Pub Date : 2024-12-07DOI: 10.1038/s41416-024-02925-y
Jie Lin, Michael I. Orestes, Craig D. Shriver, Kangmin Zhu
Little research has been conducted on the relationship between statin use and the survival of head and neck cancer patients. This study assessed whether statin use after head and neck cancer diagnosis is associated with overall survival among patients in the U.S. military health system (MHS) that provides universal health care to its beneficiaries. The study included 1842 patients with head and neck squamous cell carcinoma (HNSCC) from MHS. Statin use was extracted from the pharmacy database of the Military Health System Data Repository (MDR). Time-dependent multivariate Cox proportional hazards models were used to assess the relationship between post-diagnosis statin use and overall survival with the adjustment for potential confounders. Compared to non-users, increased post-diagnosis cumulative use of statins (per one-year of use) conferred a significant improved survival with adjusted hazard ratio (HR) of 0.70 (95% Confidence Interval, CI = 0.55 to 0.90). When analysis was stratified by status of statin use prior to HNSCC diagnosis, the HRs were 0.31 (95% CI = 0.15–0.65) and 0.81 (95% CI = 0.59–1.11) for post-diagnosis users who also used it before HNSCC diagnosis and those who only used it after the diagnosis, respectively. Prolonged statin use was associated with improved survival among HNSCC patients in MHS.
背景：关于他汀类药物使用与头颈癌患者生存之间关系的研究很少。本研究评估了他汀类药物在头颈癌诊断后的使用是否与美国军事卫生系统（MHS）患者的总生存率相关，该系统为其受益者提供全民医疗保健。方法：研究对象为1842例MHS患者头颈部鳞状细胞癌（HNSCC）。从军事卫生系统数据库（MDR）的药学数据库中提取他汀类药物的使用情况。使用时间相关的多变量Cox比例风险模型评估诊断后他汀类药物使用与总生存率之间的关系，并对潜在混杂因素进行调整。结果：与未使用他汀类药物的患者相比，诊断后累积使用他汀类药物（每使用一年）的增加显著提高了生存率，校正风险比（HR）为0.70（95%置信区间，CI = 0.55至0.90）。根据HNSCC诊断前他汀类药物的使用情况进行分层分析时，诊断后在HNSCC诊断前也使用他汀类药物的患者和诊断后仅使用他汀类药物的患者的hr分别为0.31 （95% CI = 0.15-0.65）和0.81 （95% CI = 0.59-1.11）。结论：延长他汀类药物的使用与MHS中HNSCC患者的生存率提高有关。
{"title":"Post-diagnosis statin use and survival among head and neck cancer patients: a cohort study in a universal health care system","authors":"Jie Lin, Michael I. Orestes, Craig D. Shriver, Kangmin Zhu","doi":"10.1038/s41416-024-02925-y","DOIUrl":"10.1038/s41416-024-02925-y","url":null,"abstract":"Little research has been conducted on the relationship between statin use and the survival of head and neck cancer patients. This study assessed whether statin use after head and neck cancer diagnosis is associated with overall survival among patients in the U.S. military health system (MHS) that provides universal health care to its beneficiaries. The study included 1842 patients with head and neck squamous cell carcinoma (HNSCC) from MHS. Statin use was extracted from the pharmacy database of the Military Health System Data Repository (MDR). Time-dependent multivariate Cox proportional hazards models were used to assess the relationship between post-diagnosis statin use and overall survival with the adjustment for potential confounders. Compared to non-users, increased post-diagnosis cumulative use of statins (per one-year of use) conferred a significant improved survival with adjusted hazard ratio (HR) of 0.70 (95% Confidence Interval, CI = 0.55 to 0.90). When analysis was stratified by status of statin use prior to HNSCC diagnosis, the HRs were 0.31 (95% CI = 0.15–0.65) and 0.81 (95% CI = 0.59–1.11) for post-diagnosis users who also used it before HNSCC diagnosis and those who only used it after the diagnosis, respectively. Prolonged statin use was associated with improved survival among HNSCC patients in MHS.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 3","pages":"259-265"},"PeriodicalIF":6.4,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791442","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 : 2024-12-05DOI: 10.1038/s41416-024-02901-6
Sanjay Popat, Adam Januszewski, Mary O’Brien, Tanya Ahmad, Conrad Lewanski, Ulrike Dernedde, Petra Jankowska, Clive Mulatero, Riyaz Shah, Jonathan Hicks, Tom Geldart, Mathilda Cominos, Gill Gray, James Spicer, Karen Bell, Simon Roitt, Clive Morris, Yenting Ngai, Laura Hughes, Allan Hackshaw, William Wilson
