M. Saraiva, L. Spindler, T. Manzione, T. Ribeiro, N. Fathallah, Miguel Martins, P. Cardoso, F. Mendes, Joana Fernandes, João Ferreira, Guilherme Macedo, Sidney R. Nadal, V. de Parades
High-resolution anoscopy (HRA) plays a central role in the detection and treatment of precursors of anal squamous cell carcinoma (ASCC). Artificial intelligence (AI) algorithms have shown high levels of efficiency in detecting and differentiating HSIL from low-grade squamous intraepithelial lesions (LSIL) in HRA images. Our aim was to develop a deep learning system for the automatic detection and differentiation of HSIL versus LSIL using HRA images from both conventional and digital proctoscopes. A convolutional neural network (CNN) was developed based on 151 HRA exams performed at two volume centers using conventional and digital HRA systems. A total of 57,822 images were included, 28,874 images containing HSIL and 28,948 LSIL. Partial subanalyses were performed to evaluate the performance of the CNN in the subset of images acetic acid and lugol iodine staining and after treatment of the anal canal. The overall accuracy of the CNN in distinguishing HSIL from LSIL during the testing stage was 94.6%. The algorithm had an overall sensitivity and specificity of 93.6% and 95.7%, respectively (AUC 0.97). For staining with acetic acid, HSIL was differentiated from LSIL with an overall accuracy of 96.4%, while for lugol and after therapeutic manipulation, these values were 96.6% and 99.3%, respectively. The introduction of AI algorithms to HRA may enhance the early diagnosis of ASCC precursors, and this system was shown to perform adequately across conventional and digital HRA interfaces.
{"title":"Deep Learning and High-Resolution Anoscopy: Development of an Interoperable Algorithm for the Detection and Differentiation of Anal Squamous Cell Carcinoma Precursors—A Multicentric Study","authors":"M. Saraiva, L. Spindler, T. Manzione, T. Ribeiro, N. Fathallah, Miguel Martins, P. Cardoso, F. Mendes, Joana Fernandes, João Ferreira, Guilherme Macedo, Sidney R. Nadal, V. de Parades","doi":"10.3390/cancers16101909","DOIUrl":"https://doi.org/10.3390/cancers16101909","url":null,"abstract":"High-resolution anoscopy (HRA) plays a central role in the detection and treatment of precursors of anal squamous cell carcinoma (ASCC). Artificial intelligence (AI) algorithms have shown high levels of efficiency in detecting and differentiating HSIL from low-grade squamous intraepithelial lesions (LSIL) in HRA images. Our aim was to develop a deep learning system for the automatic detection and differentiation of HSIL versus LSIL using HRA images from both conventional and digital proctoscopes. A convolutional neural network (CNN) was developed based on 151 HRA exams performed at two volume centers using conventional and digital HRA systems. A total of 57,822 images were included, 28,874 images containing HSIL and 28,948 LSIL. Partial subanalyses were performed to evaluate the performance of the CNN in the subset of images acetic acid and lugol iodine staining and after treatment of the anal canal. The overall accuracy of the CNN in distinguishing HSIL from LSIL during the testing stage was 94.6%. The algorithm had an overall sensitivity and specificity of 93.6% and 95.7%, respectively (AUC 0.97). For staining with acetic acid, HSIL was differentiated from LSIL with an overall accuracy of 96.4%, while for lugol and after therapeutic manipulation, these values were 96.6% and 99.3%, respectively. The introduction of AI algorithms to HRA may enhance the early diagnosis of ASCC precursors, and this system was shown to perform adequately across conventional and digital HRA interfaces.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140964335","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}
Katsuhiko Murakami, Shin-ichiro Tago, Sho Takishita, Hiroaki Morikawa, Rikuhiro Kojima, K. Yokoyama, M. Ogawa, Hidehito Fukushima, Hiroyuki Takamori, Yasuhito Nannya, S. Imoto, Masaru Fuji
When analyzing cancer sample genomes in clinical practice, many structural variants (SVs), other than single nucleotide variants (SNVs), have been identified. To identify driver variants, the leading candidates must be narrowed down. When fusion genes are involved, selection is particularly difficult, and highly accurate predictions from AI is important. Furthermore, we also wanted to determine how the prediction can make more reliable diagnoses. Here, we developed an explainable AI (XAI) suitable for SVs with gene fusions, based on the XAI technology we previously developed for the prediction of SNV pathogenicity. To cope with gene fusion variants, we added new data to the previous knowledge graph for SVs and we improved the algorithm. Its prediction accuracy was as high as that of existing tools. Moreover, our XAI could explain the reasons for these predictions. We used some variant examples to demonstrate that the reasons are plausible in terms of pathogenic basic mechanisms. These results can be seen as a hopeful step toward the future of genomic medicine, where efficient and correct decisions can be made with the support of AI.
