Pub Date : 2025-11-27DOI: 10.1038/s41416-025-03291-z
Mererid Evans, Chris Hurt, Rhian Rhys, Abhishek Mahajan, Andrew McQueen, Joanna Dixon, Max Robinson, Neil Robinson, Keith Hunter, Adam Christian, Adam Jones, Aline Queiroz, Shao Hui Huang, Brian O’Sullivan, Joanna Canham, Christie Heiberg, Terry Jones
Imaging-detected and pathological extranodal extension (iENE, pENE) negatively impact prognosis in Human Papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC), as reflected in future TNM staging updates. Correlation between iENE and pENE in HPV-positive OPSCC is currently unknown yet is vital to determine how iENE should be used to influence treatment decisions. PATHOS is a trial of de-intensified adjuvant treatment after transoral surgery for HPV-positive OPSCC. 291 consecutively recruited patients undergoing surgery at three UK centres were included. Pre-operative cross-sectional imaging (CT and/or MRI) was independently scored for iENE by 2 expert radiologists; pENE was scored by 2 expert pathologists. Inter-rater agreement for iENE was fair in round 1 (Gwet’s AC: 0.34 (95%CI:0.26–0.41)) but improved to very good after second review (Gwet’s AC: 0.88 (95%CI:0.85–0.93), Agreement: 0.91 (95%CI:0.87–0.94)). Sensitivity of iENE for predicting pENE was relatively low (at best: 56.4% (95%CI:42.3–69.7) and specificity was high (at worst: 70.9% (95%CI:65.0–76.3)). Excluding cases with suboptimal image quality and recent core biopsy produced modest improvements in sensitivity (up to 59.4% (95%CI:40.6–76.3)) and specificity (up to 87.8% (95%CI:80.4–93.2)). The high specificity could help select iENE-negative patients for surgery, but higher sensitivity is required before excluding surgery based solely on iENE positivity.
{"title":"Correlation between imaging-detected and pathological extranodal extension in a randomised trial in Human Papillomavirus-positive oropharyngeal cancer","authors":"Mererid Evans, Chris Hurt, Rhian Rhys, Abhishek Mahajan, Andrew McQueen, Joanna Dixon, Max Robinson, Neil Robinson, Keith Hunter, Adam Christian, Adam Jones, Aline Queiroz, Shao Hui Huang, Brian O’Sullivan, Joanna Canham, Christie Heiberg, Terry Jones","doi":"10.1038/s41416-025-03291-z","DOIUrl":"10.1038/s41416-025-03291-z","url":null,"abstract":"Imaging-detected and pathological extranodal extension (iENE, pENE) negatively impact prognosis in Human Papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC), as reflected in future TNM staging updates. Correlation between iENE and pENE in HPV-positive OPSCC is currently unknown yet is vital to determine how iENE should be used to influence treatment decisions. PATHOS is a trial of de-intensified adjuvant treatment after transoral surgery for HPV-positive OPSCC. 291 consecutively recruited patients undergoing surgery at three UK centres were included. Pre-operative cross-sectional imaging (CT and/or MRI) was independently scored for iENE by 2 expert radiologists; pENE was scored by 2 expert pathologists. Inter-rater agreement for iENE was fair in round 1 (Gwet’s AC: 0.34 (95%CI:0.26–0.41)) but improved to very good after second review (Gwet’s AC: 0.88 (95%CI:0.85–0.93), Agreement: 0.91 (95%CI:0.87–0.94)). Sensitivity of iENE for predicting pENE was relatively low (at best: 56.4% (95%CI:42.3–69.7) and specificity was high (at worst: 70.9% (95%CI:65.0–76.3)). Excluding cases with suboptimal image quality and recent core biopsy produced modest improvements in sensitivity (up to 59.4% (95%CI:40.6–76.3)) and specificity (up to 87.8% (95%CI:80.4–93.2)). The high specificity could help select iENE-negative patients for surgery, but higher sensitivity is required before excluding surgery based solely on iENE positivity.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"428-438"},"PeriodicalIF":6.8,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03291-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1038/s41416-025-03297-7
Axel Van Meer, Jacques Gilis, Baptiste Oosterlinck, Timon Vandamme, Joris De Man, Benedicte Y. De Winter, Annemieke Smet