Here we present long-term outcomes of first line afatinib in comorbid patients with suspected or confirmed EGFR mutant NSCLC otherwise considered unsuitable for chemotherapy, and the clinical utility of serial ctDNA monitoring. TIMELY (NCT01415011) was a multicentre, single arm, phase II trial conducted in the UK. Patients aged ≥18 were treated with daily oral afatinib (40 mg) until disease progression or unacceptable toxicity. Blood samples for ctDNA analysis were obtained at baseline and 12-weekly until treatment discontinuation. The primary endpoint was PFS. Thirty-nine patients were enrolled between March 2013 and August 2015. Median follow-up was 98 months (range 69-101). Median PFS was 7.9 months (95% CI 4.6-10.5). Seven patients (18%) continued afatinib beyond 18 months, 3 beyond 36 months and 2 were still on treatment at last follow-up 101 months post-treatment initiation. Analysis of baseline ctDNA samples identified 8 EGFR mutant cases that were not identified by tissue genotyping and ctDNA clearance was associated with improved PFS and OS. Afatinib is a viable treatment option for tissue or ctDNA-detected EGFR mutant NSCLC comorbid patients, with a proportion achieving long-term clinical benefit. Plasma ctDNA testing improved EGFR mutant identification and its clearance predicted improved PFS and OS.
背景：在这里，我们介绍了一线阿法替尼治疗疑似或确诊EGFR突变的非小细胞肺癌合并症患者的长期结果，否则被认为不适合化疗，以及连续ctDNA监测的临床应用。方法：TIMELY （NCT01415011）是在英国进行的一项多中心、单组、II期临床试验。年龄≥18岁的患者每日口服阿法替尼（40mg），直至疾病进展或出现不可接受的毒性。在基线和12周时采集血液样本进行ctDNA分析，直至停止治疗。主要终点为PFS。结果：2013年3月至2015年8月共纳入39例患者。中位随访时间为98个月（范围69-101）。中位PFS为7.9个月（95% CI 4.6-10.5）。7例（18%）患者持续使用阿法替尼超过18个月，3例超过36个月，2例在治疗开始后101个月的最后随访中仍在治疗。基线ctDNA样本分析确定了8例未通过组织基因分型确定的EGFR突变病例，ctDNA清除与改善PFS和OS相关。结论：对于组织或ctdna检测的EGFR突变型NSCLC合并症患者，阿法替尼是一种可行的治疗选择，且有一定比例的患者可获得长期临床获益。血浆ctDNA检测提高了EGFR突变体的识别，其清除率预测了PFS和OS的改善。
{"title":"Long term efficacy of first-line afatinib and the clinical utility of ctDNA monitoring in patients with suspected or confirmed EGFR mutant non-small cell lung cancer who were unsuitable for chemotherapy","authors":"Sanjay Popat, Adam Januszewski, Mary O’Brien, Tanya Ahmad, Conrad Lewanski, Ulrike Dernedde, Petra Jankowska, Clive Mulatero, Riyaz Shah, Jonathan Hicks, Tom Geldart, Mathilda Cominos, Gill Gray, James Spicer, Karen Bell, Simon Roitt, Clive Morris, Yenting Ngai, Laura Hughes, Allan Hackshaw, William Wilson","doi":"10.1038/s41416-024-02901-6","DOIUrl":"10.1038/s41416-024-02901-6","url":null,"abstract":"Here we present long-term outcomes of first line afatinib in comorbid patients with suspected or confirmed EGFR mutant NSCLC otherwise considered unsuitable for chemotherapy, and the clinical utility of serial ctDNA monitoring. TIMELY (NCT01415011) was a multicentre, single arm, phase II trial conducted in the UK. Patients aged ≥18 were treated with daily oral afatinib (40 mg) until disease progression or unacceptable toxicity. Blood samples for ctDNA analysis were obtained at baseline and 12-weekly until treatment discontinuation. The primary endpoint was PFS. Thirty-nine patients were enrolled between March 2013 and August 2015. Median follow-up was 98 months (range 69-101). Median PFS was 7.9 months (95% CI 4.6-10.5). Seven patients (18%) continued afatinib beyond 18 months, 3 beyond 36 months and 2 were still on treatment at last follow-up 101 months post-treatment initiation. Analysis of baseline ctDNA samples identified 8 EGFR mutant cases that were not identified by tissue genotyping and ctDNA clearance was associated with improved PFS and OS. Afatinib is a viable treatment option for tissue or ctDNA-detected EGFR mutant NSCLC comorbid patients, with a proportion achieving long-term clinical benefit. Plasma ctDNA testing improved EGFR mutant identification and its clearance predicted improved PFS and OS.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 3","pages":"245-252"},"PeriodicalIF":6.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02901-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784126","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 : 2024-12-03DOI: 10.1038/s41416-024-02918-x
Y. Kususda, H. Miyake, M. E. Gleave, M. Fujisawa
{"title":"Editorial Expression of Concern: Clusterin inhibition using OGX-011 synergistically enhances antitumour activity of sorafenib in a human renal cell carcinoma model","authors":"Y. Kususda, H. Miyake, M. E. Gleave, M. Fujisawa","doi":"10.1038/s41416-024-02918-x","DOIUrl":"10.1038/s41416-024-02918-x","url":null,"abstract":"","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 1","pages":"138-138"},"PeriodicalIF":6.4,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02918-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766361","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 : 2024-12-02DOI: 10.1038/s41416-024-02910-5
Han Xiao, Jianping Wang, Zongpeng Weng, Xiaoxuan Lin, Man Shu, Jingxian Shen, Peng Sun, Muyan Cai, Xiao Xiang, Bin Li, Lihong Wei, Yiyu Shi, Jiaming Lai, Ming Kuang, Jingping Yun, Shuling Chen, Sui Peng
