Clinical Cancer Research最新文献

{"title":"Personalized MRD Assessment in Peri-surgical ctDNA for Prognostic Prediction in Hepatocellular Carcinoma","authors":"Jie Hu, Haoran Tang, Can-Can Jia, Xiang-Yu Zhang, Ying Xu, Jin-Peng Tan, Jia Fan, Shidong Jia, Jian Zhou","doi":"10.1158/1078-0432.ccr-24-1897","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1897","url":null,"abstract":"Objective: Detecting residual disease is a critical clinical requirement in the peri-surgical management of patients with resectable hepatocellular carcinoma (HCC). Previous studies focused on specific genomic regions exhibiting limited sensitivity and failed to meet the minimal residual disease (MRD) testing threshold. We introduce a next-generation sequencing (NGS) based assay, informed by baseline samples, facilitating MRD detection in hepatectomized HCC patients and offering prognostic predictions. Experimental Design: This study involved 88 HCC patients who underwent surgical resections January 2016 to May 2016 in Zhongshan Hospital Fudan University. Tumor and normal tissue samples were collected during surgery, while plasma samples were obtained both before surgery and up to seven days post-surgery. Using an NGS-based personalized circulating tumor DNA assay, we analyzed MRD in both pre-surgical and post-surgical blood samples and the correlation with prognosis. Results: With a median follow-up period of 80.7 months, our findings demonstrated significant correlations between pre-surgical ctDNA tumor fractions, post-surgical plasma MRD status, and both recurrence-free survival (RFS) and overall survival (OS). Post-surgical MRD status emerged as the most significant risk factor for cancer recurrence (HR=2.17, 95% CI: 1.09-4.30, p=0.027) compared to other clinical characteristics in multivariate Cox regression analysis. Notably, MRD status showed potential as a prognostic indicator among clinically low-recurrent-risk patients, such as those with BCLC stage 0-A, CNLC stage I-II. Conclusion: Evaluating personalized MRD provided crucial prognostic insights into RFS and OS. It efficiently identified patients at high risk of recurrence, even among those initially perceived as low-risk cases.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A tumor-naive ctDNA assay detects minimal residual disease in resected stage II or III colorectal cancer and predicts recurrence: subset analysis from the GALAXY study in CIRCULATE-Japan","authors":"Yoshiaki Nakamura, Kristiyana Kaneva, Christine Lo, Daniel Neems, Jonathan E. Freaney, Hala Boulos, Seung Won Hyun, Farahnaz Islam, Jason Yamada-Hanff, Terri M. Driessen, Anne Sonnenschein, Dana F. DeSantis, Daisuke Kotani, Jun Watanabe, Masahito Kotaka, Saori Mishima, Hideaki Bando, Kentaro Yamazaki, Hiroya Taniguchi, Ichiro Takemasa, Takeshi Kato, Chithra Sangli, Robert Tell, Richard Blidner, Takayuki Yoshino, Kate Sasser, Eiji Oki, Halla Nimeiri","doi":"10.1158/1078-0432.ccr-24-2396","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2396","url":null,"abstract":"Purpose: Analysis of circulating tumor DNA (ctDNA) may enable early identification of patients likely to relapse, presenting an opportunity for early interventions and improved outcomes. Tumor-naïve plasma-only approaches for molecular residual disease (MRD) assessment accelerate turnaround time, enabling rapid treatment decisions and ongoing surveillance. Experimental Design: Plasma samples were obtained from 80 study participants with stage II or III colorectal cancer (CRC) selected from CIRCULATE-Japan GALAXY. MRD status was assessed using a tumor-naïve ctDNA assay (xM) that integrates methylation and genomic variant data, delivering a binary call. MRD was assessed at 4 weeks post-surgery (landmark timepoint (LMT)) using methylation and genomic variant data and longitudinally (median 22.1 months) using only methylation data. Results: At LMT, 69/80 study participants were evaluable (36 recurrent; 33 non-recurrent). Of recurrent study participants, 22/36 had detectable ctDNA (MRD+) at LMT and 29/33 non-recurrent study participants had undetectable ctDNA (MRD-), yielding clinical sensitivity of 61.1% and specificity of 87.9%. Additionally, 74 study participants were evaluable for longitudinal performance with a clinical sensitivity of 83.3% and specificity of 89.5%. Median lead time from first MRD+ result to recurrence was 4.77 months overall, and 5.30 months for study participants with no adjuvant treatment. At 12 weeks post-surgery, MRD status strongly correlated with disease-free survival (DFS) [adj. HR 9.69], outperforming carcinoembryonic antigen (CEA) correlation [HR 2.13]. Conclusions: This tumor-naïve MRD assay demonstrated clinically meaningful performance at LMT and longitudinally, accurately predicting clinical recurrence. MRD status was a stronger prognostic biomarker to DFS compared to standard of care CEA.