{"title":"Pathogenicity Prediction of Gene Fusion in Structural Variations: A Knowledge Graph-Infused Explainable Artificial Intelligence (XAI) Framework","authors":"Katsuhiko Murakami, Shin-ichiro Tago, Sho Takishita, Hiroaki Morikawa, Rikuhiro Kojima, K. Yokoyama, M. Ogawa, Hidehito Fukushima, Hiroyuki Takamori, Yasuhito Nannya, S. Imoto, Masaru Fuji","doi":"10.3390/cancers16101915","DOIUrl":"https://doi.org/10.3390/cancers16101915","url":null,"abstract":"When analyzing cancer sample genomes in clinical practice, many structural variants (SVs), other than single nucleotide variants (SNVs), have been identified. To identify driver variants, the leading candidates must be narrowed down. When fusion genes are involved, selection is particularly difficult, and highly accurate predictions from AI is important. Furthermore, we also wanted to determine how the prediction can make more reliable diagnoses. Here, we developed an explainable AI (XAI) suitable for SVs with gene fusions, based on the XAI technology we previously developed for the prediction of SNV pathogenicity. To cope with gene fusion variants, we added new data to the previous knowledge graph for SVs and we improved the algorithm. Its prediction accuracy was as high as that of existing tools. Moreover, our XAI could explain the reasons for these predictions. We used some variant examples to demonstrate that the reasons are plausible in terms of pathogenic basic mechanisms. These results can be seen as a hopeful step toward the future of genomic medicine, where efficient and correct decisions can be made with the support of AI.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140962741","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}
Bernd C. Schmid, Dominic Marsland, Eilish Jacobs, Günther A. Rezniczek
Perioperative anxiety is common among patients undergoing surgery, potentially leading to negative outcomes. Immersive virtual reality (VR) has shown promise in reducing anxiety in various clinical settings. This study aimed to evaluate the effectiveness of VR in reducing perioperative anxiety in patients undergoing gynecological oncology surgery and was conducted as a single-center, double-arm, single-blinded randomized controlled trial at the Gold Coast University Hospital, Queensland, Australia. Participants were randomized into the VR intervention + care as usual (CAU) group (n = 39) and the CAU group (n = 41). Anxiety scores were assessed using a six-tier visual facial anxiety scale at baseline, after the intervention/CAU on the same day, and, several days up to weeks later, immediately before surgery. There was no significant difference in baseline anxiety scores, type of operation, or suspected cancer between the two groups. The VR intervention significantly reduced anxiety scores from baseline to preoperative assessment (p < 0.001). The median anxiety score in the VR intervention group decreased from 3 (interquartile range 2 to 5) at baseline to 2 (2 to 3) prior to surgery, while the control group’s scores were 4 (2 to 5) and 4 (3 to 5), respectively. Multivariate analysis showed that group assignment was the sole outcome predictor, not age, type of procedure, or the time elapsed until surgery. Thus, VR exposure was effective in reducing perioperative anxiety in patients undergoing gynecological oncology surgery. The use of VR as a preparation tool may improve patient experience and contribute to better surgical outcomes, warranting further research into exploring the potential benefits of VR in other surgical specialties and its long-term impact on patient recovery.
