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}
Developing effective therapies for cough in lung cancer is an unmet need Neuromodulators like pregabalin may act centrally as cough suppressants. Randomized double-blind placebo-controlled study in patients with locally advanced/metastatic lung cancer and at least 2 weeks of moderate or severe cough. Randomization was 1:1 to pregabalin 300 mg orally daily or matching placebo, both administered for 9 weeks. Primary endpoint was the change in cough severity as measured by the difference in VAS scores. Between Jul 2022 and Dec 2023, we enrolled 166 patients: 83 to each arm. Baseline cough severity was grade 2 in 128 (77.1%) and grade 3 in 38 (22.9%) patients; median cough duration was 12 weeks (IQR, 6–20). Systemic cancer-directed therapy was started in 78 (94.0%) and 72 (86.7%) patients in the pregabalin and placebo arms, respectively; P = 0.187. The mean (SD) VAS score (in mm) decreased from 71.58 (14.99) at baseline, to 45.54 (26.60) on day 7, and 22.27 (24.20) by week 9 in the pregabalin arm; and 71.75 (17.58), 46.35 (25.00), and 23.08 (22.42), respectively in the placebo arm; P = 0.877. Pregabalin does not significantly decrease cough in patients with lung cancer. Systemic cancer-directed therapy is the most effective antitussive. Name of the registry: Clinical Trials Registry India Registration number: CTRI/2020/11/029275 Website: www.ctri.nic.in
{"title":"Pregabalin for chronic cough due to lung cancer: randomized, double-blind, placebo-controlled trial","authors":"Vanita Noronha, Nandini Menon, Vijay M. Patil, Minit Shah, Amit Joshi, Srushti Shah, Kavita Nawale, Rohan Surve, Gunj Bafna, Shweta Jogdhankar, Priyanka Shelar, Ankush Shetake, Ashish Singh, Sushmita Salian, Pundlik Jadhav, Hetakshi Shah, Neha Mer, Ananya Vohra, Swaratika Majumdar, Shripad Banavali, Rajendra Badwe, Kumar Prabhash","doi":"10.1038/s41416-024-02913-2","DOIUrl":"10.1038/s41416-024-02913-2","url":null,"abstract":"Developing effective therapies for cough in lung cancer is an unmet need Neuromodulators like pregabalin may act centrally as cough suppressants. Randomized double-blind placebo-controlled study in patients with locally advanced/metastatic lung cancer and at least 2 weeks of moderate or severe cough. Randomization was 1:1 to pregabalin 300 mg orally daily or matching placebo, both administered for 9 weeks. Primary endpoint was the change in cough severity as measured by the difference in VAS scores. Between Jul 2022 and Dec 2023, we enrolled 166 patients: 83 to each arm. Baseline cough severity was grade 2 in 128 (77.1%) and grade 3 in 38 (22.9%) patients; median cough duration was 12 weeks (IQR, 6–20). Systemic cancer-directed therapy was started in 78 (94.0%) and 72 (86.7%) patients in the pregabalin and placebo arms, respectively; P = 0.187. The mean (SD) VAS score (in mm) decreased from 71.58 (14.99) at baseline, to 45.54 (26.60) on day 7, and 22.27 (24.20) by week 9 in the pregabalin arm; and 71.75 (17.58), 46.35 (25.00), and 23.08 (22.42), respectively in the placebo arm; P = 0.877. Pregabalin does not significantly decrease cough in patients with lung cancer. Systemic cancer-directed therapy is the most effective antitussive. Name of the registry: Clinical Trials Registry India Registration number: CTRI/2020/11/029275 Website: www.ctri.nic.in","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 1","pages":"58-68"},"PeriodicalIF":6.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02913-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726117","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 : 2024-11-26DOI: 10.1038/s41416-024-02914-1
Maryse J. Luijendijk, Sanne M. Buijs, Agnes Jager, Stijn L. W. Koolen, Elsken van der Wall, Sanne B. Schagen, Ron H. J. Mathijssen
Tamoxifen may adversely affect cognitive function by interfering with estrogen action in the brain. Despite growing evidence for a relationship between tamoxifen and cognitive problems, findings remain inconclusive. While some tamoxifen-related side effects seem exposure-dependent with concentrations of tamoxifen or its main metabolite, endoxifen, this has never been investigated for cognitive function. We investigated cognitive function after two years of tamoxifen and its association with tamoxifen and endoxifen exposure. 135 women with breast cancer completed the Amsterdam Cognition Scan (ACS), an online neuropsychological test battery, after two years of tamoxifen. Test scores were converted to standardized Z-scores based on a matched ‘no-cancer’ control group. Tamoxifen and endoxifen concentrations and tamoxifen dose were regressed separately on cognitive functioning. Patients reported mild cognitive complaints and had worse verbal learning, processing speed, executive functioning, and motor functioning compared to matched controls. After correcting for age, mean tamoxifen and endoxifen levels, as well as tamoxifen dose, were associated with worse performance on several cognitive domains. Tamoxifen is adversely associated with objective as well as self-reported cognitive function, which may depend on the level of exposure to tamoxifen and endoxifen. Further research is warranted to confirm this hypothesis.