Aberrant mucin expression is implicated in lower gastrointestinal tract (GIT) cancers, yet its clinicopathological relevance remains poorly understood. To identify distinct mucin signatures in association with (pre)tumour subtypes, anatomical location, and clinical outcomes, we conducted a systematic review and meta-analysis of MEDLINE articles published between January 2001 and September 2025. Studies were included if they assessed mucin expression in lower GIT (pre)malignant lesions. Fifty-eight studies were eligible. MUC2 and MUC5AC expression was upregulated in serrated polyps and mucinous- and microsatellite instability (MSI)-associated proximal adenocarcinomas, whereas a downregulation of MUC2 was noted in advanced adenomas and non-mucinous distal tumours. Discrepancies in survival in relation to high-level or low-level MUC2 further suggested that this glycoprotein cooperates with other mucins during carcinogenesis. Notably, abundant MUC1 expression was seen in adenomas with high-grade dysplasia and together with high-level MUC13 correlated with (non-)mucinous CRC types and poor prognosis. Similar mucin signatures were also found in small intestinal adenocarcinoma, yet MUC2 was downregulated and increased MUC5AC rather associated with a worse survival, emphasizing the role of tumour location in influencing tumour behaviour. In conclusion, aberrant mucin signatures reflect distinct molecular pathways in (pre)malignant GIT lesions and highlight their potential utility as biomarkers and therapeutic targets.
{"title":"Clinicopathological and prognostic significance of mucin signatures in lower gastrointestinal cancer–a systematic review and meta-analysis","authors":"Axel Van Meer, Jacques Gilis, Baptiste Oosterlinck, Timon Vandamme, Joris De Man, Benedicte Y. De Winter, Annemieke Smet","doi":"10.1038/s41416-025-03297-7","DOIUrl":"10.1038/s41416-025-03297-7","url":null,"abstract":"Aberrant mucin expression is implicated in lower gastrointestinal tract (GIT) cancers, yet its clinicopathological relevance remains poorly understood. To identify distinct mucin signatures in association with (pre)tumour subtypes, anatomical location, and clinical outcomes, we conducted a systematic review and meta-analysis of MEDLINE articles published between January 2001 and September 2025. Studies were included if they assessed mucin expression in lower GIT (pre)malignant lesions. Fifty-eight studies were eligible. MUC2 and MUC5AC expression was upregulated in serrated polyps and mucinous- and microsatellite instability (MSI)-associated proximal adenocarcinomas, whereas a downregulation of MUC2 was noted in advanced adenomas and non-mucinous distal tumours. Discrepancies in survival in relation to high-level or low-level MUC2 further suggested that this glycoprotein cooperates with other mucins during carcinogenesis. Notably, abundant MUC1 expression was seen in adenomas with high-grade dysplasia and together with high-level MUC13 correlated with (non-)mucinous CRC types and poor prognosis. Similar mucin signatures were also found in small intestinal adenocarcinoma, yet MUC2 was downregulated and increased MUC5AC rather associated with a worse survival, emphasizing the role of tumour location in influencing tumour behaviour. In conclusion, aberrant mucin signatures reflect distinct molecular pathways in (pre)malignant GIT lesions and highlight their potential utility as biomarkers and therapeutic targets.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"367-376"},"PeriodicalIF":6.8,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03297-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Perineural invasion (PNI) frequently occurs in oral squamous cell carcinoma (OSCC) and predicts poor prognosis. Although PNI is increasingly recognised as a process driven by tumour-nerve crosstalk, the underlying molecular mechanisms remain unclear. We investigated the role of sympathetic nerve–derived neuropeptide Y (NPY) and its receptor NPY1R in OSCC PNI. NPY/NPY1R expression was assessed in human OSCC tissues by immunostaining, qPCR, and TCGA data analysis. Functional studies using Cal27 and SCC9 cells included migration, invasion, and sphere assays. The causal role of NPY1R was tested by lentiviral knockdown/overexpression, validated in tongue orthotopic xenografts, and further examined by NPY1R pharmacological inhibition in vivo. NPY was enriched in the PNI microenvironment, and malignant OSCC expressed high NPY1R, particularly at invasive fronts. Mechanistically, NPY activated ERK and Smad2 via NPY1R, synergising with TGFβ signalling in tumour cells expressing TβRI. This crosstalk enhanced proliferation, invasion, and PNI in vivo. Importantly, NPY1R inhibition markedly reduced tumour growth, metastasis, and PNI. We identify NPY-NPY1R-TGFβ crosstalk as a novel mechanism enabling OSCC to exploit neural signals for PNI, highlighting a promising therapeutic target to block neural invasion and improve patient outcomes.
