Pub Date : 2024-08-19DOI: 10.1101/2024.08.18.24312178
Yuan Ji, Yunxuan Zhang, Andrew Liu Ji
PURPOSE We propose and demonstrate the feasibility and desirability of a novel model-free dose-finding design for phase I clinical trials. METHODS The Generalized 3+3 (G3+3) design uses a set of simple rules summarized as follows: For 3 or 6 patients at a dose, apply the 3+3 design for making dosing decisions. For other numbers, if the observed toxicity rate (OTR) is less than 0.2, escalate to the next higher dose; if the OTR is greater than 0.29, de-escalate to the next lower dose; otherwise, stay at the current dose. RESULTS The G3+3 design is the only design that can replicate the decisions of the 3+3 design for 3 or 6 patients among the popular designs compared like BOIN and i3+3. G3+3 generates desirable decisions when the number of patients treated is not 3 or 6, like the popular designs. Computer simulation verifies the superior operating characteristics of the G3+3 design. CONCLUSION The G3+3 design generalizes the popular 3+3 design so that desirable decisions can be made for any number of patients at a dose. Since G3+3 does not rely on statistical models, is simple and transparent, and can be implemented without a software tool, it is expected to facilitate and enhance modern phase I dose-finding trials and early-phase drug development.
{"title":"The Generalized 3+3 (G3+3) Design for Phase I Dose-Finding Trials","authors":"Yuan Ji, Yunxuan Zhang, Andrew Liu Ji","doi":"10.1101/2024.08.18.24312178","DOIUrl":"https://doi.org/10.1101/2024.08.18.24312178","url":null,"abstract":"PURPOSE We propose and demonstrate the feasibility and desirability of a novel model-free dose-finding design for phase I clinical trials. METHODS The Generalized 3+3 (G3+3) design uses a set of simple rules summarized as follows: For 3 or 6 patients at a dose, apply the 3+3 design for making dosing decisions. For other numbers, if the observed toxicity rate (OTR) is less than 0.2, escalate to the next higher dose; if the OTR is greater than 0.29, de-escalate to the next lower dose; otherwise, stay at the current dose. RESULTS The G3+3 design is the only design that can replicate the decisions of the 3+3 design for 3 or 6 patients among the popular designs compared like BOIN and i3+3. G3+3 generates desirable decisions when the number of patients treated is not 3 or 6, like the popular designs. Computer simulation verifies the superior operating characteristics of the G3+3 design. CONCLUSION The G3+3 design generalizes the popular 3+3 design so that desirable decisions can be made for any number of patients at a dose. Since G3+3 does not rely on statistical models, is simple and transparent, and can be implemented without a software tool, it is expected to facilitate and enhance modern phase I dose-finding trials and early-phase drug development.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1101/2024.08.17.24311219
Christoph Weigel, Haley L Klimaszewski, Selamawit Addissie, Sarah Schlotter, Fode Tounkara, James P Dugan, Bradley M Haverkos, Lynda Villagomez, Mark Lustberg, Pierluigi Porcu, Timothy Voorhees, Michael A Caligiuri, Ginny Bumgardner, Christopher C Oakes, Robert A Baiocchi
Epstein-Barr virus (EBV)-associated central nervous system lymphoproliferative diseases (CNSL) are aggressive clinical conditions with poor prognosis. We have reported that durable responses in patients with primary CNS post-transplant lymphoproliferative disease (PTLD) were associated with detection of two ganciclovir (GCV)/zidovudine (AZT) viral drug target proteins, the EBV kinases BGLF4 and BXLF1 in CNSL biopsies. These are associated with lytic EBV and the mechanism for expression in latently infected EBV+ CNSL has been unknown. By carrying out RNA expression analysis in CNSL tissue biopsies (n=12), we confirmed expression of LMP1, BXLF1, and BGLF4, but not BZLF1, pointing to an incomplete lytic EBV program. Biopsies from systemic PTLD (n=24) were used for comparison and showed significantly less expression of BGLF4. By quantifying DNA methylation in EBV gene promoters we showed significantly decreased promoter methylation at BGLF4 in CNSL versus systemic PTLD (p=0.0006). Luciferase reporter analysis of the BGLF4 upstream sequence revealed 3 regions of promoter activity and 5ˈ RACE in n=4 EBV-infected cell lines and n=5 CNSL biopsy samples identified transcription start sites at these promoters. We identified DNA methylation loss at single CpG dinucleotides which were specifically demethylated in CNSL, while surrounding EBV methylation remained high. Lastly, TET knockout and expression of TET1/2-suppressive mutant IDH1 in a latent HEK293 EBV model indicated that active demethylation is necessary for activity of BGLF4 promoters. We detail the epigenetic basis of BGLF4 expression in CNSL via locus-specific promoter activation that may hold value for determination of antiviral drug sensitivity.
