induction chemotherapy (ICT) samples, circulating GDF-15 (cGDF-15) levels were quantified by enzyme-linked immunosorbent assay, and local GDF-15 tumor expression (tGDF-15) was assessed by immunohistochemistry.</div></div><div><h3>Results</h3><div>Lower baseline cGDF-15 levels (≤0.8 ng/ml) were significantly associated with increased median overall survival [21.92 (95% CI 19.73-24.16) versus 12.68 [95% confidence interval (CI) 10.56-14.81] months, <em>P</em> < 0.001, and significantly higher secondary R0 resection rates (36.5% versus 13.9%, <em>P</em> = 0.0051). In contrast to CA 19-9, cGDF-15 levels significantly increased after ICT [median 1.0 ng/ml [interquartile range (IQR) 0.62-1.5 ng/ml] at baseline versus median 2.37 ng/ml (IQR 1.32-4.43 ng/ml) at week 16], especially after treatment using platinum-based agents. In initial tumor specimens, GDF-15 expression was rare and predominantly confined to tumor cells. tGDF-15 correlated with high cGDF-15 levels at baseline [median 1.8 ng/ml (1.13-2.34 ng/ml) in positive tumor specimens, versus 0.76 ng/ml (0.55-1.17 ng/ml) in negative tumor specimens; <em>P</em> = 0.0087]. Similarly to cGDF-15, tGDF-15 expression increased after ICT (from 10% to 41% positive tumor specimens).</div></div><div><h3>Conclusions</h3><div>High cGDF-15 levels at baseline are a negative prognostic and predictive biomarker in localized, non-metastatic PDAC. Considering that GDF-15 is further up-regulated by neoadjuvant multiagent chemotherapy, our data, together with recent findings on clinical effects of GDF-15, provide a strong rationale for upfront therapeutic GDF-15 blockade in localized PDAC.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100274"},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791900","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}
Pub Date : 2025-12-15DOI: 10.1016/j.esmogo.2025.100276
P. Andena , G. Tine , F. Nichetti , A. Pretta , L. Bartalini , S. Ljevar , A. Michelotti , L. Salvatore , M. Prisciandaro , A. Franza , G. Grelli , P. Ziranu , M. Bensi , V. Mazzaferro , J. Coppa , C. Sciortino , G. Zapelloni , C. Pircher , S.K. Garattini , C. Vivaldi , M. Niger
Background
Diabetes mellitus (DM) is a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Preclinical evidence suggests higher glucose levels may enhance chemotherapy injury to PDAC cells. Clinical evidence of DM’s impact in patients with PDAC receiving palliative treatment remains conflicting, however.
Materials and methods
PANCAKE, an Italian multicenter observational study, assessed the impact of DM and blood glucose levels on progression-free survival during first-line treatment and overall survival (OS) in patients with advanced PDAC.
Results
Among 663 patients with available baseline and on-treatment glycemic values, DM was confirmed in 193 patients (29.1%). Pre-existing DM was associated with a modest but significant OS benefit [median OS 11.6 versus 10.3 months, adjusted hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-0.99; P = 0.036]. This benefit was significantly associated with the chemotherapy regimen: it was observed only in patients treated with first-line gemcitabine–nab-paclitaxel, but not with FOLFIRINOX. A longitudinal, Bayesian joint modelling approach accounting for the concomitant use of glucose-lowering medications confirmed a statistically significant, but clinically modest prognostic effect of glycemic trends, as a 10 mg/dl-point increase from baseline blood glucose values resulted associated with a 4% reduction in the risk of death (HR for OS 0.9967, 95% CI 0.9939-0.9995).
Conclusions
DM and higher blood glucose levels show a statistically significant, though clinically modest, impact on the OS of patients affected by advanced PDAC, which may be differential according to the chemotherapy regimen. This evidence lays the foundations to guide future studies on pharmacological and dietary approaches targeting tumor metabolism in this setting.
{"title":"Impact of diabetes mellitus on treatment efficacy in patients with advanced pancreatic cancer: the Italian, multicenter, observational PANCAKE study","authors":"P. Andena , G. Tine , F. Nichetti , A. Pretta , L. Bartalini , S. Ljevar , A. Michelotti , L. Salvatore , M. Prisciandaro , A. Franza , G. Grelli , P. Ziranu , M. Bensi , V. Mazzaferro , J. Coppa , C. Sciortino , G. Zapelloni , C. Pircher , S.K. Garattini , C. Vivaldi , M. Niger","doi":"10.1016/j.esmogo.2025.100276","DOIUrl":"10.1016/j.esmogo.2025.100276","url":null,"abstract":"<div><h3>Background</h3><div>Diabetes mellitus (DM) is a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Preclinical evidence suggests higher glucose levels may enhance chemotherapy injury to PDAC cells. Clinical evidence of DM’s impact in patients with PDAC receiving palliative treatment remains conflicting, however.</div></div><div><h3>Materials and methods</h3><div>PANCAKE, an Italian multicenter observational study, assessed the impact of DM and blood glucose levels on progression-free survival during first-line treatment and overall survival (OS) in patients with advanced PDAC.</div></div><div><h3>Results</h3><div>Among 663 patients with available baseline and on-treatment glycemic values, DM was confirmed in 193 patients (29.1%). Pre-existing DM was associated with a modest but significant OS benefit [median OS 11.6 versus 10.3 months, adjusted hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-0.99; <em>P</em> = 0.036]. This benefit was significantly associated with the chemotherapy regimen: it was observed only in patients treated with first-line gemcitabine–nab-paclitaxel, but not with FOLFIRINOX. A longitudinal, Bayesian joint modelling approach accounting for the concomitant use of glucose-lowering medications confirmed a statistically significant, but clinically modest prognostic effect of glycemic trends, as a 10 mg/dl-point increase from baseline blood glucose values resulted associated with a 4% reduction in the risk of death (HR for OS 0.9967, 95% CI 0.9939-0.9995).</div></div><div><h3>Conclusions</h3><div>DM and higher blood glucose levels show a statistically significant, though clinically modest, impact on the OS of patients affected by advanced PDAC, which may be differential according to the chemotherapy regimen. This evidence lays the foundations to guide future studies on pharmacological and dietary approaches targeting tumor metabolism in this setting.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100276"},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791901","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}