{"title":"A Preparatory Virtual Reality Experience Reduces Anxiety before Surgery in Gynecologic Oncology Patients: A Randomized Controlled Trial","authors":"Bernd C. Schmid, Dominic Marsland, Eilish Jacobs, Günther A. Rezniczek","doi":"10.3390/cancers16101913","DOIUrl":"https://doi.org/10.3390/cancers16101913","url":null,"abstract":"Perioperative anxiety is common among patients undergoing surgery, potentially leading to negative outcomes. Immersive virtual reality (VR) has shown promise in reducing anxiety in various clinical settings. This study aimed to evaluate the effectiveness of VR in reducing perioperative anxiety in patients undergoing gynecological oncology surgery and was conducted as a single-center, double-arm, single-blinded randomized controlled trial at the Gold Coast University Hospital, Queensland, Australia. Participants were randomized into the VR intervention + care as usual (CAU) group (n = 39) and the CAU group (n = 41). Anxiety scores were assessed using a six-tier visual facial anxiety scale at baseline, after the intervention/CAU on the same day, and, several days up to weeks later, immediately before surgery. There was no significant difference in baseline anxiety scores, type of operation, or suspected cancer between the two groups. The VR intervention significantly reduced anxiety scores from baseline to preoperative assessment (p < 0.001). The median anxiety score in the VR intervention group decreased from 3 (interquartile range 2 to 5) at baseline to 2 (2 to 3) prior to surgery, while the control group’s scores were 4 (2 to 5) and 4 (3 to 5), respectively. Multivariate analysis showed that group assignment was the sole outcome predictor, not age, type of procedure, or the time elapsed until surgery. Thus, VR exposure was effective in reducing perioperative anxiety in patients undergoing gynecological oncology surgery. The use of VR as a preparation tool may improve patient experience and contribute to better surgical outcomes, warranting further research into exploring the potential benefits of VR in other surgical specialties and its long-term impact on patient recovery.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140962829","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}
To explore the most suitable dosage regimen for limited-stage small cell lung cancer (LS-SCLC) and provide references for clinical selection, strict inclusion criteria were applied, and studies were screened from Pubmed, Embase, and Web of Science. Subsequently, data on two-year overall survival rates and dosage regimens were collected, and scatter plots were constructed to provide a comprehensive perspective. The survival benefits of various dosage regimens were evaluated, and a linear quadratic equation was utilized to fit the relationship between the biologically effective dose (BED10) and the two-year overall survival rate. Among the five randomized controlled trials, the two-year overall survival rate of ConvTRT regimens with BED10 > 60 Gy (rough value) was only at or below the median of all ConvTRT regimens or all included study regimens, indicating that increasing the number and total dose of ConvTRT does not necessarily lead to better prognosis. In the exploration of HypoTRT regimens, there was a linear positive correlation between BED10 and the two-year overall survival rate (p < 0.0001), while the exploration of HyperTRT regimens was relatively limited, with the majority focused on the 45 Gy/30 F regimen. However, the current 45 Gy/30 F regimen is not sufficient to control LS-SCLC, resulting in a high local recurrence rate. High-dose ConvTRT regimens have long treatment durations and may induce tumor regrowth which may cause reduced efficacy. Under reasonable toxicity reactions, HyperTRT or HypoTRT with higher radiotherapy doses is recommended for treating LS-SCLC.
为了探索最适合局限期小细胞肺癌（LS-SCLC）的用药方案，并为临床选择提供参考，我们采用了严格的纳入标准，并从Pubmed、Embase和Web of Science中筛选了相关研究。随后，收集了两年总生存率和剂量方案的数据，并绘制了散点图，以提供全面的视角。评估了各种剂量方案的生存优势，并利用线性二次方程拟合了生物有效剂量（BED10）与两年总生存率之间的关系。在五项随机对照试验中，BED10 > 60 Gy（粗略值）的ConvTRT治疗方案的两年总生存率仅处于或低于所有ConvTRT治疗方案或所有纳入研究的治疗方案的中位数，这表明增加ConvTRT的数量和总剂量并不一定会带来更好的预后。在对 HypoTRT 方案的探讨中，BED10 与两年总生存率之间呈线性正相关（p < 0.0001），而对 HyperTRT 方案的探讨则相对有限，大部分集中在 45 Gy/30 F 方案上。然而，目前的 45 Gy/30 F 方案不足以控制 LS-SCLC，导致局部复发率较高。高剂量ConvTRT方案治疗时间长，可能诱发肿瘤再生，导致疗效下降。在毒性反应合理的情况下，建议采用高剂量的HyperTRT或HypoTRT放疗方案治疗LS-SCLC。
{"title":"The Dose/Fractionation Debate in Limited-Stage Small Cell Lung Cancer","authors":"Kaixin Du, Xuehong Liao, Kazushi Kishi","doi":"10.3390/cancers16101908","DOIUrl":"https://doi.org/10.3390/cancers16101908","url":null,"abstract":"To explore the most suitable dosage regimen for limited-stage small cell lung cancer (LS-SCLC) and provide references for clinical selection, strict inclusion criteria were applied, and studies were screened from Pubmed, Embase, and Web of Science. Subsequently, data on two-year overall survival rates and dosage regimens were collected, and scatter plots were constructed to provide a comprehensive perspective. The survival benefits of various dosage regimens were evaluated, and a linear quadratic equation was utilized to fit the relationship between the biologically effective dose (BED10) and the two-year overall survival rate. Among the five randomized controlled trials, the two-year overall survival rate of ConvTRT regimens with BED10 > 60 Gy (rough value) was only at or below the median of all ConvTRT regimens or all included study regimens, indicating that increasing the number and total dose of ConvTRT does not necessarily lead to better prognosis. In the exploration of HypoTRT regimens, there was a linear positive correlation between BED10 and the two-year overall survival rate (p < 0.0001), while the exploration of HyperTRT regimens was relatively limited, with the majority focused on the 45 Gy/30 F regimen. However, the current 45 Gy/30 F regimen is not sufficient to control LS-SCLC, resulting in a high local recurrence rate. High-dose ConvTRT regimens have long treatment durations and may induce tumor regrowth which may cause reduced efficacy. Under reasonable toxicity reactions, HyperTRT or HypoTRT with higher radiotherapy doses is recommended for treating LS-SCLC.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140962447","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}