{"title":"Epigenetic Activation of the EBV Protein Kinase Determines Antiviral Drug Response in Central Nervous System Lymphoma","authors":"Christoph Weigel, Haley L Klimaszewski, Selamawit Addissie, Sarah Schlotter, Fode Tounkara, James P Dugan, Bradley M Haverkos, Lynda Villagomez, Mark Lustberg, Pierluigi Porcu, Timothy Voorhees, Michael A Caligiuri, Ginny Bumgardner, Christopher C Oakes, Robert A Baiocchi","doi":"10.1101/2024.08.17.24311219","DOIUrl":"https://doi.org/10.1101/2024.08.17.24311219","url":null,"abstract":"Epstein-Barr virus (EBV)-associated central nervous system lymphoproliferative diseases (CNSL) are aggressive clinical conditions with poor prognosis. We have reported that durable responses in patients with primary CNS post-transplant lymphoproliferative disease (PTLD) were associated with detection of two ganciclovir (GCV)/zidovudine (AZT) viral drug target proteins, the EBV kinases BGLF4 and BXLF1 in CNSL biopsies. These are associated with lytic EBV and the mechanism for expression in latently infected EBV+ CNSL has been unknown.\u0000By carrying out RNA expression analysis in CNSL tissue biopsies (n=12), we confirmed expression of LMP1, BXLF1, and BGLF4, but not BZLF1, pointing to an incomplete lytic EBV program. Biopsies from systemic PTLD (n=24) were used for comparison and showed significantly less expression of BGLF4. By quantifying DNA methylation in EBV gene promoters we showed significantly decreased promoter methylation at BGLF4 in CNSL versus systemic PTLD (p=0.0006). Luciferase reporter analysis of the BGLF4 upstream sequence revealed 3 regions of promoter activity and 5ˈ RACE in n=4 EBV-infected cell lines and n=5 CNSL biopsy samples identified transcription start sites at these promoters. We identified DNA methylation loss at single CpG dinucleotides which were specifically demethylated in CNSL, while surrounding EBV methylation remained high. Lastly, TET knockout and expression of TET1/2-suppressive mutant IDH1 in a latent HEK293 EBV model indicated that active demethylation is necessary for activity of BGLF4 promoters. We detail the epigenetic basis of BGLF4 expression in CNSL via locus-specific promoter activation that may hold value for determination of antiviral drug sensitivity.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1101/2024.08.18.24312164
Thi Hue Hanh Nguyen, Giang Hoang Vu, Tu Thi Nguyen, Tuan Anh Nguyen, Vu Uyen Tran, Luyen Thi Vu, Giang Thi Huong Nguyen, Nhat Duy Nguyen, Trung Hieu Tran, Van Thien Chi Nguyen, Thanh Dat Nguyen, Trong Hieu Nguyen, Dac Ho Vo, Thi Tuong Vi Van, Thanh Thi Do, Minh Phong Le, Le Anh Khoa Huynh, Duy Sinh Nguyen, Hung Sang Tang, Hoai-Nghia Nguyen, Minh-Duy Phan, Hoa Giang, Lan N Tu, Le Son Tran
Background Multi-cancer early detection (MCED) through a single blood test significantly advances cancer diagnosis. However, most MCED tests rely on a single type of biomarkers, leading to limited sensitivity, particularly for early-stage cancers. We previously developed SPOT-MAS, a multimodal ctDNA-based assay analyzing methylation and fragmentomic profiles to detect five common cancers. Despite its potential, SPOT-MAS exhibited moderate sensitivities for early-stage cancers. This study investigated whether integrating hotspot mutations into SPOT-MAS could enhance its detection rates. Method A targeted amplicon sequencing approach was developed to profile 700 hotspot mutations in cell-free DNA and integrated into the SPOT-MAS assay, creating a single-blood draw workflow. This workflow, namely SPOT-MAS Plus was retrospectively validated in a cohort of 255 non-metastatic cancer patients (breast, colorectal, gastric, liver, and lung) and 304 healthy individuals. Results Hotspot mutations were detected in 131 of 255 (51.4%) cancer patients, with the highest rates in liver cancer (96.5%), followed by colorectal (59.3%) and lung cancer (53.7%). Lower detection rates were found for cancers with low tumor mutational burden, such as breast (31.3%) and gastric (41.9%) cancers. In contrast, SPOT-MAS demonstrated higher sensitivities for these cancers (51.6% for breast and 62.9% for gastric). The combination of hotspot mutations with SPOT-MAS predictions improved early-stage cancer detection, achieving an overall sensitivity of 78.5% at a specificity of 97.7%. Enhanced sensitivities were observed for colorectal (81.36%) and lung cancer (82.9%). Conclusion The integration of genetic and epigenetic alterations into a multimodal assay significantly enhances the early detection of various cancers. Further validation in larger cohorts is necessary to support broader clinical applications.
