Maya M Moubarak, Antonio C Pagano Zottola, Claire M Larrieu, Sylvain Cuvellier, T. Daubon, O. C. Martin
Chronic oxidative stress plays a critical role in the development of brain malignancies due to the high rate of brain oxygen utilization and concomitant production of reactive oxygen species (ROS). The nuclear factor-erythroid-2-related factor 2 (NRF2), a master regulator of antioxidant signaling, is a key factor in regulating brain physiology and the development of age-related neurodegenerative diseases. Also, NRF2 is known to exert a protective antioxidant effect against the onset of oxidative stress-induced diseases, including cancer, along with its pro-oncogenic activities through regulating various signaling pathways and downstream target genes. In glioblastoma (GB), grade IV glioma, tumor resistance, and recurrence are caused by the glioblastoma stem cell (GSC) population constituting a small bulk of the tumor core. The persistence and self-renewal capacity of these cell populations is enhanced by NRF2 expression in GB tissues. This review outlines NRF2's dual involvement in cancer and highlights its regulatory role in human brain physiology and diseases, in addition to the development of primary brain tumors and therapeutic potential, with a focus on GB.
{"title":"Exploring the Multifaceted Role of NRF2 in Brain Physiology and Cancer: A Comprehensive Review","authors":"Maya M Moubarak, Antonio C Pagano Zottola, Claire M Larrieu, Sylvain Cuvellier, T. Daubon, O. C. Martin","doi":"10.1093/noajnl/vdad160","DOIUrl":"https://doi.org/10.1093/noajnl/vdad160","url":null,"abstract":"Chronic oxidative stress plays a critical role in the development of brain malignancies due to the high rate of brain oxygen utilization and concomitant production of reactive oxygen species (ROS). The nuclear factor-erythroid-2-related factor 2 (NRF2), a master regulator of antioxidant signaling, is a key factor in regulating brain physiology and the development of age-related neurodegenerative diseases. Also, NRF2 is known to exert a protective antioxidant effect against the onset of oxidative stress-induced diseases, including cancer, along with its pro-oncogenic activities through regulating various signaling pathways and downstream target genes. In glioblastoma (GB), grade IV glioma, tumor resistance, and recurrence are caused by the glioblastoma stem cell (GSC) population constituting a small bulk of the tumor core. The persistence and self-renewal capacity of these cell populations is enhanced by NRF2 expression in GB tissues. This review outlines NRF2's dual involvement in cancer and highlights its regulatory role in human brain physiology and diseases, in addition to the development of primary brain tumors and therapeutic potential, with a focus on GB.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"22 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139162730","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}
Aiguo Li, John C Hancock, Martha Quezado, Susie Ahn, Nicole J Briceno, O. Celiku, Surabhi Ranjan, O. Aboud, Nicole Colwell, Sun A Kim, E. Nduom, Skyler Kuhn, Deric M. Park, Elizabeth Vera, Ken Aldape, Terri S. Armstrong, Mark R Gilbert
Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare, but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to an osteosarcoma at second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation. Tumor samples were collected at all three stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results. The glioblastoma tumor from this patient possessed mixed features of all three TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced TGF-β and BMP signaling were associated with tumor transformation. Regulatory network analysis revealed that TGF-β family signaling committed the lineage tumor to osteogenesis by stimulating expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation. This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.