Agnieszka Żyłka, Katarzyna Dobruch-Sobczak, Hanna Piotrzkowska-Wróblewska, Maciej Jędrzejczyk, Elwira Bakuła-Zalewska, Piotr Góralski, Jacek Gałczyński, Marek Dedecjus
Background: Ultrasonography is a primary method used in the evaluation of thyroid nodules, but no single feature of this method predicts malignancy with high accuracy. Therefore, this paper aims to assess the utility of contrast-enhanced ultrasound (CEUS) in the differential diagnosis of thyroid nodules. Methods: The study group comprised 188 adult patients (155 women and 33 men) who preoperatively underwent CEUS of a thyroid nodule classified as Bethesda categories II–VI after fine-needle aspiration biopsy. During the CEUS examination, 1.5 mL of SonoVue contrast was injected intravenously, after which 15 qualitative CEUS enhancement patterns were analysed. Results: The histopathologic results comprised 65 benign thyroid nodules and 123 thyroid carcinomas. The dominant malignant CEUS features, such as hypo- and heterogeneous enhancement and slow wash-in phase, were evaluated, whereas high enhancement, ring enhancement, and a slow wash-out phase were assessed as predictors of benign lesions. Two significant combinations of B-mode and CEUS patterns were noted, namely, hypoechogenicity with heterogeneous enhancement and non-smooth margins with hypo- or iso-enhancement. Conclusions: The preliminary results indicate that CEUS is a useful tool in assessing the risk of malignancy of thyroid lesions. The combination of the qualitative enhancement parameters and B-mode sonographic features significantly increases the method’s usefulness.
{"title":"The Utility of Contrast-Enhanced Ultrasound (CEUS) in Assessing the Risk of Malignancy in Thyroid Nodules","authors":"Agnieszka Żyłka, Katarzyna Dobruch-Sobczak, Hanna Piotrzkowska-Wróblewska, Maciej Jędrzejczyk, Elwira Bakuła-Zalewska, Piotr Góralski, Jacek Gałczyński, Marek Dedecjus","doi":"10.3390/cancers16101911","DOIUrl":"https://doi.org/10.3390/cancers16101911","url":null,"abstract":"Background: Ultrasonography is a primary method used in the evaluation of thyroid nodules, but no single feature of this method predicts malignancy with high accuracy. Therefore, this paper aims to assess the utility of contrast-enhanced ultrasound (CEUS) in the differential diagnosis of thyroid nodules. Methods: The study group comprised 188 adult patients (155 women and 33 men) who preoperatively underwent CEUS of a thyroid nodule classified as Bethesda categories II–VI after fine-needle aspiration biopsy. During the CEUS examination, 1.5 mL of SonoVue contrast was injected intravenously, after which 15 qualitative CEUS enhancement patterns were analysed. Results: The histopathologic results comprised 65 benign thyroid nodules and 123 thyroid carcinomas. The dominant malignant CEUS features, such as hypo- and heterogeneous enhancement and slow wash-in phase, were evaluated, whereas high enhancement, ring enhancement, and a slow wash-out phase were assessed as predictors of benign lesions. Two significant combinations of B-mode and CEUS patterns were noted, namely, hypoechogenicity with heterogeneous enhancement and non-smooth margins with hypo- or iso-enhancement. Conclusions: The preliminary results indicate that CEUS is a useful tool in assessing the risk of malignancy of thyroid lesions. The combination of the qualitative enhancement parameters and B-mode sonographic features significantly increases the method’s usefulness.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140963775","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}
Retinoic acid receptor-related orphan receptor alpha (RORα), a candidate tumor suppressor, is prevalently downregulated or lost in malignant breast cancer cells. However, the mechanisms of how RORα expression is regulated in breast epithelial cells remain incompletely understood. Protein arginine N-methyltransferase 5 (PRMT5), a type II methyltransferase catalyzing the symmetric methylation of the amino acid arginine in target proteins, was reported to regulate protein stability. To study whether and how PRMT5 regulates RORα, we examined the direct interaction between RORα and PRMT5 by immunoprecipitation and GST pull-down assays. The results showed that PRMT5 directly bound to RORα, and PRMT5 mainly symmetrically dimethylated the DNA-binding domain (DBD) but not the ligand-binding domain (LBD) of RORα. To investigate whether RORα protein stability is regulated by PRMT5, we transfected HEK293FT cells with RORα and PRMT5-expressing or PRMT5-silencing (shPRMT5) vectors and then examined RORα protein stability by a cycloheximide chase assay. The results showed that PRMT5 increased RORα protein stability, while silencing PRMT5 accelerated RORα protein degradation. In PRMT5-silenced mammary epithelial cells, RORα protein expression was decreased, accompanied by an enhanced epithelial–mesenchymal transition morphology and cell invasion and migration abilities. In PRMT5-overexpressed mammary epithelial cells, RORα protein was accumulated, and cell invasion was suppressed. These findings revealed a novel mechanism by which PRMT5 regulates RORα protein stability.