{"title":"Combination of hotspot mutations with methylation and fragmentomic profiles to enhance Multi-Cancer Early Detection","authors":"Thi Hue Hanh Nguyen, Giang Hoang Vu, Tu Thi Nguyen, Tuan Anh Nguyen, Vu Uyen Tran, Luyen Thi Vu, Giang Thi Huong Nguyen, Nhat Duy Nguyen, Trung Hieu Tran, Van Thien Chi Nguyen, Thanh Dat Nguyen, Trong Hieu Nguyen, Dac Ho Vo, Thi Tuong Vi Van, Thanh Thi Do, Minh Phong Le, Le Anh Khoa Huynh, Duy Sinh Nguyen, Hung Sang Tang, Hoai-Nghia Nguyen, Minh-Duy Phan, Hoa Giang, Lan N Tu, Le Son Tran","doi":"10.1101/2024.08.18.24312164","DOIUrl":"https://doi.org/10.1101/2024.08.18.24312164","url":null,"abstract":"Background\u0000Multi-cancer early detection (MCED) through a single blood test significantly advances cancer diagnosis. However, most MCED tests rely on a single type of biomarkers, leading to limited sensitivity, particularly for early-stage cancers. We previously developed SPOT-MAS, a multimodal ctDNA-based assay analyzing methylation and fragmentomic profiles to detect five common cancers. Despite its potential, SPOT-MAS exhibited moderate sensitivities for early-stage cancers. This study investigated whether integrating hotspot mutations into SPOT-MAS could enhance its detection rates. Method\u0000A targeted amplicon sequencing approach was developed to profile 700 hotspot mutations in cell-free DNA and integrated into the SPOT-MAS assay, creating a single-blood draw workflow. This workflow, namely SPOT-MAS Plus was retrospectively validated in a cohort of 255 non-metastatic cancer patients (breast, colorectal, gastric, liver, and lung) and 304 healthy individuals. Results\u0000Hotspot mutations were detected in 131 of 255 (51.4%) cancer patients, with the highest rates in liver cancer (96.5%), followed by colorectal (59.3%) and lung cancer (53.7%). Lower detection rates were found for cancers with low tumor mutational burden, such as breast (31.3%) and gastric (41.9%) cancers. In contrast, SPOT-MAS demonstrated higher sensitivities for these cancers (51.6% for breast and 62.9% for gastric). The combination of hotspot mutations with SPOT-MAS predictions improved early-stage cancer detection, achieving an overall sensitivity of 78.5% at a specificity of 97.7%. Enhanced sensitivities were observed for colorectal (81.36%) and lung cancer (82.9%). Conclusion\u0000The integration of genetic and epigenetic alterations into a multimodal assay significantly enhances the early detection of various cancers. Further validation in larger cohorts is necessary to support broader clinical applications.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"63 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1101/2024.08.07.24311612
Svenja Wandke, Hannah Fuehres, Mareike Rutenkroeger, Klaus Lang, Martin Haerter, Karin Oechsle, Isabelle Scholl
Objective: Healthcare professionals (HCPs) in cancer care often face patient deaths, yet there is a notable absence of comprehensive evidence regarding their grief. This scoping review seeks to identify key aspects of professional grief in cancer care and give an overview pertaining its' conceptualization and frequency and intensity. Methods: The primary search covered three databases (PUBMED, PSYNDEX, and PsycINFO). Two independent reviewers assessed 2,248 records, selecting 34 eligible articles. Results: Most studies originated from North America and Israel, with limited evidence from the global south, East Asia and Europe, as well as few quantitative studies. HCPs exhibit classic grief symptoms (such as sadness) and distinct features (e.g., feelings of guilt) in response to patient deaths, though a clear definition and measures of professional grief are lacking. Grief frequency varies highly (from 23% to 100%). Conclusions: Future research should refine definitions and measures to better support HCPs in effectively managing professional grief in cancer care.
{"title":"Professional grief in cancer care - A scoping review","authors":"Svenja Wandke, Hannah Fuehres, Mareike Rutenkroeger, Klaus Lang, Martin Haerter, Karin Oechsle, Isabelle Scholl","doi":"10.1101/2024.08.07.24311612","DOIUrl":"https://doi.org/10.1101/2024.08.07.24311612","url":null,"abstract":"Objective: Healthcare professionals (HCPs) in cancer care often face patient deaths, yet there is a notable absence of comprehensive evidence regarding their grief. This scoping review seeks to identify key aspects of professional grief in cancer care and give an overview pertaining its' conceptualization and frequency and intensity. Methods: The primary search covered three databases (PUBMED, PSYNDEX, and PsycINFO). Two independent reviewers assessed 2,248 records, selecting 34 eligible articles. Results: Most studies originated from North America and Israel, with limited evidence from the global south, East Asia and Europe, as well as few quantitative studies. HCPs exhibit classic grief symptoms (such as sadness) and distinct features (e.g., feelings of guilt) in response to patient deaths, though a clear definition and measures of professional grief are lacking. Grief frequency varies highly (from 23% to 100%). Conclusions: Future research should refine definitions and measures to better support HCPs in effectively managing professional grief in cancer care.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141939812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1101/2024.08.07.24311537
Gwo Fuang Ho, Soo Chin Lee, Anita Zarina Bustam, Adlinda Alip, Nur Fadhlina Abdul Satar, Marniza Saad, Rozita Abdul Malik, Siew Eng Lim, Samuel GW Ow, Andrea Wong, Wan-Qin Chong, Yvonne LE Ang, Audrey Weng Yan Lee, Siti Norhidayu Hasan, Nabilah Tuan Zaid, Kian Boon Law, Yok Yong Toh, Hooi Chiao Tan, Bawani Selvam, Joanna Lim, Jia Wern Pan, Soo Hwang Teo
Background: A common germline deletion polymorphism in the APOBEC3B gene increases the rate of somatic hypermutation in breast cancer, which in turn is associated with greater neoantigen burden and immune activation. This phase II study evaluated the impact of the APOBEC3B deletion polymorphism on the response to pembrolizumab monotherapy in metastatic HER2-negative breast cancer patients. Patients and methods: Eligible patients had a confirmed diagnosis of metastatic HER2-negative breast cancer, 1-3 prior lines of therapy, and documented homozygous or heterozygous germline deletion of APOBEC3B. Patients received 200 mg of pembrolizumab intravenously every 3 weeks for up to 2 years. The primary endpoint was objective response rate. Secondary endpoints were disease control rate, progression-free survival, and overall survival. Results: All enrolled patients (N = 44) were women, 36% had PD-L1-positive tumours, and 62% had received 2 or more previous lines of therapy for metastatic disease. ORR (95% CI) was 20.5% (9.8-35.5) in the total and 30.0% (6.7-65.3) in the PD-L1-positive populations. Disease control rate (95% CI) was 52.3% (36.7-67.5) and 40% (12.2-73.8), respectively. Median PFS was 3.1 months (95% CI, 2.1-4.3), and 6-month PFS rate was 29.5% (95% CI, 18.7-46.6). Median OS was 15.2 months (95% CI, 11.7-26.5), and 12-month OS rate was 60.2% (95% CI, 46.5-77.7). Treatment-related adverse events occurred in 30 (68.2%) patients, including 1 (2.3%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumour activity in a subset of previously treated metastatic HER2- breast cancer patients with germline APOBEC3B deletion.