简介他莫昔芬可能会干扰雌激素在大脑中的作用，从而对认知功能产生不利影响。尽管越来越多的证据表明他莫昔芬与认知问题之间存在关系，但研究结果仍不确定。虽然一些与他莫昔芬相关的副作用似乎与他莫昔芬或其主要代谢物内昔芬的浓度有关，但从未对认知功能进行过调查。我们对服用他莫昔芬两年后的认知功能及其与他莫昔芬和内昔芬暴露的关系进行了调查。方法：135 名患有乳腺癌的妇女在服用他莫昔芬两年后完成了阿姆斯特丹认知扫描（ACS），这是一种在线神经心理测试。测试分数根据匹配的 "无癌症 "对照组转换成标准化 Z 分数。分别对他莫昔芬和内昔芬浓度及他莫昔芬剂量与认知功能进行回归分析：结果：与匹配的对照组相比，患者有轻微的认知障碍，语言学习能力、处理速度、执行功能和运动功能较差。在对年龄进行校正后，他莫昔芬和内昔芬的平均水平以及他莫昔芬的剂量与几个认知领域的表现较差有关：结论：他莫昔芬与客观认知功能以及自我报告的认知功能均有不利关系，这可能取决于他莫昔芬和内昔芬的暴露水平。要证实这一假设，还需要进一步的研究。
{"title":"Effects of tamoxifen on cognitive function in patients with primary breast cancer","authors":"Maryse J. Luijendijk, Sanne M. Buijs, Agnes Jager, Stijn L. W. Koolen, Elsken van der Wall, Sanne B. Schagen, Ron H. J. Mathijssen","doi":"10.1038/s41416-024-02914-1","DOIUrl":"10.1038/s41416-024-02914-1","url":null,"abstract":"Tamoxifen may adversely affect cognitive function by interfering with estrogen action in the brain. Despite growing evidence for a relationship between tamoxifen and cognitive problems, findings remain inconclusive. While some tamoxifen-related side effects seem exposure-dependent with concentrations of tamoxifen or its main metabolite, endoxifen, this has never been investigated for cognitive function. We investigated cognitive function after two years of tamoxifen and its association with tamoxifen and endoxifen exposure. 135 women with breast cancer completed the Amsterdam Cognition Scan (ACS), an online neuropsychological test battery, after two years of tamoxifen. Test scores were converted to standardized Z-scores based on a matched ‘no-cancer’ control group. Tamoxifen and endoxifen concentrations and tamoxifen dose were regressed separately on cognitive functioning. Patients reported mild cognitive complaints and had worse verbal learning, processing speed, executive functioning, and motor functioning compared to matched controls. After correcting for age, mean tamoxifen and endoxifen levels, as well as tamoxifen dose, were associated with worse performance on several cognitive domains. Tamoxifen is adversely associated with objective as well as self-reported cognitive function, which may depend on the level of exposure to tamoxifen and endoxifen. Further research is warranted to confirm this hypothesis.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"180-187"},"PeriodicalIF":6.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726108","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}
S-phase kinase-associated protein 2 (SKP2) is a typical oncogene aberrantly overexpressing in a variety of cancer types, but it remains elusive whether SKP2 regulates the antitumor immunity of triple-negative breast cancer. The efficacy of anti-PD-1 was evaluated in the orthotopic xenografts of immunocompetent mice models. The infiltration of cytotoxic T cells in tumor microenvironment(TME) were assessed by immunofluorescence staining. The levels of pro-inflammatory chemokines were analyzed by ELISA. The protein interaction was analyzed by co-immunoprecipitation and GST pull-down. The genomic instability was analyzed by fluorescent microscopy. SKP2 inhibition significantly improved the antitumor efficacy of immune checkpoint blockade (ICB). Furthermore, SKP2 inhibition activated the cGAS/STING signal pathway and induced the