{"title":"Regulation of RORα Stability through PRMT5-Dependent Symmetric Dimethylation","authors":"Gaofeng Xiong, Brynne Obringer, Austen Jones, Elise Horton, Ren Xu","doi":"10.3390/cancers16101914","DOIUrl":"https://doi.org/10.3390/cancers16101914","url":null,"abstract":"Retinoic acid receptor-related orphan receptor alpha (RORα), a candidate tumor suppressor, is prevalently downregulated or lost in malignant breast cancer cells. However, the mechanisms of how RORα expression is regulated in breast epithelial cells remain incompletely understood. Protein arginine N-methyltransferase 5 (PRMT5), a type II methyltransferase catalyzing the symmetric methylation of the amino acid arginine in target proteins, was reported to regulate protein stability. To study whether and how PRMT5 regulates RORα, we examined the direct interaction between RORα and PRMT5 by immunoprecipitation and GST pull-down assays. The results showed that PRMT5 directly bound to RORα, and PRMT5 mainly symmetrically dimethylated the DNA-binding domain (DBD) but not the ligand-binding domain (LBD) of RORα. To investigate whether RORα protein stability is regulated by PRMT5, we transfected HEK293FT cells with RORα and PRMT5-expressing or PRMT5-silencing (shPRMT5) vectors and then examined RORα protein stability by a cycloheximide chase assay. The results showed that PRMT5 increased RORα protein stability, while silencing PRMT5 accelerated RORα protein degradation. In PRMT5-silenced mammary epithelial cells, RORα protein expression was decreased, accompanied by an enhanced epithelial–mesenchymal transition morphology and cell invasion and migration abilities. In PRMT5-overexpressed mammary epithelial cells, RORα protein was accumulated, and cell invasion was suppressed. These findings revealed a novel mechanism by which PRMT5 regulates RORα protein stability.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140964735","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}
Ugo Giordano, Monika Mordak-Domagała, Małgorzata Sobczyk-Kruszelnicka, Sebastian Giebel, Lidia Gil, Krzysztof D. Dudek, Jarosław Dybko
Despite notable advancements in immunotherapy in the past decades, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a promising, potentially curative treatment modality. Only a limited number of studies have performed a direct comparison of two prevalent rabbit anti-thymocyte globulin (r-ATG) formulations—specifically, Thymoglobuline (ATG-T, formerly Genzyme) and Grafalon (ATG-G, formerly Fresenius). The primary objective of our retrospective analysis was to compare the outcomes of adult patients undergoing matched or mismatched unrelated donor (MUD/MMUD) allo-HCT, with a graft-versus-host disease (GvHD) prophylaxis based on either ATG-T or ATG-G. A total of 87 patients who had undergone allo-HCT between 2012 and 2022 were included. We observed no significant differences between ATG-T and ATG-G concerning the occurrence of acute graft-versus-host disease (aGvHD), regardless of its severity. Conversely, chronic graft-versus-host disease (cGvHD) occurred less frequently in the ATG-T group compared to the ATG-G group (7.5% vs. 38.3%, p = 0.001). The negative impact of ATG-G on cGvHD was confirmed by multivariate analysis (HR 8.12, 95% CI 2.06–32.0, p = 0.003). Patients treated with ATG-T manifested a higher incidence of cytomegalovirus (CMV) reactivations (70% vs. 31.9%, p < 0.001), with a shorter time between transplant and CMV (<61 days, 77.8% vs. 33.3%, p = 0.008) and a higher median CMV copy number (1000 vs. 0, p = 0.004). Notably, despite a higher occurrence of CMV reactivations in the ATG-T cohort, most patients were asymptomatic compared to ATG-G (85.7% vs. 43.8%, p = 0.005). By multivariate analysis, only aGvHD had an influence on CMV reactivations (HR 0.18, 95% CI 0.04–0.75, p = 0.019). Finally, we observed no significant differences in terms of 5-year overall survival (OS) and 3-year relapse-free survival (RFS) while comparing ATG-T and ATG-G (32.0% vs. 40.3%, p = 0.423; 66.7% vs. 60.4%, p = 0.544, respectively).