{"title":"Crosstalk of NPY and TGFβ orchestrates the signaling to facilitate perineural invasion of oral squamous cell carcinoma","authors":"Jing Bi, Ketong Liu, Yiru Luo, Yueqi Zhou, Zhengyan Liu, Junting Tao, Jinhui Wei, Marene Landstrom, Yabing Mu, Guangxiang Zang","doi":"10.1038/s41416-025-03261-5","DOIUrl":"10.1038/s41416-025-03261-5","url":null,"abstract":"Perineural invasion (PNI) frequently occurs in oral squamous cell carcinoma (OSCC) and predicts poor prognosis. Although PNI is increasingly recognised as a process driven by tumour-nerve crosstalk, the underlying molecular mechanisms remain unclear. We investigated the role of sympathetic nerve–derived neuropeptide Y (NPY) and its receptor NPY1R in OSCC PNI. NPY/NPY1R expression was assessed in human OSCC tissues by immunostaining, qPCR, and TCGA data analysis. Functional studies using Cal27 and SCC9 cells included migration, invasion, and sphere assays. The causal role of NPY1R was tested by lentiviral knockdown/overexpression, validated in tongue orthotopic xenografts, and further examined by NPY1R pharmacological inhibition in vivo. NPY was enriched in the PNI microenvironment, and malignant OSCC expressed high NPY1R, particularly at invasive fronts. Mechanistically, NPY activated ERK and Smad2 via NPY1R, synergising with TGFβ signalling in tumour cells expressing TβRI. This crosstalk enhanced proliferation, invasion, and PNI in vivo. Importantly, NPY1R inhibition markedly reduced tumour growth, metastasis, and PNI. We identify NPY-NPY1R-TGFβ crosstalk as a novel mechanism enabling OSCC to exploit neural signals for PNI, highlighting a promising therapeutic target to block neural invasion and improve patient outcomes.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"377-390"},"PeriodicalIF":6.8,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03261-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1038/s41416-025-03264-2
Lucía Mateos, Paula Jiménez-Fonseca, Javier Gallego, Arturo Lecumberri, Ana Custodio, Eva Martínez de Castro, Raquel Hernández San Gil, Ana Fernández Montes, María Luisa Limón, Rosario Vidal-Tocino, Juana María Cano, Javier López Robles, Mireia Gil, Daniel Acosta Eyzaguirre, Gema Marín Zafra, Antonio José Mérida-García, Alejandro Francisco Fernández, Paula Ribera Fernández, Cinta Hierro, María Carmen Riesco, Montse García Araque, Maribel Ruiz Martín, Paola Pimentel, Laura Visa, Paula Cerdá, Mónica Granja, Ana Belén Rupérez Blanco, Lourdes Gutiérrez, Alberto Carmona-Bayonas
Translating trial findings to real-world cure rates for resectable oesophageal and gastroesophageal junction (GEJ) adenocarcinoma is critical. Standard endpoints like disease-free survival (DFS) may not distinguish durable cures from delayed recurrences. This analysis of the AGAMENON-SEOM registry (NCT04958720) compared perioperative chemotherapy versus neoadjuvant chemoradiotherapy (nCRT). We estimated cure rates and analysed DFS and overall survival (OS) using mixture cure models and Cox proportional hazards models. In 500 patients, perioperative FLOT improved DFS (HR 0.60; p = 0.01) and OS (adjusted HR 0.63; p = 0.015) compared to CROSS-based nCRT. Notably, cure models confirmed a higher cure fraction for FLOT in high-risk subgroups (e.g., stage III, high neutrophil-to-lymphocyte ratio). While platinum-fluoropyrimidine–based nCRT ± immunotherapy yielded higher R0 and pathological complete response rates, its estimated cure rate was comparable to FLOT, both overall and across all subgroups. Cure is an informative endpoint in localised oesophageal cancer. In this registry analysis, perioperative FLOT was associated with higher cure rates than CROSS, particularly in high-risk subgroups. Exploratory findings suggest that alternative neoadjuvant strategies, such as those incorporating ICIs or FOLFOX, warrant further investigation.