{"title":"Pembrolizumab monotherapy for previously treated metastatic HER2-negative breast cancer with germline APOBEC3B deletion: results of the phase II AUROR study","authors":"Gwo Fuang Ho, Soo Chin Lee, Anita Zarina Bustam, Adlinda Alip, Nur Fadhlina Abdul Satar, Marniza Saad, Rozita Abdul Malik, Siew Eng Lim, Samuel GW Ow, Andrea Wong, Wan-Qin Chong, Yvonne LE Ang, Audrey Weng Yan Lee, Siti Norhidayu Hasan, Nabilah Tuan Zaid, Kian Boon Law, Yok Yong Toh, Hooi Chiao Tan, Bawani Selvam, Joanna Lim, Jia Wern Pan, Soo Hwang Teo","doi":"10.1101/2024.08.07.24311537","DOIUrl":"https://doi.org/10.1101/2024.08.07.24311537","url":null,"abstract":"Background: A common germline deletion polymorphism in the APOBEC3B gene increases the rate of somatic hypermutation in breast cancer, which in turn is associated with greater neoantigen burden and immune activation. This phase II study evaluated the impact of the APOBEC3B deletion polymorphism on the response to pembrolizumab monotherapy in metastatic HER2-negative breast cancer patients. Patients and methods: Eligible patients had a confirmed diagnosis of metastatic HER2-negative breast cancer, 1-3 prior lines of therapy, and documented homozygous or heterozygous germline deletion of APOBEC3B. Patients received 200 mg of pembrolizumab intravenously every 3 weeks for up to 2 years. The primary endpoint was objective response rate. Secondary endpoints were disease control rate, progression-free survival, and overall survival. Results: All enrolled patients (N = 44) were women, 36% had PD-L1-positive tumours, and 62% had received 2 or more previous lines of therapy for metastatic disease. ORR (95% CI) was 20.5% (9.8-35.5) in the total and 30.0% (6.7-65.3) in the PD-L1-positive populations. Disease control rate (95% CI) was 52.3% (36.7-67.5) and 40% (12.2-73.8), respectively. Median PFS was 3.1 months (95% CI, 2.1-4.3), and 6-month PFS rate was 29.5% (95% CI, 18.7-46.6). Median OS was 15.2 months (95% CI, 11.7-26.5), and 12-month OS rate was 60.2% (95% CI, 46.5-77.7). Treatment-related adverse events occurred in 30 (68.2%) patients, including 1 (2.3%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumour activity in a subset of previously treated metastatic HER2- breast cancer patients with germline APOBEC3B deletion.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141939811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1101/2024.08.06.24311562
Hakan Bozcuk, Mustafa Yildiz
Background: Although several models exist to predict risk of febrile neutropenia in cancer patients, there is still need to more accurately quantify this risk to minimize morbidity of and mortality from this treatment toxicity. Material and methods: From previous reports of our group, un updated predictive model had emerged. We refined our algorithm even further by using Balanced Bagging Classifier (BBC) machine learning in the previous model derivation cohort, discarding all the missing data. Moreover, we made a web application to make it accessible for experimental clinical use. Results: We used clinical data from 3439 cycles of chemotherapy obtained from the periods of 2010-2011 and 2015-2019, with 133 episodes of febrile neutropenia observed (after 4% of chemotherapy cycles). BBC resulted in a more efficient model as reflected by an area under curve (AUC) of 0.97, accuracy of 0.95, sensitivity of 0.93, and specificity of 0.95. Permutation importance analysis revealed previous febrile neutropenia, cancer type and receipt of previous radiotherapy as the most important features for the BBC model. The web app that integrates the BBC model with a user-friendly user interface has been found to be clinically useful. Conclusions: Using machine learning with our previous data, we are now able to predict the risk of febrile neutropenia more effectively after chemotherapy in cancer patients. The resultant web application is functional and makes use of the developed machine learning model to predict febrile neutropenia.