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic, epigenomic and transcriptomic inter- and intra-tumor heterogeneity in desmoid tumors","authors":"Chelsea De Bellis, Sujay Vennam, Christopher Eeles, Pegah Rahimizadeh, Justin Cates, Thomas Stricker, Jenny Hoffman, Kristen Ganjoo, Gregory W. Charville, Benjamin Haibe-Kains, Matt van de Rijn, Joanna Przybyl","doi":"10.1158/1078-0432.ccr-24-1240","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1240","url":null,"abstract":"Purpose: Desmoid tumors are bland fibroblastic tumors that do not metastasize but have a high rate of local recurrence. Previously published studies proposed two different transcriptomic signatures to predict relapse. Molecular heterogeneity has been well established in high-grade sarcomas but little is known about molecular variability within locally aggressive tumors such as desmoids. Experimental Design: We performed transcriptomic profiling of 31 specimens from 20 primary desmoid tumors to identify genes predictive of relapse. We also performed multi-omic analysis including DNA methylation, copy number alterations, point mutations and gene expression on 24 specimens from different regions of primary and recurrent desmoid tumors from 3 patients (7-9 specimens per patient). Results: We observed highly variable expression of transcriptomic prognostic signatures, both in patients who did or did not progress. Signatures associated with favorable and unfavorable outcome were detected in different regions within the same tumor. Further multi-omic studies showed remarkable intra- and inter-tumor heterogeneity of genomic, epigenomic and transcriptomic patterns. The transcriptomic profiles showed the highest degree of variability within tumors and between primary and recurrent tumors from the same patient. Conclusions: This study shows an unexpected degree of intra- and inter-tumor heterogeneity in desmoid tumors. Our analysis indicates that molecular analysis of a single tumor biopsy may underestimate the magnitude of molecular alterations in desmoid tumors. Our study also shows that recurrent desmoid tumors acquire multiple new molecular alterations. Thus, molecular heterogeneity is an important consideration in drug development and validation of prognostic and predictive biomarkers for desmoid tumors.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Randomized Phase II Study of Durvalumab with or without Tremelimumab in Patients with Metastatic Castration Resistant Prostate Cancer.","authors":"Eric Winquist, Sebastien J. Hotte, Kim Chi, Srikala Sridhar, Susan Ellard, Michael Ong, Nayyer Iqbal, Muhammad Salim, Urban Emmenegger, Joel R. Gingerich, Aly-Khan Lalani, Pierre Major, Christian Kollmannsberger, Steven Yip, Aaron Hansen, Daygen Finch, Christina Canil, James Hutchenreuther, Francisco Vera-Badillo, Martin Smoragiewicz, Michael Cabanero, Ming-Sound Tsao, Elie Ritch, Alexander W. Wyatt, Lesley Seymour","doi":"10.1158/1078-0432.ccr-24-1612","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1612","url":null,"abstract":"PURPOSE: Programmed death-ligand 1 (PD-L1) is overexpressed by dendritic cells in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on androgen receptor pathway inhibitors. We tested whether checkpoint blockade could enhance antitumor activity in mCRPC. METHODS: In a multicenter open-label non-comparative randomized phase II study, patients with mCRPC treated with £ 1 prior cytotoxic chemotherapy, with measurable disease and progression on abiraterone and/or enzalutamide were randomized to durvalumab (D) 1500mg IV Q4 weeks ± 4 doses of tremelimumab (T) 75mg IV. The primary endpoint was