背景：将试验结果转化为可切除食管和胃食管交界（GEJ）腺癌的实际治愈率是至关重要的。无病生存期（DFS）等标准终点可能无法区分持久治愈和延迟复发。方法：AGAMENON-SEOM注册表（NCT04958720）的分析比较了围手术期化疗和新辅助放化疗（nCRT）。我们使用混合治愈模型和Cox比例风险模型估计治愈率并分析DFS和总生存期（OS）。结果：500例患者围手术期FLOT较CROSS-based nCRT改善了DFS （HR 0.60, p = 0.01）和OS（调整后HR 0.63, p = 0.015）。值得注意的是，治愈模型证实了FLOT在高风险亚组（例如，III期，中性粒细胞与淋巴细胞比例高）中的治愈率更高。虽然基于铂-氟嘧啶的nCRT±免疫疗法产生更高的R0和病理完全缓解率，但其估计治愈率与FLOT相当，无论是总体还是所有亚组。结论：治愈是局部食管癌的一个重要终点。在这项注册表分析中，围手术期FLOT的治愈率高于CROSS，特别是在高危亚组中。探索性研究结果表明，替代的新辅助策略，如合并ICIs或FOLFOX，值得进一步研究。
{"title":"Does perioperative FLOT increase cure rates in resectable esophageal adenocarcinoma? A mixture cure model analysis","authors":"Lucía Mateos, Paula Jiménez-Fonseca, Javier Gallego, Arturo Lecumberri, Ana Custodio, Eva Martínez de Castro, Raquel Hernández San Gil, Ana Fernández Montes, María Luisa Limón, Rosario Vidal-Tocino, Juana María Cano, Javier López Robles, Mireia Gil, Daniel Acosta Eyzaguirre, Gema Marín Zafra, Antonio José Mérida-García, Alejandro Francisco Fernández, Paula Ribera Fernández, Cinta Hierro, María Carmen Riesco, Montse García Araque, Maribel Ruiz Martín, Paola Pimentel, Laura Visa, Paula Cerdá, Mónica Granja, Ana Belén Rupérez Blanco, Lourdes Gutiérrez, Alberto Carmona-Bayonas","doi":"10.1038/s41416-025-03264-2","DOIUrl":"10.1038/s41416-025-03264-2","url":null,"abstract":"Translating trial findings to real-world cure rates for resectable oesophageal and gastroesophageal junction (GEJ) adenocarcinoma is critical. Standard endpoints like disease-free survival (DFS) may not distinguish durable cures from delayed recurrences. This analysis of the AGAMENON-SEOM registry (NCT04958720) compared perioperative chemotherapy versus neoadjuvant chemoradiotherapy (nCRT). We estimated cure rates and analysed DFS and overall survival (OS) using mixture cure models and Cox proportional hazards models. In 500 patients, perioperative FLOT improved DFS (HR 0.60; p = 0.01) and OS (adjusted HR 0.63; p = 0.015) compared to CROSS-based nCRT. Notably, cure models confirmed a higher cure fraction for FLOT in high-risk subgroups (e.g., stage III, high neutrophil-to-lymphocyte ratio). While platinum-fluoropyrimidine–based nCRT ± immunotherapy yielded higher R0 and pathological complete response rates, its estimated cure rate was comparable to FLOT, both overall and across all subgroups. Cure is an informative endpoint in localised oesophageal cancer. In this registry analysis, perioperative FLOT was associated with higher cure rates than CROSS, particularly in high-risk subgroups. Exploratory findings suggest that alternative neoadjuvant strategies, such as those incorporating ICIs or FOLFOX, warrant further investigation.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"414-427"},"PeriodicalIF":6.8,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03264-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Radioresistance is an objective biological factor that affects the efficacy of clinical radiotherapy in hepatocellular carcinoma (HCC). However, the mechanism involved has not yet been fully understood. Integrative analysis of HCC patient data with RNA-seq and IHC. Radiosensitivity assessed by colony formation assays using HCC cell lines and xenograft models established in B-NDG mice. USP11 promoter activity measured by dual luciferase reporter. Protein interactions analyzed by Co-IP/GST pulldown; post-translational modifications by ubiquitylation assays. Rac1 activity was quantified by measuring GTP-bound levels. Rac1 structural dynamics simulated through molecular dynamics. Functional validation performed using pharmacological inhibitors, genetic depletion and site-directed mutagenesis. Elevated activated Rac1(Rac1-GTP) predicted poor radiotherapeutic response. Ionizing radiation (IR) activated Rac1 and induced its nuclear translocation. Rac1-GTP is required for the transcriptional upregulation of USP11. USP11 stabilised Rac1-GTP via deubiquitination at residues K123/K147/K183, forming a self-reinforcing Rac1-USP11 amplification loop driving radioresistance. USP11 knockdown or mutation of Rac1 deubiquitination sites (K123/K147/K183) destabilized Rac1-GTP and reversed radioresistance. Elevated Rac1-GTP and USP11 correlated with adverse clinical outcomes. Critically, combined NSC23766/Mitoxantrone treatment showed enhanced radiosensitization. This study identifies the Rac1-USP11 reciprocal feedback loop as a novel, self-reinforcing mechanism driving radioresistance in HCC. Targeting this loop via combined Rac1-GTP/USP11 inhibition represents a promising therapeutic strategy for radiosensitizing HCC.