背景：尽管有多种模型可用于预测癌症患者发热性中性粒细胞减少症的风险，但仍需要更准确地量化这一风险，以尽量减少这种治疗毒性的发病率和死亡率：根据我们小组之前的报告，已经出现了一个最新的预测模型。我们在之前的模型推导队列中使用了平衡袋分类器（BBC）机器学习，剔除了所有缺失数据，从而进一步完善了我们的算法。此外，我们还制作了一个网络应用程序，以便临床实验使用：我们使用了2010-2011年和2015-2019年期间3439个化疗周期的临床数据，其中观察到133次发热性中性粒细胞减少症（4%的化疗周期后）。BBC 模型的曲线下面积（AUC）为 0.97，准确率为 0.95，灵敏度为 0.93，特异性为 0.95，因此更有效。置换重要性分析显示，既往发热性中性粒细胞减少症、癌症类型和既往接受过放疗是 BBC 模型最重要的特征。将BBC模型与友好的用户界面整合在一起的网络应用程序在临床上非常有用：结论：通过对以往数据进行机器学习，我们现在能够更有效地预测癌症患者化疗后发热性中性粒细胞减少症的风险。最终开发出的网络应用程序功能强大，可利用开发的机器学习模型预测发热性中性粒细胞减少症。
{"title":"A Balanced Bagging Classifier machine learning model-based web application to predict risk of febrile neutropenia in cancer patients","authors":"Hakan Bozcuk, Mustafa Yildiz","doi":"10.1101/2024.08.06.24311562","DOIUrl":"https://doi.org/10.1101/2024.08.06.24311562","url":null,"abstract":"Background: Although several models exist to predict risk of febrile neutropenia in cancer patients, there is still need to more accurately quantify this risk to minimize morbidity of and mortality from this treatment toxicity.\u0000Material and methods: From previous reports of our group, un updated predictive model had emerged. We refined our algorithm even further by using Balanced Bagging Classifier (BBC) machine learning in the previous model derivation cohort, discarding all the missing data. Moreover, we made a web application to make it accessible for experimental clinical use.\u0000Results: We used clinical data from 3439 cycles of chemotherapy obtained from the periods of 2010-2011 and 2015-2019, with 133 episodes of febrile neutropenia observed (after 4% of chemotherapy cycles). BBC resulted in a more efficient model as reflected by an area under curve (AUC) of 0.97, accuracy of 0.95, sensitivity of 0.93, and specificity of 0.95. Permutation importance analysis revealed previous febrile neutropenia, cancer type and receipt of previous radiotherapy as the most important features for the BBC model. The web app that integrates the BBC model with a user-friendly user interface has been found to be clinically useful.\u0000Conclusions: Using machine learning with our previous data, we are now able to predict the risk of febrile neutropenia more effectively after chemotherapy in cancer patients. The resultant web application is functional and makes use of the developed machine learning model to predict febrile neutropenia.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141939810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1101/2024.08.05.24310618
Taryn D Treger, Jenny Wegert, Anna Wenger, Tim H.H. Coorens, Reem Al-Saadi, Paul Kemps, Jonathan Kennedy, Conor Parks, Nathaniel D Anderson, Angus Hodder, Aleksandra Letunovska, Hyunchul Jung, Toochi Ogbonnah, Mi Trinh, Henry Lee-Six, Guillaume Morcrette, Marry M. van den Heuvel-Eibrink, Jarno Drost, Ruben van Boxtel, Eline J Bertrums, Bianca F Goemans, Evangelia Antoniou, Dirk Reinhardt, Heike Streitenberger, Barbara Ziegler, Jack Bartram, J. Ciaran Hutchinson, Gordan M Vujanic, Christian Vokuhl, Tanzina Chowdhury, Rhoikos Furtwangler, Norbert Graf, Kathy Pritchard-Jones, Manfred Gessler, Sam Behjati
Ten percent of children with cancer harbour a predisposition mutation. In children with the kidney cancer, Wilms tumour, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumour genetic development. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic germline or mosaic predisposition. We examined 237 neoplasms (including two secondary leukaemias), utilising whole genome sequencing, RNA sequencing and genome wide methylation, validating our findings in an independent cohort. Tumour development differed between predisposed and sporadic cases, and amongst predisposed children according to specific mutations and their developmental timing. Differences pervaded the repertoire of driver events, including high risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Predisposition constrains the development of Wilms tumour, suggesting that a variant specific approach to the management of these children merits consideration.
{"title":"Somatic development of Wilms tumour via normal kidneys in predisposed children","authors":"Taryn D Treger, Jenny Wegert, Anna Wenger, Tim H.H. Coorens, Reem Al-Saadi, Paul Kemps, Jonathan Kennedy, Conor Parks, Nathaniel D Anderson, Angus Hodder, Aleksandra Letunovska, Hyunchul Jung, Toochi Ogbonnah, Mi Trinh, Henry Lee-Six, Guillaume Morcrette, Marry M. van den Heuvel-Eibrink, Jarno Drost, Ruben van Boxtel, Eline J Bertrums, Bianca F Goemans, Evangelia Antoniou, Dirk Reinhardt, Heike Streitenberger, Barbara Ziegler, Jack Bartram, J. Ciaran Hutchinson, Gordan M Vujanic, Christian Vokuhl, Tanzina Chowdhury, Rhoikos Furtwangler, Norbert Graf, Kathy Pritchard-Jones, Manfred Gessler, Sam Behjati","doi":"10.1101/2024.08.05.24310618","DOIUrl":"https://doi.org/10.1101/2024.08.05.24310618","url":null,"abstract":"Ten percent of children with cancer harbour a predisposition mutation. In children with the kidney cancer, Wilms tumour, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumour genetic development. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic germline or mosaic predisposition. We examined 237 neoplasms (including two secondary leukaemias), utilising whole genome sequencing, RNA sequencing and genome wide methylation, validating our findings in an independent cohort. Tumour development differed between predisposed and sporadic cases, and amongst predisposed children according to specific mutations and their developmental timing. Differences pervaded the repertoire of driver events, including high risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Predisposition constrains the development of Wilms tumour, suggesting that a variant specific approach to the management of these children merits consideration.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141939778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1101/2024.08.05.24311508
Lixuan Feng, Ben Gordon, Xin Su, Ariane Brassard, Iqraa Dhoparee-Doomah, Sabrina Leo, Rashami Awasthi, France Bourdeau, Betty Giannias, Heather Gill, Enrico Minnella, Lorenzo Ferri, Sara Najmeh, Jonathan Spicer, Francesco Carli, Jonathan Cools-Lartigue
BACKGROUND: While the clinical benefits of multimodal prehabilitation in cancer patients are well defined, the underlying immune modulations have not been studied. The objective of this study was to examine how prehabilitation can alter lung cancer immunity. METHODS: Newly diagnosed lung cancer patients were referred to the prehabilitation clinic for preoperative personalized multimodal intervention (exercise training, nutritional optimization, and anxiety reduction) and blood samples were collected at baseline and surgery. Tumor samples were collected at surgery and compared to matched control samples from patients who did not receive prehabilitation. An animal model was used to study prehabilitation and tumor growth kinetics. RESULTS: Twenty-eight lung cancer patients who underwent multimodal prehabilitation were included (McGill University Health Centre Research Ethics Board #2023-9005). After prehabilitation, patient-isolated peripheral blood mononuclear cells (PBMCs) showed significantly increased cytotoxicity against cancer cells (p < 0.0001) and significantly increased circulating natural killer (NK) cells in cohort (p = 0.0290) and paired analyses (p = 0.0312). Compared to matched controls, patients who received prehabilitation had significantly more intra-tumor NK cells (p = 0.0172). In vivo, we observed a significant increase in circulating NK cells (p = 0.0364) and slower tumor growth (p = 0.0396) with prehabilitation. When NK cells were depleted in prehabilitated mice, we observed a decrease in the protective effects of prehabilitation (p = 0.0314) and overall, we observed a significant correlation between circulating NK cells and reduced tumor volume (p = 0.0203, r = -0.5143). CONCLUSIONS: Multimodal prehabilitation may play a role in antitumor immunity by increasing peripheral and tumour-infiltrating NK cells leading to a reduced cancer burden. Future studies on the protective effect of prehabilitation on postoperative immunity should be conducted.