objective response (OR) by iRECIST using a Simon 2-stage design. Correlative testing included PD-L1/CD8 immunohistochemistry on baseline tumour biopsies and deep targeted sequencing of plasma cell-free DNA. RESULTS: 52 patients were enrolled. Median age was 70 years (range, 50-83 years) and 52% had prior taxane therapy for mCRPC. In stage 1, 13 patients were randomized to D with no OR observed. D+T advanced to stage 2 with 39 patients enrolled (receiving a median 3 cycles, range 1-53). D+T related adverse events (AEs) were mainly £ grade 2 but led to discontinuation in 7 patients . There were seven OR (19.4% [95% confidence interval: 8.2-36.0%]; intention to treat (ITT) 17.9% [95% confidence interval: 7.5-33.5%]). Five responding tumours were PD-L1 positive and two exhibited DNA damage repair defects. Responses were observed without high tumour mutational burden or other genomic indices of immunotherapy sensitivity. CONCLUSION: D+T is active in mCRPC but patient selection remains a challenge. Further studies to develop predictive biomarkers are warranted.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic variants in cancer susceptibility genes predispose to Ductal Carcinoma In situ of the breast","authors":"Huaizhi Huang, Ronan E. Couch, Rachid Karam, Chunling Hu, Nicholas Boddicker, Eric C. Polley, Jie Na, Christine B. Ambrosone, Song Yao, Amy Trentham-Dietz, A. Heather Eliassen, Kathryn Penney, Kristen Brantley, Clara Bodelon, Lauren R. Teras, James Hodge, Alpa Patel, Christopher A. Haiman, Esther M. John, Susan L. Neuhausen, Elena Martinez, James V. Lacey, Katie M. O'Brien, Dale P. Sandler, Clarice R. Weinberg, Julie R. Palmer, Kimberly A. Bertrand, Celine M. Vachon, Janet E. Olson, Kathryn E. Ruddy, Hoda Anton-Culver, Argyrios Ziogas, David E. Goldgar, Katherine L. Nathanson, Susan M. Domchek, Jeffrey N. Weitzel, Peter Kraft, Jill S. Dolinsky, Tina Pesaran, Marcy E. Richardson, Siddhartha Yadav, Fergus J. Couch","doi":"10.1158/1078-0432.ccr-24-1884","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1884","url":null,"abstract":"Purpose: To determine the relationship between germline pathogenic variants (PVs) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS). Methods: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls, and between DCIS and infiltrating ductal carcinoma (IDC) cases from a clinical-testing cohort (n=9,887), a population-based cohort (n=3,876) and the UK Biobank (n=2421). The risk of contralateral breast cancer for DCIS cases with PVs was estimated in the population-based cohort. Results: Germline PVs were observed in 6.5% and 4.6% of women with DCIS in the clinical-testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PVs frequencies were significantly lower among women with DCIS than IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PVs were significantly associated with an increased risk of DCIS (OR>2.0), but only BRCA2 PVs were associated with high-risk (OR>4) in both cohorts. The cumulative incidence of contralateral breast cancer among carriers of PVs in high penetrance genes with DCIS was 23% over 15 years. Conclusions: The enrichment of PVs in ATM, BRCA1, BRCA2, CHEK2 and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of contralateral breast cancer in carriers of PVs in high penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilizing Patient-derived Xenografts to Model Precision Oncology for Biliary Tract Cancer","authors":"Timothy P. DiPeri, Kurt W. Evans, Stephen Scott, Xiaofeng Zheng, Kaushik Varadarajan, Lawrence N. Kwong, Michael Kahle, Hop S. Tran Cao, Ching-Wei Tzeng, Thuy Vu, Sunhee Kim, Fei Su, Maria Gabriela Raso, Yasmeen Rizvi, Ming Zhao, Huamin Wang, Sunyoung S. Lee, Timothy A. Yap, Jordi Rodon, Milind Javle, Funda Meric-Bernstam","doi":"10.1158/1078-0432.ccr-24-1233","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1233","url":null,"abstract":"Purpose: Biliary tract cancers (BTCs), which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant BTC models which recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in BTCs to create a resource for modeling precision oncology. Experimental Design: PDXs were derived from BTC collected from surgical resections or metastatic biopsies. Alterations present in the PDXs were