Targeted therapy for intrahepatic cholangiocarcinoma (ICC) shows superior survival outcomes but patients with certain targetable alterations are no more than 20%. Genetic alteration screening for all ICC patients is of high cost and not routinely performed. This study intends to develop a histopathology-based artificial intelligence (AI)-assisted system for predicting genetic alteration of ICC. We constructed a Genetic Alteration Prediction (GAP) system based on multi-instance learning and self-supervised learning to predict genetic alterations using whole-slide images (WSIs) of H&E-stained slides. A total of 2069 WSIs from 232 ICC patients underwent surgery of the FAH-SYSU dataset were used for model construction and adjustment by five-fold cross-validation. Another 150 patients from three medical centres were used as independent external validations. We also compared the cost-effectiveness of GAP-assisted precise treatment and all-sequencing strategy to non-sequencing strategy. The GAP was able to predict actionable genetic alterations of ICC, including FGFR2 and IDH. The area under the receiver operating characteristic curves (AUC) for FGFR2 and IDH were 0.754 and 0.713 in the internal dataset, and 0.724 and 0.656 in the external dataset, respectively. Furthermore, compared to giving chemotherapy without sequencing for every patient, GAP-assisted precise treatment could increase 1 progression-free quality-adjusted life month with a cost of $13871.72, the co-responding figure for all-sequencing strategy is $44538.93. Decision curve analysis showed that AI-assisted strategy provides better clinical benefits. We constructed an AI-assisted genetic alteration screening system which is predictable to ICC actionable targets and has potential to assist precise targeted treatment of advanced ICC.
{"title":"A histopathology-based artificial intelligence system assisting the screening of genetic alteration in intrahepatic cholangiocarcinoma","authors":"Han Xiao, Jianping Wang, Zongpeng Weng, Xiaoxuan Lin, Man Shu, Jingxian Shen, Peng Sun, Muyan Cai, Xiao Xiang, Bin Li, Lihong Wei, Yiyu Shi, Jiaming Lai, Ming Kuang, Jingping Yun, Shuling Chen, Sui Peng","doi":"10.1038/s41416-024-02910-5","DOIUrl":"10.1038/s41416-024-02910-5","url":null,"abstract":"Targeted therapy for intrahepatic cholangiocarcinoma (ICC) shows superior survival outcomes but patients with certain targetable alterations are no more than 20%. Genetic alteration screening for all ICC patients is of high cost and not routinely performed. This study intends to develop a histopathology-based artificial intelligence (AI)-assisted system for predicting genetic alteration of ICC. We constructed a Genetic Alteration Prediction (GAP) system based on multi-instance learning and self-supervised learning to predict genetic alterations using whole-slide images (WSIs) of H&E-stained slides. A total of 2069 WSIs from 232 ICC patients underwent surgery of the FAH-SYSU dataset were used for model construction and adjustment by five-fold cross-validation. Another 150 patients from three medical centres were used as independent external validations. We also compared the cost-effectiveness of GAP-assisted precise treatment and all-sequencing strategy to non-sequencing strategy. The GAP was able to predict actionable genetic alterations of ICC, including FGFR2 and IDH. The area under the receiver operating characteristic curves (AUC) for FGFR2 and IDH were 0.754 and 0.713 in the internal dataset, and 0.724 and 0.656 in the external dataset, respectively. Furthermore, compared to giving chemotherapy without sequencing for every patient, GAP-assisted precise treatment could increase 1 progression-free quality-adjusted life month with a cost of $13871.72, the co-responding figure for all-sequencing strategy is $44538.93. Decision curve analysis showed that AI-assisted strategy provides better clinical benefits. We constructed an AI-assisted genetic alteration screening system which is predictable to ICC actionable targets and has potential to assist precise targeted treatment of advanced ICC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"195-202"},"PeriodicalIF":6.4,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766336","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 : 2024-11-30DOI: 10.1038/s41416-024-02916-z
Adam J. Shephard, Hanya Mahmood, Shan E. Ahmed Raza, Syed Ali Khurram, Nasir M. Rajpoot