{"title":"The Rac1-USP11 feedback amplification loop: a radiation-activated engine driving radioresistance in hepatocellular carcinoma","authors":"Kaixiao Zhou, Yabo Jiang, Jiahao Guo, Haobo Zhang, Yuhao Hu, Xuanyu Meng, Yecheng Li, Shaohua Wei, Jian Wang, Xubiao Wei, Shuqun Cheng, Jianping Cao, Yang Jiao","doi":"10.1038/s41416-025-03265-1","DOIUrl":"10.1038/s41416-025-03265-1","url":null,"abstract":"Radioresistance is an objective biological factor that affects the efficacy of clinical radiotherapy in hepatocellular carcinoma (HCC). However, the mechanism involved has not yet been fully understood. Integrative analysis of HCC patient data with RNA-seq and IHC. Radiosensitivity assessed by colony formation assays using HCC cell lines and xenograft models established in B-NDG mice. USP11 promoter activity measured by dual luciferase reporter. Protein interactions analyzed by Co-IP/GST pulldown; post-translational modifications by ubiquitylation assays. Rac1 activity was quantified by measuring GTP-bound levels. Rac1 structural dynamics simulated through molecular dynamics. Functional validation performed using pharmacological inhibitors, genetic depletion and site-directed mutagenesis. Elevated activated Rac1(Rac1-GTP) predicted poor radiotherapeutic response. Ionizing radiation (IR) activated Rac1 and induced its nuclear translocation. Rac1-GTP is required for the transcriptional upregulation of USP11. USP11 stabilised Rac1-GTP via deubiquitination at residues K123/K147/K183, forming a self-reinforcing Rac1-USP11 amplification loop driving radioresistance. USP11 knockdown or mutation of Rac1 deubiquitination sites (K123/K147/K183) destabilized Rac1-GTP and reversed radioresistance. Elevated Rac1-GTP and USP11 correlated with adverse clinical outcomes. Critically, combined NSC23766/Mitoxantrone treatment showed enhanced radiosensitization. This study identifies the Rac1-USP11 reciprocal feedback loop as a novel, self-reinforcing mechanism driving radioresistance in HCC. Targeting this loop via combined Rac1-GTP/USP11 inhibition represents a promising therapeutic strategy for radiosensitizing HCC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"391-403"},"PeriodicalIF":6.8,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03265-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1038/s41416-025-03236-6
The ROMIO writing group, co-applicants and study group
Results of RCTs are criticised because the quality assurance (QA) of surgical interventions is not considered. This is particularly true in cancer trials, because higher standards of surgery may confer more favourable outcomes. Although methods for surgical QA exist, it is unclear how to operationalise and report them in the context of pragmatic cancer trials. We describe the development and application of QA processes to an RCT comparing laparoscopically assisted (LAO) and open oesophagectomy (OO) in patients with localised oesophageal cancer. Three QA measures were developed in Phase 1 and tested for feasibility in Phase 2: (i) centre/surgeon entry criteria, (ii) agreement of key components of LAO/OO, and (iii)monitoring adherence to intervention protocols using CRFs and intra-operative photographs. All centres met entry criteria and 30/31 Phase 2 surgeons submitted two videos. Although photos were received for 88.8% of procedures, only 44(14.9%) were complete. Adherence to key intervention components (abdominal/thoracic nodal clearance, hiatal dissection) was consistently reported as better in CRFs than that observed in the intra-operative photographs. Embedding QA measures into pragmatic surgical cancer RCTs is feasible, and provides important data about the quality of interventions. Methods to streamline data collection and analyses are needed prior to widespread use.