identified by whole exome sequencing and RNASeq. PDXs were treated with approved and investigational agents. Efficacy was assessed by change in tumor volume from baseline. Event-free survival was defined as time to tumor doubling from baseline. Responses were categorized at day 21: >30% decrease=partial response; >20% increase in tumor volume=progressive disease, and any non-PR/PD was considered stable disease. Results: Genomic sequencing demonstrated key actionable alterations across this cohort, including alterations in FGFR2, IDH1, ERRB2, PIK3CA, PTEN and KRAS. RNAseq demonstrated fusions and expression of antibody drug conjugate targets including TROP2, HER2 and Nectin4. Therapeutic matching revealed objective responses to approved and investigational agents that have been shown to have antitumor activity clinically. Conclusions: Here, we developed a catalog of BTC PDXs which underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of BTC PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Re-irradiation plus pembrolizumab: Phase II study for recurrent glioblastoma patients","authors":"Fabio M. Iwamoto, Shyam K. Tanguturi, Lakshmi Nayak, Tony J. Wang, Arati Desai, Robert A. Lustig, Stephen Bagley, Eric T. Wong, Lauren M. Hertan, Christine McCluskey, Julia Hayden, Alona Muzikansky, Shreya Nakhawa, Julia Japo, Connor C. Bossi, Maxime Meylan, Ye Tian, Graham L. Barlow, Paul Speliakos, Georges Ayoub, David M. Meredith, Keith L. Ligon, Daphne Haas-Kogan, Kun Huang, Kai W. Wucherpfennig, Patrick Y. Wen, David A. Reardon","doi":"10.1158/1078-0432.ccr-24-1629","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1629","url":null,"abstract":"Purpose: Radiation therapy may enhance anti-tumor immune responses by several mechanisms including induction of immunogenic cell death. We performed a phase 2 study of pembrolizumab with re-irradiation in patients with recurrent glioblastoma. Methods: Sixty recurrent glioblastoma patients received pembrolizumab with re-irradiation alone (cohort A, bevacizumab-naïve; n=30) or with bevacizumab continuation (cohort B, n=30). Dual primary endpoints including overall response rate (ORR) and overall survival at either 12 (OS-12; cohort A) or six months (OS-6; cohort B) were assessed per cohort relative to historical benchmarks. Paired paraffin-embedded formalin-fixed tumor samples were assessed for immunologic biomarkers by immunohistochemistry using digital quantification and Co-Detection-by-InDEXing (CODEX). Results: Study therapy was well tolerated with most toxicities being grade ≤ 3. For cohort B, the primary endpoint of OS-6 was achieved (57%), however survival was not improved for cohort A patients. The ORR was 3.3% and 6.7% for cohorts A and B, respectively. CODEX analysis of paired tumor samples from 5 patients revealed an increase of activated T cells in the tumor microenvironment after study therapy. Conclusions: Compared to historical controls, re-irradiation plus pembrolizumab appeared to improve survival among bevacizumab-refractory patients but not among bevacizumab-naïve patients. CODEX revealed evidence of intratumoral infiltration of activated immune effector cells. A randomized, properly controlled trial of PD-1 blockade plus re-irradiation is warranted to further evaluate this regimen for bevacizumab refractory patients, but alternative approaches are needed for bevacizumab-naïve patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting c-MET for Endoscopic Detection of Dysplastic Lesions Within Barrett’s Esophagus Using EMI-137 Fluorescence Imaging","authors":"Yi-Jhih Huang, Jonas Rieder, Kel Vin. Tan, Anna Tenditnaya, Borivoj Vojnovic, Dimitris Gorpas, Michael Quante, Katherine A. Vallis","doi":"10.1158/1078-0432.ccr-24-1522","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1522","url":null,"abstract":"Purpose: Esophageal cancer (EC) carries a poor prognosis with 5-year overall survival of less than 20%. Barrett’s esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). The aim of this study was to investigate the ability of EMI-137, a mesenchymal-epithelial transition factor (c-MET)-targeting optical imaging tracer, to detect dysplasia in BE. Experimental Design: c-MET expression in human esophageal tissue was investigated using