Oral epithelial dysplasia (OED) poses a significant clinical challenge due to its potential for malignant transformation and the lack of reliable prognostic markers. Current OED grading systems do not reliably predict transformation and suffer from considerable observer variability. Recent studies have highlighted that peri-epithelial lymphocytes may play an important role in OED malignant transformation, with indication that intra-epithelial lymphocytes (IELs) may also be important. We propose a novel artificial intelligence (AI) based IEL score from Haematoxylin and Eosin (H&E) stained Whole Slide Images (WSIs) of OED tissue slides. We determine the prognostic value of our IEL score on a digital dataset of 219 OED WSIs (acquired using three different scanners), compared to pathologist-led clinical grading. Our IEL scores demonstrated significant prognostic value (C-index = 0.67, p < 0.001) and were shown to improve both the binary/WHO grading systems in multivariate analyses (p < 0.001). Nuclear analyses confirmed the positive association between higher IEL scores, more severe OED and malignant transformation (p < 0.05). This underscores the potential importance of IELs, and by extension our IEL score, as prognostic indicators in OED. Further validation through prospective multi-centric studies is warranted to confirm the clinical utility of IELs.
{"title":"A novel AI-based score for assessing the prognostic value of intra-epithelial lymphocytes in oral epithelial dysplasia","authors":"Adam J. Shephard, Hanya Mahmood, Shan E. Ahmed Raza, Syed Ali Khurram, Nasir M. Rajpoot","doi":"10.1038/s41416-024-02916-z","DOIUrl":"10.1038/s41416-024-02916-z","url":null,"abstract":"Oral epithelial dysplasia (OED) poses a significant clinical challenge due to its potential for malignant transformation and the lack of reliable prognostic markers. Current OED grading systems do not reliably predict transformation and suffer from considerable observer variability. Recent studies have highlighted that peri-epithelial lymphocytes may play an important role in OED malignant transformation, with indication that intra-epithelial lymphocytes (IELs) may also be important. We propose a novel artificial intelligence (AI) based IEL score from Haematoxylin and Eosin (H&E) stained Whole Slide Images (WSIs) of OED tissue slides. We determine the prognostic value of our IEL score on a digital dataset of 219 OED WSIs (acquired using three different scanners), compared to pathologist-led clinical grading. Our IEL scores demonstrated significant prognostic value (C-index = 0.67, p < 0.001) and were shown to improve both the binary/WHO grading systems in multivariate analyses (p < 0.001). Nuclear analyses confirmed the positive association between higher IEL scores, more severe OED and malignant transformation (p < 0.05). This underscores the potential importance of IELs, and by extension our IEL score, as prognostic indicators in OED. Further validation through prospective multi-centric studies is warranted to confirm the clinical utility of IELs.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"168-179"},"PeriodicalIF":6.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02916-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766350","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 : 2024-11-29DOI: 10.1038/s41416-024-02912-3
Fabian Stögbauer, Markus Wirth, Maren Lauterbach, Barbara Wollenberg, Benedikt Schmidl, Cosima C. Hoch, Iordanis Ourailidis, Jochen Hess, Markus Eckstein, Arndt Hartmann, Heinrich Iro, Antoniu-Oreste Gostian, Matthias Balk, Moritz Jesinghaus, Julika Ribbat-Idel, Verena-Wilbeth Sailer, Sven Perner, Karl-Ludwig Bruchhage, Markus Hoffmann, Lukas Lükewille, Christiane Maria Stuhlmann-Laeisz, Christoph Röcken, Carolin Mogler, Jan Budczies, Melanie Boxberg
We aimed to validate the prognostic significance of tumor budding (TB) in p16-positive oropharyngeal squamous cell carcinomas (OPSCC). We analyzed digitized H&E-stained slides from a multicenter cohort of five large university centers consisting of n = 275 cases of p16-positive OPSCC. We evaluated TB along with other histological parameters (morphology, tumor-stroma-ratio, lymphovascular invasion (LVI), perineural invasion) and calculated survival outcomes using both univariate and multivariate analyses. TB was identified as an independent prognostic parameter, with TB-high cases showing inferior outcomes in univariate (HR: 3.08, 95%-CI: 1.71–5.54) and multivariate analyses (HR: 4.03, 95%-CI: 1.65–9.83). Similarly, LVI remained an independent prognostic factor (HR: 3.00, 95%-CI: 1.22–7.38). A combined classification including TB and LVI stratified cases into low-, intermediate- and high-risk categories. We could not detect correlations between TB and the number of lymph node metastases or between TB and an extracapsular extension of lymph node metastases. In addition to LVI, we could identify TB as an independent prognostic factor in p16-positive OPSCC in this multicenter study cohort. Thus, evaluating TB along with LVI in a combined scheme for prognostication might help to establish a more personalized treatment regimen for patients with p16-positive OPSCC.