{"title":"TGF-β and BMP Signaling are Associated with the Transformation of Glioblastoma to Gliosarcoma and then Osteosarcoma","authors":"Aiguo Li, John C Hancock, Martha Quezado, Susie Ahn, Nicole J Briceno, O. Celiku, Surabhi Ranjan, O. Aboud, Nicole Colwell, Sun A Kim, E. Nduom, Skyler Kuhn, Deric M. Park, Elizabeth Vera, Ken Aldape, Terri S. Armstrong, Mark R Gilbert","doi":"10.1093/noajnl/vdad164","DOIUrl":"https://doi.org/10.1093/noajnl/vdad164","url":null,"abstract":"\u0000 \u0000 \u0000 Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare, but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to an osteosarcoma at second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation.\u0000 \u0000 \u0000 \u0000 Tumor samples were collected at all three stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results.\u0000 \u0000 \u0000 \u0000 The glioblastoma tumor from this patient possessed mixed features of all three TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced TGF-β and BMP signaling were associated with tumor transformation. Regulatory network analysis revealed that TGF-β family signaling committed the lineage tumor to osteogenesis by stimulating expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation.\u0000 \u0000 \u0000 \u0000 This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 46","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138961270","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}
Rik van den Elshout, Benthe Ariëns, Joost Blaauboer, Frederick J A Meijer, Anja G van der Kolk, Morteza Esmaeili, Tom W J Scheenen, D. Henssen
Survival outcomes for glioblastoma (GBM) patients remain unfavorable, and tumor recurrence is often observed. Understanding the radiological growth patterns of GBM could aid in improving outcome. This study aimed to examine the relationship between contrast-enhancing tumor growth direction and white matter, using an image registration and deformation strategy. In GBM patients two pretreatment scans (diagnostic and neuronavigation) were gathered retrospectively, co-registered to a template and DTI atlas. The GBM lesions were segmented and co-registered to the same space. Growth vectors were derived and divided into vector populations parallel (Φ = 0-20 degrees) and perpendicular (Φ = 70-90 degrees) to white matter. To test for statistical significance between parallel and perpendicular groups, a paired samples Students T-test was performed. O6-methylguanine-DNA methyltransferase (MGMT) methylation status and its correlation to growth rate was also tested using a one-way ANOVA test. For 78 GBM patients (mean age 61 years ± 13 SD, 32 men), the included GBM lesions showed a predominant preference of perineural satellitosis (p<0.001), with a mean percentile growth of 30.8% (95CI 29.6% – 32.0%) parallel (0° < |Φ| <20°) to white matter. Perpendicular tumor growth with respect to white matter microstructure (70° < |Φ| <90°) showed to be 22.7% (95CI 21.3% – 24.1%) of total tumor growth direction. The presented strategy showed that tumor growth direction in pretreatment GBM patients correlated with white matter architecture. Future studies with patient-specific DTI data are required to verify the accuracy of this method prospectively to identify its usefulness as a clinical metric in pre- and posttreatment setting.
{"title":"Quantification perineural satellitosis in pretreatment glioblastoma with structural MRI and a diffusion tensor imaging template","authors":"Rik van den Elshout, Benthe Ariëns, Joost Blaauboer, Frederick J A Meijer, Anja G van der Kolk, Morteza Esmaeili, Tom W J Scheenen, D. Henssen","doi":"10.1093/noajnl/vdad168","DOIUrl":"https://doi.org/10.1093/noajnl/vdad168","url":null,"abstract":"\u0000 \u0000 \u0000 Survival outcomes for glioblastoma (GBM) patients remain unfavorable, and tumor recurrence is often observed. Understanding the radiological growth patterns of GBM could aid in improving outcome. This study aimed to examine the relationship between contrast-enhancing tumor growth direction and white matter, using an image registration and deformation strategy.\u0000 \u0000 \u0000 \u0000 In GBM patients two pretreatment scans (diagnostic and neuronavigation) were gathered retrospectively, co-registered to a template and DTI atlas. The GBM lesions were segmented and co-registered to the same space. Growth vectors were derived and divided into vector populations parallel (Φ = 0-20 degrees) and perpendicular (Φ = 70-90 degrees) to white matter. To test for statistical significance between parallel and perpendicular groups, a paired samples Students T-test was performed. O6-methylguanine-DNA methyltransferase (MGMT) methylation status and its correlation to growth rate was also tested using a one-way ANOVA test.\u0000 \u0000 \u0000 \u0000 For 78 GBM patients (mean age 61 years ± 13 SD, 32 men), the included GBM lesions showed a predominant preference of perineural satellitosis (p<0.001), with a mean percentile growth of 30.8% (95CI 29.6% – 32.0%) parallel (0° < |Φ| <20°) to white matter. Perpendicular tumor growth with respect to white matter microstructure (70° < |Φ| <90°) showed to be 22.7% (95CI 21.3% – 24.1%) of total tumor growth direction.\u0000 \u0000 \u0000 \u0000 The presented strategy showed that tumor growth direction in pretreatment GBM patients correlated with white matter architecture. Future studies with patient-specific DTI data are required to verify the accuracy of this method prospectively to identify its usefulness as a clinical metric in pre- and posttreatment setting.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138961879","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}
Vincent W S Leong, Sabbir Khan, P. Sharma, Shaofang Wu, Riya R Thomas, Xiaolong Li, Sanjay K. Singh, Frederick F Lang, W. A. Yung, D. Koul
The most prevalent cancer treatments cause cell death through DNA damage. However, DNA damage response (DDR) repair pathways, initiated by tumor cells, can withstand the effects of anticancer drugs, providing justification for combining DDR inhibitors with DNA-damaging anticancer treatments. Cell viability assays were performed with CellTiter-Glo assay. DNA damage was evaluated using Western blotting analysis. RNA-seq and single-cell level expression was used to identify the DDR signatures. In vivo studies were conducted in mice to determine the effect of ATris with TMZ sensitization. We found a subpopulation of glioma sphere-forming cells (GSCs) with substantial synergism with temozolomide (TMZ) using a panel of 3 clinical-grade ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis), (elimusertib, berzosertib, and ceralasertib). Interestingly, most synergistic cell lines had O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, indicating that ATRi mainly benefit tumors with no MGMT repair. Further, TMZ activated the ATR-checkpoint kinase 1 (Chk1) axis in an MGMT-dependent way. TMZ caused ATR-dependent Chk1 phosphorylation and DNA double-strand breaks as shown by increased γH2AX. Increased DNA damage and decreased Chk1 phosphorylation was observed upon the addition of ATRis to TMZ in MGMT-methylated (MGMT-) GSCs.TMZ also improved sensitivity to ATRis in vivo, as shown by increased mouse survival with the TMZ and ATRi combination treatment. This research provides a rationale for selectively targeting MGMT-methylated cells using ATRis and TMZ combination. Overall, we believe that MGMT methylation status in GBM could serve as a robust biomarker for patient selection for ATRi combined with TMZ.