背景：虽然多模式康复治疗对癌症患者的临床益处已得到明确界定，但对其背后的免疫调节机制尚未进行研究。本研究旨在探讨康复治疗如何改变肺癌免疫。方法：新诊断的肺癌患者被转诊至康复前门诊，接受术前个性化多模式干预（运动训练、营养优化和减轻焦虑），并在基线和手术时采集血液样本。在手术时采集肿瘤样本，并与未接受术前康复治疗的患者的匹配对照样本进行比较。使用动物模型研究康复前治疗和肿瘤生长动力学。结果：28名肺癌患者接受了多模式预康复治疗（麦吉尔大学健康中心研究伦理委员会编号2023-9005）。经过预康复治疗后，患者分离的外周血单核细胞（PBMCs）对癌细胞的细胞毒性明显增加（p < 0.0001），在队列分析（p = 0.0290）和配对分析（p = 0.0312）中，循环自然杀伤（NK）细胞明显增加。与匹配的对照组相比，接受康复前治疗的患者肿瘤内的 NK 细胞明显增多（p = 0.0172）。在体内，我们观察到循环中的 NK 细胞明显增加（p = 0.0364），接受预康复治疗的患者肿瘤生长速度减慢（p = 0.0396）。当康复前小鼠的 NK 细胞被耗尽时，我们观察到康复前的保护作用下降（p = 0.0314），总体而言，我们观察到循环 NK 细胞与肿瘤体积缩小之间存在显著相关性（p = 0.0203，r = -0.5143）。结论：多模式康复前治疗可通过增加外周和肿瘤浸润的 NK 细胞在抗肿瘤免疫中发挥作用，从而减少癌症负担。今后应继续研究康复前治疗对术后免疫的保护作用。
{"title":"Multimodal prehabilitation enhances innate antitumor immunity via NK cell recruitment","authors":"Lixuan Feng, Ben Gordon, Xin Su, Ariane Brassard, Iqraa Dhoparee-Doomah, Sabrina Leo, Rashami Awasthi, France Bourdeau, Betty Giannias, Heather Gill, Enrico Minnella, Lorenzo Ferri, Sara Najmeh, Jonathan Spicer, Francesco Carli, Jonathan Cools-Lartigue","doi":"10.1101/2024.08.05.24311508","DOIUrl":"https://doi.org/10.1101/2024.08.05.24311508","url":null,"abstract":"BACKGROUND: While the clinical benefits of multimodal prehabilitation in cancer patients are well defined, the underlying immune modulations have not been studied. The objective of this study was to examine how prehabilitation can alter lung cancer immunity. METHODS: Newly diagnosed lung cancer patients were referred to the prehabilitation clinic for preoperative personalized multimodal intervention (exercise training, nutritional optimization, and anxiety reduction) and blood samples were collected at baseline and surgery. Tumor samples were collected at surgery and compared to matched control samples from patients who did not receive prehabilitation. An animal model was used to study prehabilitation and tumor growth kinetics. RESULTS: Twenty-eight lung cancer patients who underwent multimodal prehabilitation were included (McGill University Health Centre Research Ethics Board #2023-9005). After prehabilitation, patient-isolated peripheral blood mononuclear cells (PBMCs) showed significantly increased cytotoxicity against cancer cells (p < 0.0001) and significantly increased circulating natural killer (NK) cells in cohort (p = 0.0290) and paired analyses (p = 0.0312). Compared to matched controls, patients who received prehabilitation had significantly more intra-tumor NK cells (p = 0.0172). In vivo, we observed a significant increase in circulating NK cells (p = 0.0364) and slower tumor growth (p = 0.0396) with prehabilitation. When NK cells were depleted in prehabilitated mice, we observed a decrease in the protective effects of prehabilitation (p = 0.0314) and overall, we observed a significant correlation between circulating NK cells and reduced tumor volume (p = 0.0203, r = -0.5143). CONCLUSIONS: Multimodal prehabilitation may play a role in antitumor immunity by increasing peripheral and tumour-infiltrating NK cells leading to a reduced cancer burden. Future studies on the protective effect of prehabilitation on postoperative immunity should be conducted.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141939813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1101/2024.08.02.24311442
Yukun Wen
Background As one of the major cancers threatening human health, Breast Cancer (BC) has become the health concern of WHO (World Health Organization) all the year round. In recent years, new cases of BC have gradually increased, reaching 11.7% in 2020. In terms of treatment, the cell death is a basic way to treat cancer, and necroptosis is found to be a programmed form of necrotic cell death, which is related to cancer progression, metastasis and immune monitoring. In this study, the influence and role of Necroptosis-Related Genes (NRGs) in BC were analyzed, and the subtypes, prognostic model and subgroups were studied, respectively. Methods Four aspects were included in the research content. 1) Difference analysis. The Wilcoxon Test was applied to identify differences between normal people and BC patients. 2) Sub-type analysis. Based on Cox regression analysis, the key genes related to prognosis were extracted and applied to the Consensus clustering technology. Subsequently, after obtaining the subtypes, the Wilcoxon Test was applied to extract the differential genes of subtypes. 3) Prognostic analysis. Further, according to the survival time and state of patients, the genes related to the severity of the disease were extracted by the Cox regression, and the classification modeling of high risk and low risk was carried out by Lasso. 