{"title":"Tumor budding and lymphovascular invasion as prognostic factors in p16-positive oropharyngeal squamous cell carcinomas","authors":"Fabian Stögbauer, Markus Wirth, Maren Lauterbach, Barbara Wollenberg, Benedikt Schmidl, Cosima C. Hoch, Iordanis Ourailidis, Jochen Hess, Markus Eckstein, Arndt Hartmann, Heinrich Iro, Antoniu-Oreste Gostian, Matthias Balk, Moritz Jesinghaus, Julika Ribbat-Idel, Verena-Wilbeth Sailer, Sven Perner, Karl-Ludwig Bruchhage, Markus Hoffmann, Lukas Lükewille, Christiane Maria Stuhlmann-Laeisz, Christoph Röcken, Carolin Mogler, Jan Budczies, Melanie Boxberg","doi":"10.1038/s41416-024-02912-3","DOIUrl":"10.1038/s41416-024-02912-3","url":null,"abstract":"We aimed to validate the prognostic significance of tumor budding (TB) in p16-positive oropharyngeal squamous cell carcinomas (OPSCC). We analyzed digitized H&E-stained slides from a multicenter cohort of five large university centers consisting of n = 275 cases of p16-positive OPSCC. We evaluated TB along with other histological parameters (morphology, tumor-stroma-ratio, lymphovascular invasion (LVI), perineural invasion) and calculated survival outcomes using both univariate and multivariate analyses. TB was identified as an independent prognostic parameter, with TB-high cases showing inferior outcomes in univariate (HR: 3.08, 95%-CI: 1.71–5.54) and multivariate analyses (HR: 4.03, 95%-CI: 1.65–9.83). Similarly, LVI remained an independent prognostic factor (HR: 3.00, 95%-CI: 1.22–7.38). A combined classification including TB and LVI stratified cases into low-, intermediate- and high-risk categories. We could not detect correlations between TB and the number of lymph node metastases or between TB and an extracapsular extension of lymph node metastases. In addition to LVI, we could identify TB as an independent prognostic factor in p16-positive OPSCC in this multicenter study cohort. Thus, evaluating TB along with LVI in a combined scheme for prognostication might help to establish a more personalized treatment regimen for patients with p16-positive OPSCC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"212-221"},"PeriodicalIF":6.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02912-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754759","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 : 2024-11-29DOI: 10.1038/s41416-024-02904-3
Marine Bruciamacchie, Véronique Garambois, Nadia Vie, Thomas Bessede, Henri-Alexandre Michaud, Laure-Agnès Chepeaux, Laurent Gros, Nathalie Bonnefoy, Mathilde Robin, Dorian Brager, Kevin Bigot, Alexandre Evrard, Philippe Pourquier, Jacques Colinge, Muriel Mathonnet, Ismahane Belhabib, Christine Jean, Corinne Bousquet, Pierre-Emmanuel Colombo, Marta Jarlier, Diégo Tosi, Céline Gongora, Christel Larbouret
In pancreatic ductal adenocarcinoma (PDAC), the dense stroma rich in cancer-associated fibroblasts (CAFs) and the immunosuppressive microenvironment confer resistance to treatments. To overcome such resistance, we tested the combination of FOLFIRINOX (DNA damage-inducing chemotherapy drugs) with VE-822 (an ataxia-telangiectasia and RAD3-related inhibitor that targets DNA damage repair). PDAC spheroid models and organoids were used to assess the combination effects. Tumour growth and the immune and fibrotic microenvironment were evaluated by immunohistochemistry, single-cell analysis and spatial proteomics in patient-derived xenograft (PDX) and orthotopic immunocompetent KPC mouse models. The FOLFIRINOX and VE-822 combination had a strong synergistic effect in several PDAC cell lines, whatever their BRCA1, BRCA2 and ATM mutation status and resistance to standard chemotherapy agents. This was associated with high DNA damage and inhibition of DNA repair signalling pathways, leading to increased apoptosis. In immunocompetent and PDX mouse models of PDAC, the combination inhibited tumour growth more effectively than FOLFIRINOX alone. This was associated with tumour microenvironment remodelling, particularly decreased proportion of fibroblast activated protein-positive CAFs and increased anti-tumorigenic immune cell infiltration and interaction. The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.