尽管过去几十年来免疫疗法取得了显著进步，但异体造血干细胞移植（allo-HCT）仍是一种前景广阔、可能治愈的治疗方式。只有少数研究对两种常用的兔抗胸腺细胞球蛋白（r-ATG）制剂进行了直接比较，特别是胸腺球蛋白（ATG-T，原Genzyme公司）和格拉法隆（ATG-G，原费森尤斯公司）。我们进行回顾性分析的主要目的是比较接受匹配或不匹配非亲属供者（MUD/MMUD）异体肝移植的成年患者在使用ATG-T或ATG-G预防移植物抗宿主病（GvHD）后的疗效。共纳入了87名在2012年至2022年期间接受过异体肝移植的患者。我们观察到，ATG-T 和 ATG-G 在急性移植物抗宿主病 (aGvHD) 的发生率上没有明显差异，无论其严重程度如何。相反，与 ATG-G 组相比，ATG-T 组的慢性移植物抗宿主病（cGvHD）发生率较低（7.5% 对 38.3%，P = 0.001）。多变量分析证实了ATG-G对cGvHD的负面影响（HR 8.12，95% CI 2.06-32.0，p = 0.003）。接受ATG-T治疗的患者巨细胞病毒（CMV）复发率更高（70% vs. 31.9%，p < 0.001），移植与CMV之间的间隔时间更短（<61天，77.8% vs. 33.3%，p = 0.008），CMV拷贝数中位数更高（1000 vs. 0，p = 0.004）。值得注意的是，尽管ATG-T队列中CMV再激活发生率较高，但与ATG-G队列相比，大多数患者无症状（85.7% vs. 43.8%，p = 0.005）。通过多变量分析，只有 aGvHD 对 CMV 再激活有影响（HR 0.18，95% CI 0.04-0.75，p = 0.019）。最后，我们观察到 ATG-T 和 ATG-G 的 5 年总生存率（OS）和 3 年无复发生存率（RFS）没有明显差异（分别为 32.0% vs. 40.3%，p = 0.423；66.7% vs. 60.4%，p = 0.544）。
{"title":"Comparing the Outcomes of Matched and Mismatched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation with Different Anti-Thymocyte Globulin Formulations: A Retrospective, Double-Centre Experience on Behalf of the Polish Adult Leukemia Group","authors":"Ugo Giordano, Monika Mordak-Domagała, Małgorzata Sobczyk-Kruszelnicka, Sebastian Giebel, Lidia Gil, Krzysztof D. Dudek, Jarosław Dybko","doi":"10.3390/cancers16101891","DOIUrl":"https://doi.org/10.3390/cancers16101891","url":null,"abstract":"Despite notable advancements in immunotherapy in the past decades, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a promising, potentially curative treatment modality. Only a limited number of studies have performed a direct comparison of two prevalent rabbit anti-thymocyte globulin (r-ATG) formulations—specifically, Thymoglobuline (ATG-T, formerly Genzyme) and Grafalon (ATG-G, formerly Fresenius). The primary objective of our retrospective analysis was to compare the outcomes of adult patients undergoing matched or mismatched unrelated donor (MUD/MMUD) allo-HCT, with a graft-versus-host disease (GvHD) prophylaxis based on either ATG-T or ATG-G. A total of 87 patients who had undergone allo-HCT between 2012 and 2022 were included. We observed no significant differences between ATG-T and ATG-G concerning the occurrence of acute graft-versus-host disease (aGvHD), regardless of its severity. Conversely, chronic graft-versus-host disease (cGvHD) occurred less frequently in the ATG-T group compared to the ATG-G group (7.5% vs. 38.3%, p = 0.001). The negative impact of ATG-G on cGvHD was confirmed by multivariate analysis (HR 8.12, 95% CI 2.06–32.0, p = 0.003). Patients treated with ATG-T manifested a higher incidence of cytomegalovirus (CMV) reactivations (70% vs. 31.9%, p < 0.001), with a shorter time between transplant and CMV (<61 days, 77.8% vs. 33.3%, p = 0.008) and a higher median CMV copy number (1000 vs. 0, p = 0.004). Notably, despite a higher occurrence of CMV reactivations in the ATG-T cohort, most patients were asymptomatic compared to ATG-G (85.7% vs. 43.8%, p = 0.005). By multivariate analysis, only aGvHD had an influence on CMV reactivations (HR 0.18, 95% CI 0.04–0.75, p = 0.019). Finally, we observed no significant differences in terms of 5-year overall survival (OS) and 3-year relapse-free survival (RFS) while comparing ATG-T and ATG-G (32.0% vs. 40.3%, p = 0.423; 66.7% vs. 60.4%, p = 0.544, respectively).","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140967950","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}
Joo Hye Song, Eun Ran Kim, Yiyu Hong, Insuk Sohn, Soomin Ahn, Seok-Hyung Kim, Kee-Taek Jang
According to the current guidelines, additional surgery is performed for endoscopically resected specimens of early colorectal cancer (CRC) with a high risk of lymph node metastasis (LNM). However, the rate of LNM is 2.1–25.0% in cases treated endoscopically followed by surgery, indicating a high rate of unnecessary surgeries. Therefore, this study aimed to develop an artificial intelligence (AI) model using H&E-stained whole slide images (WSIs) without handcrafted features employing surgically and endoscopically resected specimens to predict LNM in T1 CRC. To validate with an independent cohort, we developed a model with four versions comprising various combinations of training and test sets using H&E-stained WSIs from endoscopically (400 patients) and surgically resected specimens (881 patients): Version 1, Train and Test: surgical specimens; Version 2, Train and Test: endoscopic and surgically resected specimens; Version 3, Train: endoscopic and surgical specimens and Test: surgical specimens; Version 4, Train: endoscopic and surgical specimens and Test: endoscopic specimens. The area under the curve (AUC) of the receiver operating characteristic curve was used to determine the accuracy of the AI model for predicting LNM with a 5-fold cross-validation in the training set. Our AI model with H&E-stained WSIs and without annotations showed good performance power with the validation of an independent cohort in a single center. The AUC of our model was 0.758–0.830 in the training set and 0.781–0.824 in the test set, higher than that of previous AI studies with only WSI. Moreover, the AI model with Version 4, which showed the highest sensitivity (92.9%), reduced unnecessary additional surgery by 14.2% more than using the current guidelines (68.3% vs. 82.5%). This revealed the feasibility of using an AI model with only H&E-stained WSIs to predict LNM in T1 CRC.