{"title":"Development and application of quality assurance methods for interventions in randomised controlled trials of surgical oncology: the ROMIO study (a comparison of minimally invasive and open oesophagectomy)","authors":"The ROMIO writing group, co-applicants and study group","doi":"10.1038/s41416-025-03236-6","DOIUrl":"10.1038/s41416-025-03236-6","url":null,"abstract":"Results of RCTs are criticised because the quality assurance (QA) of surgical interventions is not considered. This is particularly true in cancer trials, because higher standards of surgery may confer more favourable outcomes. Although methods for surgical QA exist, it is unclear how to operationalise and report them in the context of pragmatic cancer trials. We describe the development and application of QA processes to an RCT comparing laparoscopically assisted (LAO) and open oesophagectomy (OO) in patients with localised oesophageal cancer. Three QA measures were developed in Phase 1 and tested for feasibility in Phase 2: (i) centre/surgeon entry criteria, (ii) agreement of key components of LAO/OO, and (iii)monitoring adherence to intervention protocols using CRFs and intra-operative photographs. All centres met entry criteria and 30/31 Phase 2 surgeons submitted two videos. Although photos were received for 88.8% of procedures, only 44(14.9%) were complete. Adherence to key intervention components (abdominal/thoracic nodal clearance, hiatal dissection) was consistently reported as better in CRFs than that observed in the intra-operative photographs. Embedding QA measures into pragmatic surgical cancer RCTs is feasible, and provides important data about the quality of interventions. Methods to streamline data collection and analyses are needed prior to widespread use.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"404-413"},"PeriodicalIF":6.8,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03236-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145602599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We previously reported that IL-33 released during hepatectomy contributes to cytokine-facilitated iCCA tumor growth. However, the underlying mechanisms of the tumor microenvironment remain unexplored. In this study, we aimed to elucidate the impact of IL-33 on cancer-associated fibroblasts (CAFs). The abundance of IL-33-positive cells and alpha-SMA-positive fibroblasts (myoCAFs) was evaluated using resected specimens. Next-generation sequencing (NGS) was performed for comprehensive expression analysis. The effects of IL-33 stimulation on CAFs were investigated in vitro and in vivo using human and murine iCCA cell lines, as well as fibroblasts extracted from resected specimens. IL-33-positive cells and myoCAFs were significant risk factors for intrahepatic recurrence. NGS analysis revealed significant upregulation of various cytokines in cases with high number of IL-33-positive cells. The conditioned medium obtained from fibroblasts stimulated with IL-33 enhanced the proliferation and migration of iCCA cell lines. Among the cytokines that were increased by IL-33 stimulation in vitro, IL-6 was suspected to be the dominant. In a murine syngraft model, hepatectomy led to an increased subcutaneous tumor volume by releasing IL-33, whereas IL-6 blockade suppressed this growth. This study indicated that IL-33 facilitates iCCA growth through fibroblast activation and is associated with intrahepatic recurrence.