{"title":"ATR inhibition potentiates FOLFIRINOX cytotoxic effect in models of pancreatic ductal adenocarcinoma by remodelling the tumour microenvironment","authors":"Marine Bruciamacchie, Véronique Garambois, Nadia Vie, Thomas Bessede, Henri-Alexandre Michaud, Laure-Agnès Chepeaux, Laurent Gros, Nathalie Bonnefoy, Mathilde Robin, Dorian Brager, Kevin Bigot, Alexandre Evrard, Philippe Pourquier, Jacques Colinge, Muriel Mathonnet, Ismahane Belhabib, Christine Jean, Corinne Bousquet, Pierre-Emmanuel Colombo, Marta Jarlier, Diégo Tosi, Céline Gongora, Christel Larbouret","doi":"10.1038/s41416-024-02904-3","DOIUrl":"10.1038/s41416-024-02904-3","url":null,"abstract":"In pancreatic ductal adenocarcinoma (PDAC), the dense stroma rich in cancer-associated fibroblasts (CAFs) and the immunosuppressive microenvironment confer resistance to treatments. To overcome such resistance, we tested the combination of FOLFIRINOX (DNA damage-inducing chemotherapy drugs) with VE-822 (an ataxia-telangiectasia and RAD3-related inhibitor that targets DNA damage repair). PDAC spheroid models and organoids were used to assess the combination effects. Tumour growth and the immune and fibrotic microenvironment were evaluated by immunohistochemistry, single-cell analysis and spatial proteomics in patient-derived xenograft (PDX) and orthotopic immunocompetent KPC mouse models. The FOLFIRINOX and VE-822 combination had a strong synergistic effect in several PDAC cell lines, whatever their BRCA1, BRCA2 and ATM mutation status and resistance to standard chemotherapy agents. This was associated with high DNA damage and inhibition of DNA repair signalling pathways, leading to increased apoptosis. In immunocompetent and PDX mouse models of PDAC, the combination inhibited tumour growth more effectively than FOLFIRINOX alone. This was associated with tumour microenvironment remodelling, particularly decreased proportion of fibroblast activated protein-positive CAFs and increased anti-tumorigenic immune cell infiltration and interaction. The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"222-235"},"PeriodicalIF":6.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754558","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}
Individuals with normal weight obesity (NWO) often escape the attention of healthcare providers who may assume that a normal body mass index (BMI) correlates with low health risks. However, it remains unknown whether NWO increases the risk of breast cancer. This study included 22,257 and 52,506 pre- and postmenopausal females with normal BMI in the UK Biobank. NWO was defined as participants with a normal BMI (18.5–24.9 kg/m2) and an excess percent body fat (PBF > 33.3%). Cox proportional hazard models were used to investigate the associations of NWO and NWO-related biomarkers with incident breast cancer. NWO was not associated with premenopausal breast cancer, whereas it was associated with a higher risk of postmenopausal breast cancer (hazard ratio = 1.19, 95% CI: 1.08–1.31). In our meta-analysis, per 5-unit increment in percent body fat level was linked to a 15% (95% CI: 10–19%) elevated risk of postmenopausal breast cancer in females with normal BMI. Stratified analyses showed a stronger positive association in females with higher genetic risk. In our NWO-biomarkers analyses, NWO was linked to 34 identified biomarkers, of which three inflammation markers (monocyte count, neutrophil count, and C-reactive protein), and one ketone body metabolite (β-Hydroxybutyrate) also indicated a positive association with postmenopausal breast cancer. NWO is associated with an increased risk of postmenopausal breast cancer, indicating that relying solely on BMI neglects the higher risk faced by non-obese postmenopausal women.