{"title":"Prediction of Lymph Node Metastasis in T1 Colorectal Cancer Using Artificial Intelligence with Hematoxylin and Eosin-Stained Whole-Slide-Images of Endoscopic and Surgical Resection Specimens","authors":"Joo Hye Song, Eun Ran Kim, Yiyu Hong, Insuk Sohn, Soomin Ahn, Seok-Hyung Kim, Kee-Taek Jang","doi":"10.3390/cancers16101900","DOIUrl":"https://doi.org/10.3390/cancers16101900","url":null,"abstract":"According to the current guidelines, additional surgery is performed for endoscopically resected specimens of early colorectal cancer (CRC) with a high risk of lymph node metastasis (LNM). However, the rate of LNM is 2.1–25.0% in cases treated endoscopically followed by surgery, indicating a high rate of unnecessary surgeries. Therefore, this study aimed to develop an artificial intelligence (AI) model using H&E-stained whole slide images (WSIs) without handcrafted features employing surgically and endoscopically resected specimens to predict LNM in T1 CRC. To validate with an independent cohort, we developed a model with four versions comprising various combinations of training and test sets using H&E-stained WSIs from endoscopically (400 patients) and surgically resected specimens (881 patients): Version 1, Train and Test: surgical specimens; Version 2, Train and Test: endoscopic and surgically resected specimens; Version 3, Train: endoscopic and surgical specimens and Test: surgical specimens; Version 4, Train: endoscopic and surgical specimens and Test: endoscopic specimens. The area under the curve (AUC) of the receiver operating characteristic curve was used to determine the accuracy of the AI model for predicting LNM with a 5-fold cross-validation in the training set. Our AI model with H&E-stained WSIs and without annotations showed good performance power with the validation of an independent cohort in a single center. The AUC of our model was 0.758–0.830 in the training set and 0.781–0.824 in the test set, higher than that of previous AI studies with only WSI. Moreover, the AI model with Version 4, which showed the highest sensitivity (92.9%), reduced unnecessary additional surgery by 14.2% more than using the current guidelines (68.3% vs. 82.5%). This revealed the feasibility of using an AI model with only H&E-stained WSIs to predict LNM in T1 CRC.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140971513","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}
Viviana Cortiana, Muskan Joshi, Harshal Chorya, Harshitha Vallabhaneni, Shreevikaa Kannan, Helena S. Coloma, Chandler H. Park, Yan Leyfman
Colorectal cancer (CRC) currently ranks as the third most common cancer and the second leading cause of cancer-related deaths worldwide, posing a significant global health burden to the population. Recent studies have reported the emergence of a new clinical picture of the disease, with a notable increase in CRC rates in younger populations of <50 years of age. The American Cancer Society (ACS) now recommends CRC screening starting at age 45 for average-risk individuals. Dr. Aasma Shaukat’s Keynote Conference highlights the critical need for updated screening strategies, with an emphasis on addressing the suboptimal adherence rates and the effective management of the growing burden of CRC. Lowering the adenoma detection screening age can facilitate early identification of adenomas in younger asymptomatic patients, altering the epidemiologic landscape. However, its implications may not be as profound unless a drastic shift in the age distribution of CRC is observed. Currently, various screening options are available in practice, including stool-based tests like multitarget stool DNA (mtDNA) tests, fecal immunochemical testing (FIT), and imaging-based tests. In addition to existing screening methods, blood-based tests are now emerging as promising tools for early CRC detection. These tests leverage innovative techniques along with AI and machine learning algorithms, aiding in tumor detection at a significantly earlier stage, which was not possible before. Medicare mandates specific criteria for national coverage of blood-based