{"title":"IL-33 released during liver resection facilitates intrahepatic cholangiocarcinoma growth via cytokine secretion in cancer-associated fibroblasts","authors":"Satoshi Eguchi, Daisaku Yamada, Shogo Kobayashi, Kazuki Sasaki, Yoshifumi Iwagami, Chihiro Yamanaka, Yoshito Tomimaru, Takehiro Noda, Masaki Sakaue, Tadafumi Asaoka, Junzo Shimizu, Hidenori Takahashi, Yuichiro Doki, Hidetoshi Eguchi","doi":"10.1038/s41416-025-03256-2","DOIUrl":"10.1038/s41416-025-03256-2","url":null,"abstract":"We previously reported that IL-33 released during hepatectomy contributes to cytokine-facilitated iCCA tumor growth. However, the underlying mechanisms of the tumor microenvironment remain unexplored. In this study, we aimed to elucidate the impact of IL-33 on cancer-associated fibroblasts (CAFs). The abundance of IL-33-positive cells and alpha-SMA-positive fibroblasts (myoCAFs) was evaluated using resected specimens. Next-generation sequencing (NGS) was performed for comprehensive expression analysis. The effects of IL-33 stimulation on CAFs were investigated in vitro and in vivo using human and murine iCCA cell lines, as well as fibroblasts extracted from resected specimens. IL-33-positive cells and myoCAFs were significant risk factors for intrahepatic recurrence. NGS analysis revealed significant upregulation of various cytokines in cases with high number of IL-33-positive cells. The conditioned medium obtained from fibroblasts stimulated with IL-33 enhanced the proliferation and migration of iCCA cell lines. Among the cytokines that were increased by IL-33 stimulation in vitro, IL-6 was suspected to be the dominant. In a murine syngraft model, hepatectomy led to an increased subcutaneous tumor volume by releasing IL-33, whereas IL-6 blockade suppressed this growth. This study indicated that IL-33 facilitates iCCA growth through fibroblast activation and is associated with intrahepatic recurrence.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"519-529"},"PeriodicalIF":6.8,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145586029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-22DOI: 10.1038/s41416-025-03266-0
Aurora Gaeta, Luca Nuvoli, Chiara Doccioli, Saverio Caini, Maristella Saponara, Carolina Cimminiello, Claudia Cosma, Giuseppe Palmieri, Antonio Cossu, Francesco Vicini, Luca Mazzarella, Giulio Tosti, Paola Queirolo, Sara Gandini
Immunotherapy (IMMUNO) and targeted therapy (TT) have revolutionised melanoma treatment. However, adverse events (AEs) remain frequent and may affect treatment adherence. Female sex has been linked to a higher risk of AEs in cytotoxic therapies. This systematic review and meta-analysis investigate the effect of Sex and Gender (S/G) on AEs during IMMUNO and/or TT in melanoma. Independent studies published up to April 2024 reporting toxicity by S/G in melanoma patients were included. Summary Odds Ratios (sOR) and 95% Confidence Intervals (CI) were calculated using random-effects models. Sixty-nine studies were included. Women had a significantly higher risk of thyroid-related AEs compared to men (sOR = 2.00, 95% CI: 1.41–2.82, I2 = 32%). No significant S/G differences were found for Grade III-IV, dermatological, gastrointestinal, hypophysis, kidney, liver, or ocular toxicities. This meta-analysis highlights a S/G based difference in the occurrence of thyroid-related AEs, particularly during first-line treatment. The observed association of dermatological AEs with TT in women, while intriguing, is based on limited evidence and should be considered hypothesis-generating. Overall, these findings suggest the need for closer monitoring of women for thyroid-related, dermatological, and severe AEs, with future studies warranted to confirm these signals in larger, adequately powered cohorts.