Gene Expression Omnibus (GEO) datasets, tissue microarrays and BE biopsies. EMI-137 was tested in a dual xenograft mouse model bearing OE33 (c-MET high expression) and FLO-1 (c-MET low expression) tumors. Fluorescence molecular endoscopy (FME) was performed in a mouse model of Barrett’s-like metaplasia and dysplasia (L2-IL1β). Tumors and organs-of-interest were evaluated through ex vivo fluorescence imaging. Results:MET mRNA expression analyses and c-MET immunostaining confirmed upregulation of c-MET in BE and EAC compared to normal epithelium. There was strong accumulation of EMI-137 in OE33 xenografts 3 h post injection decreasing by more than 50% on co-injection of a 10-fold molar excess of unlabeled EMI-137. The target-to background ratio (TBR) at 3 h p.i. for OE33 and FLO-1 tumors was 10.08 and 1.42, respectively. FME of L2-IL1β mice showed uptake of EMI-137 in dysplastic lesions within BE with a TBR of 1.9 in vivo, and greater than 2 in ex vivo fluorescence imaging. Conclusions: EMI-137 accumulates in dysplastic lesions within BE and in c-MET positive EAC. EMI-137 imaging has potential as a screening and surveillance tool for patients with BE and as a means to detecting dysplasia and EAC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BRAF deletion in adult patients with Langerhans cell histiocytosis correlates with multisystem disease and poor outcome","authors":"Min Lang, Long Chang, Hao Cai, He Lin, Zheng-zheng Liu, Ming-hui Duan, Dao-bin Zhou, Xin-xin Cao","doi":"10.1158/1078-0432.ccr-24-1802","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1802","url":null,"abstract":"Background: Langerhans cell histiocytosis (LCH) is a rare and highly heterogeneous histiocytosis. There are currently few studies examining the correlation between molecular profiling and clinical phenotype or outcome in adult patients with LCH. The objective of this study was to characterize the genomic landscape of adult LCH and correlate molecular findings with clinical features and patient outcomes. Methods: This study included 254 patients aged ≥18 years with biopsy-proven LCH from January 2000 to December 2023. All patients underwent next-generation sequencing (NGS) or fluorescence quantitative PCR (qPCR) for the BRAFV600E mutation. Patient demographics, disease characteristics and treatments were collected through electronic medical records. Patient outcomes were collected through clinical and telephone follow-up. Results: Overall, 254 patients were enrolled. MAPK/PI3K pathway alterations were observed in 77.6%（n=197）of the patients. BRAFV600E mutation was the most common (30.7%, n=78), followed by BRAFindel (18.1%, n=46) andMAP2K1 mutations (12.6%, n=32). The proportion of BRAFindel was much higher in patients with MS involvement than single system disease (24.5% vs 6.6%, p＜0.001). In overall patients, BRAFindel was associated with inferior overall survival (3-year OS 89.6% vs 99.0%, p=0.014) and progression-free survival (3-year PFS 50.0% vs 78.6%, p＜0.001). In MS LCH patients, BRAFindel was associated to worse PFS (3-year PFS 47.8% vs 76.0%, p=0.001). Conclusions: This large study provides molecular and clinical pathologic characterization of adult LCH. BRAFindel was highly correlated with MS LCH, and was associated to worse outcome.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pilot Trial of Perampanel on Peritumoral Hyperexcitability in Newly Diagnosed High-grade Glioma.","authors":"Steven Tobochnik, Michael S Regan, Maria K C Dorotan, Dustine Reich, Emily Lapinskas, Md Amin Hossain, Sylwia Stopka, David M Meredith, Sandro Santagata, Melissa M Murphy, Omar Arnaout, Wenya Linda Bi, E Antonio Chiocca, Alexandra J Golby, Michael A Mooney, Timothy R Smith, Keith L Ligon, Patrick Y Wen, Nathalie Y R Agar, Jong Woo Lee","doi":"10.1158/1078-0432.CCR-24-1849","DOIUrl":"10.1158/1078-0432.CCR-24-1849","url":null,"abstract":"<p><strong>Purpose: </strong>Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability.</p><p><strong>Experimental design: </strong>An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry.</p><p><strong>Results: </strong>HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations.</p><p><strong>Conclusions: </strong>Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}