4) Sub-group analysis. Combined with the high- and low-risk labels of patients, the composition of differential genes was further analyzed. Subsequently, GO, KEGG, and ssGSEA analyses were performed separately. Results 1) There are differences in gene expression between normal and BC patients. The results showed that, PLK1, CDKN2A, and TERT were significantly different genes with |LogFC| > 2. In addition, PPI (Protein to Protein Interaction) demonstrated that CASP8, TRAF2, TNFRSF1A, HSP90AA1, CYLD, and FADD were hubs in the network. Moreover, coexpression relationship of these genes can be found in the correlation graph. 2) Unsupervised techniques suggested that there are 2 subtype characteristics in BC patients. The clustering results obtained the detailed clinical information of the 2 subtypes, and the survival analysis showed that different subtypes had different survival states. Similarly, the heat map also verified that these 2 types had different gene expression. 3) The validation demonstrated that the prognostic model has good effect. On the one hand, we found that 'BCL2', 'FLT3', and 'PLK1' were the main genes with different expression levels in high- and low-risk patients. On the other hand, not only the ROC, risk curve and survival curve were verified, but also the PCA distribution and forest plots were demonstrated. These results showed that our model has good prognostic effect. 4) There were some differences in immune scores between high- and low-risk groups. A total of 94 genes were differentially expressed in different groups. Immune cell analysis and pathway analysis showed that, in general, immune s
背景作为威胁人类健康的主要癌症之一，乳腺癌（BC）已成为世界卫生组织（WHO）常年关注的健康问题。近年来，乳腺癌新发病例逐渐增多，2020年将达到11.7%。在治疗方面，细胞死亡是治疗癌症的基本方法，而坏死细胞是一种程序化的坏死细胞死亡形式，它与癌症进展、转移和免疫监视有关。本研究分析了坏死相关基因（NRGs）在BC中的影响和作用，并分别对其亚型、预后模型和亚组进行了研究。1) 差异分析。采用 Wilcoxon 检验确定正常人与 BC 患者之间的差异。2) 亚型分析。在 Cox 回归分析的基础上，提取与预后相关的关键基因，并将其应用于共识聚类技术。随后，在得到亚型后，应用 Wilcoxon 检验提取亚型的差异基因。3) 预后分析。进一步根据患者的生存时间和状态，通过 Cox 回归提取与疾病严重程度相关的基因，并利用 Lasso 进行高风险和低风险的分类建模。4) 亚组分析。结合患者的高风险和低风险标签，进一步分析差异基因的构成。结果1）正常与 BC 患者的基因表达存在差异。结果表明，PLK1、CDKN2A和TERT是差异显著的基因，其表达量分别为|LogFC| > 2；此外，PPI（Protein to Protein Interaction）表明，CASP8、TRAF2、TNFRSF1A、HSP90AA1、CYLD和FADD是网络中的枢纽。2）无监督技术表明，BC 患者有两种亚型特征。聚类结果获得了这两种亚型的详细临床信息，生存分析表明不同亚型有不同的生存状态。3）验证结果表明，预后模型具有良好的效果。一方面，我们发现 "BCL2"、"FLT3 "和 "PLK1 "是高危和低危患者中表达水平不同的主要基因。另一方面，我们不仅验证了 ROC、风险曲线和生存曲线，还展示了 PCA 分布和森林图。这些结果表明，我们的模型具有良好的预后效果。不同组别中共有 94 个基因存在差异表达。免疫细胞分析和通路分析表明，总体而言，低风险亚组的免疫评分高于高风险亚组。我们的研究结果揭示了 NRGs 在 BC 中的关键作用，它们对肿瘤免疫非常重要，可用于预测 BC 的预后。
{"title":"Identification and Modeling of Necroptosis-Related Genes Associated with the Prognosis of Breast Cancer","authors":"Yukun Wen","doi":"10.1101/2024.08.02.24311442","DOIUrl":"https://doi.org/10.1101/2024.08.02.24311442","url":null,"abstract":"Background\u0000As one of the major cancers threatening human health, Breast Cancer (BC) has become the health concern of WHO (World Health Organization) all the year round. In recent years, new cases of BC have gradually increased, reaching 11.7% in 2020. In terms of treatment, the cell death is a basic way to treat cancer, and necroptosis is found to be a programmed form of necrotic cell death, which is related to cancer progression, metastasis and immune monitoring. In this study, the influence and role of Necroptosis-Related Genes (NRGs) in BC were analyzed, and the subtypes, prognostic model and subgroups were studied, respectively.\u0000Methods\u0000Four aspects were included in the research content. 1) Difference analysis. The Wilcoxon Test was applied to identify differences between normal people and BC patients. 2) Sub-type analysis. Based on Cox regression analysis, the key genes related to prognosis were extracted and applied to the Consensus clustering technology. Subsequently, after obtaining the subtypes, the Wilcoxon Test was applied to extract the differential genes of subtypes. 3) Prognostic analysis. Further, according to the survival time and state of patients, the genes related to the severity of the disease were extracted by the Cox regression, and the classification modeling of high risk and low risk was carried out by Lasso. 4) Sub-group analysis. Combined with the high- and low-risk labels of patients, the composition of differential genes was further analyzed. Subsequently, GO, KEGG, and ssGSEA analyses were performed separately.\u0000Results\u00001) There are differences in gene expression between normal and BC patients. The results showed that, PLK1, CDKN2A, and TERT were significantly different genes with |LogFC| > 2. In addition, PPI (Protein to Protein Interaction) demonstrated that CASP8, TRAF2, TNFRSF1A, HSP90AA1, CYLD, and FADD were hubs in the network. Moreover, coexpression relationship of these genes can be found in the correlation graph.\u00002) Unsupervised techniques suggested that there are 2 subtype characteristics in BC patients. The clustering results obtained the detailed clinical information of the 2 subtypes, and the survival analysis showed that different subtypes had different survival states. Similarly, the heat map also verified that these 2 types had different gene expression.