{"title":"Sex and gender influence on adverse events for melanoma patients: a comprehensive review and meta-analysis","authors":"Aurora Gaeta, Luca Nuvoli, Chiara Doccioli, Saverio Caini, Maristella Saponara, Carolina Cimminiello, Claudia Cosma, Giuseppe Palmieri, Antonio Cossu, Francesco Vicini, Luca Mazzarella, Giulio Tosti, Paola Queirolo, Sara Gandini","doi":"10.1038/s41416-025-03266-0","DOIUrl":"10.1038/s41416-025-03266-0","url":null,"abstract":"Immunotherapy (IMMUNO) and targeted therapy (TT) have revolutionised melanoma treatment. However, adverse events (AEs) remain frequent and may affect treatment adherence. Female sex has been linked to a higher risk of AEs in cytotoxic therapies. This systematic review and meta-analysis investigate the effect of Sex and Gender (S/G) on AEs during IMMUNO and/or TT in melanoma. Independent studies published up to April 2024 reporting toxicity by S/G in melanoma patients were included. Summary Odds Ratios (sOR) and 95% Confidence Intervals (CI) were calculated using random-effects models. Sixty-nine studies were included. Women had a significantly higher risk of thyroid-related AEs compared to men (sOR = 2.00, 95% CI: 1.41–2.82, I2 = 32%). No significant S/G differences were found for Grade III-IV, dermatological, gastrointestinal, hypophysis, kidney, liver, or ocular toxicities. This meta-analysis highlights a S/G based difference in the occurrence of thyroid-related AEs, particularly during first-line treatment. The observed association of dermatological AEs with TT in women, while intriguing, is based on limited evidence and should be considered hypothesis-generating. Overall, these findings suggest the need for closer monitoring of women for thyroid-related, dermatological, and severe AEs, with future studies warranted to confirm these signals in larger, adequately powered cohorts.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"359-366"},"PeriodicalIF":6.8,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-22DOI: 10.1038/s41416-025-03160-9
Sisi Dai, Yongcheng Liu, Tingting Guo, Hong Luo, Guanglei Yang, Songliang Yu, Sifan Zhang, Lili Jiang, Jie Liu, Ye Wang, Daxing Zhu, Xuyu Cai
Neoadjuvant immune checkpoint blockade (NA-ICB) shows promise in treating resectable and locally advanced non-small cell lung cancer (NSCLC), yet the specific T cell subtypes that expand and become functionally reactivated remain incompletely characterised. We applied single-cell RNA sequencing, TCR repertoire analysis, and flow cytometry to tumour, paired normal lung tissue, and peripheral blood samples from 26 NA-ICB-treated and 14 treatment-naïve NSCLC patients to investigate responsive T cell subtypes, their tissue origins, migration patterns, and phenotype transitions. CD8 + CX3CR1 + T cells were significantly enriched in responsive tumours, as evidenced by increased proportions (p = 0.0027) and clonal expansion in scRNA-seq, and elevated protein-level frequencies detected by flow cytometry (p = 0.021). Longitudinal analysis revealed proliferation of these cells in peripheral blood post-treatment. Shared TCR clonotypes were identified across blood and tumour samples. Pseudotime analysis indicated differentiation of these cells into exhausted and cytotoxic NK-like CD8 + T cells upon tumour infiltration. These findings suggest that CD8 + CX3CR1 + T cells may represent circulating cytotoxic precursors associated with effective NA-ICB responses, suggesting their potential as predictive biomarkers and therapeutic targets for adoptive cell therapy.
{"title":"Systemic activation and tissue infiltration of CD8 + CX3CR1 + T cells in non-small cell lung cancer treated with neoadjuvant immune checkpoint blockade","authors":"Sisi Dai, Yongcheng Liu, Tingting Guo, Hong Luo, Guanglei Yang, Songliang Yu, Sifan Zhang, Lili Jiang, Jie Liu, Ye Wang, Daxing Zhu, Xuyu Cai","doi":"10.1038/s41416-025-03160-9","DOIUrl":"10.1038/s41416-025-03160-9","url":null,"abstract":"Neoadjuvant immune checkpoint blockade (NA-ICB) shows promise in treating resectable and locally advanced non-small cell lung cancer (NSCLC), yet the specific T cell subtypes that expand and become functionally reactivated remain incompletely characterised. We applied single-cell RNA sequencing, TCR repertoire analysis, and flow cytometry to tumour, paired normal lung tissue, and peripheral blood samples from 26 NA-ICB-treated and 14 treatment-naïve NSCLC patients to investigate responsive T cell subtypes, their tissue origins, migration patterns, and phenotype transitions. CD8 + CX3CR1 + T cells were significantly enriched in responsive tumours, as evidenced by increased proportions (p = 0.0027) and clonal expansion in scRNA-seq, and elevated protein-level frequencies detected by flow cytometry (p = 0.021). Longitudinal analysis revealed proliferation of these cells in peripheral blood post-treatment. Shared TCR clonotypes were identified across blood and tumour samples. Pseudotime analysis indicated differentiation of these cells into exhausted and cytotoxic NK-like CD8 + T cells upon tumour infiltration. These findings suggest that CD8 + CX3CR1 + T cells may represent circulating cytotoxic precursors associated with effective NA-ICB responses, suggesting their potential as predictive biomarkers and therapeutic targets for adoptive cell therapy.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"504-518"},"PeriodicalIF":6.8,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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