{"title":"Normal weight obesity, circulating biomarkers and risk of breast cancer: a prospective cohort study and meta-analysis","authors":"Wenjie Wang, Xiaoyan Wang, Ying Jiang, Yingying Guo, Peifen Fu, Wei He, Xiaohua Fu","doi":"10.1038/s41416-024-02906-1","DOIUrl":"10.1038/s41416-024-02906-1","url":null,"abstract":"Individuals with normal weight obesity (NWO) often escape the attention of healthcare providers who may assume that a normal body mass index (BMI) correlates with low health risks. However, it remains unknown whether NWO increases the risk of breast cancer. This study included 22,257 and 52,506 pre- and postmenopausal females with normal BMI in the UK Biobank. NWO was defined as participants with a normal BMI (18.5–24.9 kg/m2) and an excess percent body fat (PBF > 33.3%). Cox proportional hazard models were used to investigate the associations of NWO and NWO-related biomarkers with incident breast cancer. NWO was not associated with premenopausal breast cancer, whereas it was associated with a higher risk of postmenopausal breast cancer (hazard ratio = 1.19, 95% CI: 1.08–1.31). In our meta-analysis, per 5-unit increment in percent body fat level was linked to a 15% (95% CI: 10–19%) elevated risk of postmenopausal breast cancer in females with normal BMI. Stratified analyses showed a stronger positive association in females with higher genetic risk. In our NWO-biomarkers analyses, NWO was linked to 34 identified biomarkers, of which three inflammation markers (monocyte count, neutrophil count, and C-reactive protein), and one ketone body metabolite (β-Hydroxybutyrate) also indicated a positive association with postmenopausal breast cancer. NWO is associated with an increased risk of postmenopausal breast cancer, indicating that relying solely on BMI neglects the higher risk faced by non-obese postmenopausal women.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"203-211"},"PeriodicalIF":6.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02906-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750040","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 : 2024-11-27DOI: 10.1038/s41416-024-02902-5
Andrea Pretta, Pina Ziranu, Eleonora Perissinotto, Filippo Ghelardi, Federica Marmorino, Riccardo Giampieri, Mariangela Puci, Maria Caterina De Grandis, Eleonora Lai, Vincenzo Nasca, Paolo Ciraci, Marco Puzzoni, Krisida Cerma, Carolina Sciortino, Ada Taravella, Gianluca Pretta, Lorenzo Giuliani, Camilla Damonte, Valeria Pusceddu, Giovanni Sotgiu, Rossana Berardi, Sara Lonardi, Francesca Bergamo, Filippo Pietrantonio, Chiara Cremolini, Mario Scartozzi
Despite a reduction of both incidence and mortality from CRC, recent studies have shown an increase in the incidence of early-onset CRC (EO-CRC). Data on this setting are limited. The aim of our study was to evaluate the clinical and molecular profiles of metastatic EO-CRC patients in order to identify differences compared to a late-onset CRC (LO-CRC) control group. We retrospectively collected data from 1272 metastatic colorectal cancers from 5 different Italian Institutions. The main objective was to the evaluate clinical outcome for EO-CRC patients in comparison to patients included in the control group. In the overall population, mOS was 34,7 in EO-CRC pts vs 43,0 months (mo) (p < 0,0001). In the RAS/BRAF mutated subgroup mOS in EO-CRC pts was 30,3 vs 34,0 mo (p = 0,0156). In RAS/BRAF wild-type EO-CRC mOS was 43,0 vs 50,0 mo (p = 0,0290). mPFS was 11,0 in EO-CRC pts vs 14,0 mo (p < 0,0001). Findings indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research.