tests, including sensitivity ≥ 74%, specificity ≥ 90%, FDA approval, and inclusion in professional society guidelines. Ongoing clinical trials, such as Freenome, Guardant, and CancerSEEK, offer hope for further advancements in blood-based CRC screening. The development of multicancer early detection tests like GRAIL demonstrates a tremendous potential for detecting various solid tumors and hematologic malignancies. Despite these breakthroughs, the question of accessibility and affordability still stands. The ever-evolving landscape of CRC screening reflects the strength of the scientific field in light of an altered disease epidemiology. Lowering screening age along with the integration of blood-based tests with existing screening methods holds great potential in reducing the CRC-related burden. At the same time, it is increasingly important to address the challenges of adaptation of the healthcare system to this change in the epidemiologic paradigm.
{"title":"Reimagining Colorectal Cancer Screening: Innovations and Challenges with Dr. Aasma Shaukat","authors":"Viviana Cortiana, Muskan Joshi, Harshal Chorya, Harshitha Vallabhaneni, Shreevikaa Kannan, Helena S. Coloma, Chandler H. Park, Yan Leyfman","doi":"10.3390/cancers16101898","DOIUrl":"https://doi.org/10.3390/cancers16101898","url":null,"abstract":"Colorectal cancer (CRC) currently ranks as the third most common cancer and the second leading cause of cancer-related deaths worldwide, posing a significant global health burden to the population. Recent studies have reported the emergence of a new clinical picture of the disease, with a notable increase in CRC rates in younger populations of <50 years of age. The American Cancer Society (ACS) now recommends CRC screening starting at age 45 for average-risk individuals. Dr. Aasma Shaukat’s Keynote Conference highlights the critical need for updated screening strategies, with an emphasis on addressing the suboptimal adherence rates and the effective management of the growing burden of CRC. Lowering the adenoma detection screening age can facilitate early identification of adenomas in younger asymptomatic patients, altering the epidemiologic landscape. However, its implications may not be as profound unless a drastic shift in the age distribution of CRC is observed. Currently, various screening options are available in practice, including stool-based tests like multitarget stool DNA (mtDNA) tests, fecal immunochemical testing (FIT), and imaging-based tests. In addition to existing screening methods, blood-based tests are now emerging as promising tools for early CRC detection. These tests leverage innovative techniques along with AI and machine learning algorithms, aiding in tumor detection at a significantly earlier stage, which was not possible before. Medicare mandates specific criteria for national coverage of blood-based tests, including sensitivity ≥ 74%, specificity ≥ 90%, FDA approval, and inclusion in professional society guidelines. Ongoing clinical trials, such as Freenome, Guardant, and CancerSEEK, offer hope for further advancements in blood-based CRC screening. The development of multicancer early detection tests like GRAIL demonstrates a tremendous potential for detecting various solid tumors and hematologic malignancies. Despite these breakthroughs, the question of accessibility and affordability still stands. The ever-evolving landscape of CRC screening reflects the strength of the scientific field in light of an altered disease epidemiology. Lowering screening age along with the integration of blood-based tests with existing screening methods holds great potential in reducing the CRC-related burden. At the same time, it is increasingly important to address the challenges of adaptation of the healthcare system to this change in the epidemiologic paradigm.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140969027","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}
Benjamin Schulz, Emily Leitner, Tim Schreiber, Tobias Lindner, Rico Schwarz, Nadine Aboutara, Yixuan Ma, Hugo Murua Escobar, Rupert Palme, Burkhard Hinz, Brigitte Vollmar, Dietmar Zechner
Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds.
{"title":"Sex Matters–Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer","authors":"Benjamin Schulz, Emily Leitner, Tim Schreiber, Tobias Lindner, Rico Schwarz, Nadine Aboutara, Yixuan Ma, Hugo Murua Escobar, Rupert Palme, Burkhard Hinz, Brigitte Vollmar, Dietmar Zechner","doi":"10.3390/cancers16101901","DOIUrl":"https://doi.org/10.3390/cancers16101901","url":null,"abstract":"Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140967666","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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