secretion of pro-inflammatory chemokines, thereby promoting cytotoxic T cell infiltration. Additionally, we identified CDC6, a DNA replication licensing factor as a novel substrate of SKP2 in addition to CDT1. SKP2 induced protein degradation of CDC6 and CDT1 through the ubiquitin-proteasome pathway. Conversely, SKP2 inhibition elevated CDC6 and CDT1 protein levels, which caused DNA aberrant replication, DNA damage and genomic instability, thereby resulting in the accumulation of cytosolic DNA, activating cGAS/STING signaling pathway and improving antitumor immunity. SKP2 may be used as an effective therapeutic target to enable ICB antitumor immunotherapy. Peng et al. found that SKP2 inhibition improved the antitumor immunotherapy by activating tumor cell-intrinsic immunity, thereby providing evidences that SKP2 may be used as an effective therapeutic target to enable ICB antitumor immunotherapy.
{"title":"SKP2 inhibition activates tumor cell-intrinsic immunity by inducing DNA replication stress and genomic instability","authors":"Yuchong Peng, Xuli Qi, Liuyang Ding, Jingjing Huang, Youhong Liu, Rirong Zheng, Yongming Fu, Linglong Yin, Tanggang Deng, Yubing Ye, Size Chen, Xiong Li","doi":"10.1038/s41416-024-02909-y","DOIUrl":"10.1038/s41416-024-02909-y","url":null,"abstract":"S-phase kinase-associated protein 2 (SKP2) is a typical oncogene aberrantly overexpressing in a variety of cancer types, but it remains elusive whether SKP2 regulates the antitumor immunity of triple-negative breast cancer. The efficacy of anti-PD-1 was evaluated in the orthotopic xenografts of immunocompetent mice models. The infiltration of cytotoxic T cells in tumor microenvironment(TME) were assessed by immunofluorescence staining. The levels of pro-inflammatory chemokines were analyzed by ELISA. The protein interaction was analyzed by co-immunoprecipitation and GST pull-down. The genomic instability was analyzed by fluorescent microscopy. SKP2 inhibition significantly improved the antitumor efficacy of immune checkpoint blockade (ICB). Furthermore, SKP2 inhibition activated the cGAS/STING signal pathway and induced the secretion of pro-inflammatory chemokines, thereby promoting cytotoxic T cell infiltration. Additionally, we identified CDC6, a DNA replication licensing factor as a novel substrate of SKP2 in addition to CDT1. SKP2 induced protein degradation of CDC6 and CDT1 through the ubiquitin-proteasome pathway. Conversely, SKP2 inhibition elevated CDC6 and CDT1 protein levels, which caused DNA aberrant replication, DNA damage and genomic instability, thereby resulting in the accumulation of cytosolic DNA, activating cGAS/STING signaling pathway and improving antitumor immunity. SKP2 may be used as an effective therapeutic target to enable ICB antitumor immunotherapy. Peng et al. found that SKP2 inhibition improved the antitumor immunotherapy by activating tumor cell-intrinsic immunity, thereby providing evidences that SKP2 may be used as an effective therapeutic target to enable ICB antitumor immunotherapy.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 1","pages":"81-92"},"PeriodicalIF":6.4,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709292","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：