{"title":"Early onset metastatic colorectal cancer patients as a distinctive clinical and molecular phenomenon","authors":"Andrea Pretta, Pina Ziranu, Eleonora Perissinotto, Filippo Ghelardi, Federica Marmorino, Riccardo Giampieri, Mariangela Puci, Maria Caterina De Grandis, Eleonora Lai, Vincenzo Nasca, Paolo Ciraci, Marco Puzzoni, Krisida Cerma, Carolina Sciortino, Ada Taravella, Gianluca Pretta, Lorenzo Giuliani, Camilla Damonte, Valeria Pusceddu, Giovanni Sotgiu, Rossana Berardi, Sara Lonardi, Francesca Bergamo, Filippo Pietrantonio, Chiara Cremolini, Mario Scartozzi","doi":"10.1038/s41416-024-02902-5","DOIUrl":"10.1038/s41416-024-02902-5","url":null,"abstract":"Despite a reduction of both incidence and mortality from CRC, recent studies have shown an increase in the incidence of early-onset CRC (EO-CRC). Data on this setting are limited. The aim of our study was to evaluate the clinical and molecular profiles of metastatic EO-CRC patients in order to identify differences compared to a late-onset CRC (LO-CRC) control group. We retrospectively collected data from 1272 metastatic colorectal cancers from 5 different Italian Institutions. The main objective was to the evaluate clinical outcome for EO-CRC patients in comparison to patients included in the control group. In the overall population, mOS was 34,7 in EO-CRC pts vs 43,0 months (mo) (p < 0,0001). In the RAS/BRAF mutated subgroup mOS in EO-CRC pts was 30,3 vs 34,0 mo (p = 0,0156). In RAS/BRAF wild-type EO-CRC mOS was 43,0 vs 50,0 mo (p = 0,0290). mPFS was 11,0 in EO-CRC pts vs 14,0 mo (p < 0,0001). Findings indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"188-194"},"PeriodicalIF":6.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738427","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}
Indoleamine 2,3-dioxygenase (IDO) impairs anti-pathogen and anti-tumour immunity. Mesenchymal stem cells (MSCs) modulate immunity via IDO but also suppress IFN-γ. While MSC IDO induction by IFN-γ is established, other drivers in this immunosuppressive setting remain unknown. Human bone marrow mesenchymal stem cells (MSCs) with IDO or IL-10RA knockdown were co-cultured with healthy donor T cells to assess immunosuppression. PDAC organoid anticancer activity was also tested in these co-cultures. Co-culturing MSCs with T cells in an IL-10RA-enriched environment enhances IDO expression, resulting in T cell suppression. Moreover, IL-10RA-positive MSCs collected from co-cultures with IL-10 supplementation show increased IDO expression. Conversely, MSCs with IL-10RA knockdown exhibit a significant reduction in IDO RNA and protein expression, as well as STAT3 phosphorylation status, which is a known upstream signalling pathway in IDO gene regulation, in T cell co-cultures. Down-regulation of IL-10RA also inhibits IDO activity in MSCs, resulting in reduced T cell suppression, and enabling the co-cultured T cells to kill PDAC organoids. Our research reveals IL-10RA as a pharmacological target in stromal cells for enhancing T cell-mediated PDAC eradication by downregulating IDO via blocked IL-10/IL-10RA signalling in MSCs. This advances IL-10RA interference in the tumour microenvironment (TME) to restore T cell cytotoxicity against cancers.
{"title":"IL-10RA governor the expression of IDO in the instruction of lymphocyte immunity","authors":"Tzong-Shyuan Tai, Duen-Wei Hsu, Yu-Shao Yang, Ching-Yen Tsai, Jai-Wen Shi, Chien-Hui Wu, Shu-Ching Hsu","doi":"10.1038/s41416-024-02893-3","DOIUrl":"10.1038/s41416-024-02893-3","url":null,"abstract":"Indoleamine 2,3-dioxygenase (IDO) impairs anti-pathogen and anti-tumour immunity. Mesenchymal stem cells (MSCs) modulate immunity via IDO but also suppress IFN-γ. While MSC IDO induction by IFN-γ is established, other drivers in this immunosuppressive setting remain unknown. Human bone marrow mesenchymal stem cells (MSCs) with IDO or IL-10RA knockdown were co-cultured with healthy donor T cells to assess immunosuppression. PDAC organoid anticancer activity was also tested in these co-cultures. Co-culturing MSCs with T cells in an IL-10RA-enriched environment enhances IDO expression, resulting in T cell suppression. Moreover, IL-10RA-positive MSCs collected from co-cultures with IL-10 supplementation show increased IDO expression. Conversely, MSCs with IL-10RA knockdown exhibit a significant reduction in IDO RNA and protein expression, as well as STAT3 phosphorylation status, which is a known upstream signalling pathway in IDO gene regulation, in T cell co-cultures. Down-regulation of IL-10RA also inhibits IDO activity in MSCs, resulting in reduced T cell suppression, and enabling the co-cultured T cells to kill PDAC organoids. Our research reveals IL-10RA as a pharmacological target in stromal cells for enhancing T cell-mediated PDAC eradication by downregulating IDO via blocked IL-10/IL-10RA signalling in MSCs. This advances IL-10RA interference in the tumour microenvironment (TME) to restore T cell cytotoxicity against cancers.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 1","pages":"126-136"},"PeriodicalIF":6.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02893-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726113","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}
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