\u00003) The validation demonstrated that the prognostic model has good effect. On the one hand, we found that 'BCL2', 'FLT3', and 'PLK1' were the main genes with different expression levels in high- and low-risk patients. On the other hand, not only the ROC, risk curve and survival curve were verified, but also the PCA distribution and forest plots were demonstrated. These results showed that our model has good prognostic effect.\u00004) There were some differences in immune scores between high- and low-risk groups. A total of 94 genes were differentially expressed in different groups. Immune cell analysis and pathway analysis showed that, in general, immune s","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141939814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1101/2024.08.05.24311466
Berta Cuyas, Edilmar Edilmar Alvarado-Tapias, Eng Hooi Tan, Asieh Golozar, Talita Duarte-Salles, Antonella Delmestri, Josepmaria Argemi, Wai Yi Man, Edward Burn, Carlos Guarner Argente, DANIEL PRIETO-ALHAMBRA, Danielle Newby
Background: Primary liver cancer (PLC) remains a global health challenge. Understanding trends in the disease burden and survival is crucial to inform decisions regarding screening, prevention and treatment. Methods: Population-based cohort study using UK primary care data from the Clinical Practice Research Datalink (CPRD) GOLD (2000 to 2021), replicated in CPRD Aurum. PLC incidence rates (IR), period prevalence (PP) and survival at one, five and ten years over the study period were calculated, and stratified by age, sex and diagnosis year. Results: The crude IR of PLC was 4.56 (95%CI 4.42-4.70) per 100,000 person-years between 2000 and 2021, with an increase over time across age and sex strata. Sex-specific IR for males was higher than females, 6.60 (95%CI 6.36-6.85) vs. 2.58 (95%CI 2.44-2.74) per 100,000 person-years. Crude PP showed a 7-fold increase over the study period, with PP 0.02% (95%CI 0.019%-0.022%) in 2021, and a 2.8-fold higher PP in males. Survival at one, five and ten years after diagnosis was 41.7%, 13.2% and 7.1%, respectively, for both sexes. One-year survival increased only in men, from 33.2% in 2005-2009 to 49.3% in 2015-2019. Conclusion: Over the past two decades, there has been a significant increase in the number of patients diagnosed with PLC. Despite a slight improvement in median and one-year survival in men, prognosis remains poor. To improve the survival of PLC patients, it is necessary to understand the epidemiological changes and address the preventable risk factors associated with liver disease and promote early detection and access to care.
{"title":"Secular trends in the incidence, prevalence, and survival of primary liver cancer in the United Kingdom from 2000-2021: a population-based cohort study","authors":"Berta Cuyas, Edilmar Edilmar Alvarado-Tapias, Eng Hooi Tan, Asieh Golozar, Talita Duarte-Salles, Antonella Delmestri, Josepmaria Argemi, Wai Yi Man, Edward Burn, Carlos Guarner Argente, DANIEL PRIETO-ALHAMBRA, Danielle Newby","doi":"10.1101/2024.08.05.24311466","DOIUrl":"https://doi.org/10.1101/2024.08.05.24311466","url":null,"abstract":"Background: Primary liver cancer (PLC) remains a global health challenge. Understanding trends in the disease burden and survival is crucial to inform decisions regarding screening, prevention and treatment. Methods: Population-based cohort study using UK primary care data from the Clinical Practice Research Datalink (CPRD) GOLD (2000 to 2021), replicated in CPRD Aurum. PLC incidence rates (IR), period prevalence (PP) and survival at one, five and ten years over the study period were calculated, and stratified by age, sex and diagnosis year. Results: The crude IR of PLC was 4.56 (95%CI 4.42-4.70) per 100,000 person-years between 2000 and 2021, with an increase over time across age and sex strata. Sex-specific IR for males was higher than females, 6.60 (95%CI 6.36-6.85) vs. 2.58 (95%CI 2.44-2.74) per 100,000 person-years. Crude PP showed a 7-fold increase over the study period, with PP 0.02% (95%CI 0.019%-0.022%) in 2021, and a 2.8-fold higher PP in males. Survival at one, five and ten years after diagnosis was 41.7%, 13.2% and 7.1%, respectively, for both sexes. One-year survival increased only in men, from 33.2% in 2005-2009 to 49.3% in 2015-2019. Conclusion: Over the past two decades, there has been a significant increase in the number of patients diagnosed with PLC. Despite a slight improvement in median and one-year survival in men, prognosis remains poor. To improve the survival of PLC patients, it is necessary to understand the epidemiological changes and address the preventable risk factors associated with liver disease and promote early detection and access to care.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"120 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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