{"title":"MGMT function determines the differential response of ATR inhibitors with DNA-damaging agents in glioma stem cells for GBM therapy","authors":"Vincent W S Leong, Sabbir Khan, P. Sharma, Shaofang Wu, Riya R Thomas, Xiaolong Li, Sanjay K. Singh, Frederick F Lang, W. A. Yung, D. Koul","doi":"10.1093/noajnl/vdad165","DOIUrl":"https://doi.org/10.1093/noajnl/vdad165","url":null,"abstract":"\u0000 \u0000 \u0000 The most prevalent cancer treatments cause cell death through DNA damage. However, DNA damage response (DDR) repair pathways, initiated by tumor cells, can withstand the effects of anticancer drugs, providing justification for combining DDR inhibitors with DNA-damaging anticancer treatments.\u0000 \u0000 \u0000 \u0000 Cell viability assays were performed with CellTiter-Glo assay. DNA damage was evaluated using Western blotting analysis. RNA-seq and single-cell level expression was used to identify the DDR signatures. In vivo studies were conducted in mice to determine the effect of ATris with TMZ sensitization.\u0000 \u0000 \u0000 \u0000 We found a subpopulation of glioma sphere-forming cells (GSCs) with substantial synergism with temozolomide (TMZ) using a panel of 3 clinical-grade ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis), (elimusertib, berzosertib, and ceralasertib). Interestingly, most synergistic cell lines had O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, indicating that ATRi mainly benefit tumors with no MGMT repair. Further, TMZ activated the ATR-checkpoint kinase 1 (Chk1) axis in an MGMT-dependent way. TMZ caused ATR-dependent Chk1 phosphorylation and DNA double-strand breaks as shown by increased γH2AX. Increased DNA damage and decreased Chk1 phosphorylation was observed upon the addition of ATRis to TMZ in MGMT-methylated (MGMT-) GSCs.TMZ also improved sensitivity to ATRis in vivo, as shown by increased mouse survival with the TMZ and ATRi combination treatment.\u0000 \u0000 \u0000 \u0000 This research provides a rationale for selectively targeting MGMT-methylated cells using ATRis and TMZ combination. Overall, we believe that MGMT methylation status in GBM could serve as a robust biomarker for patient selection for ATRi combined with TMZ.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"102 16","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138959401","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}
B. Ocaña-Tienda, J. Pérez-Beteta, J. A. Romero-Rosales, B. Asenjo, A. Ortiz de Mendivil, Luis Alberto Pérez Romasanta, Jose David Albillo Labarra, Fátima Nagib, María Vidal Denis, B. Luque, Estanislao Arana, Víctor M. Pérez-García
The Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) criteria are the gold standard for assessing brain metastases (BMs) treatment response. However, they are limited by their reliance on one dimension, despite the routine use of high-resolution T1-weighted MRI scans for BMs, which allows for 3D measurements. Our study aimed to investigate whether volumetric measurements could improve the response assessment in patients with BMs. We retrospectively evaluated a dataset comprising 783 BMs and analyzed the response of 185 of them from 132 patients who underwent stereotactic radiotherapy between 2007 and 2021 at five hospitals. We used T1-weighted MRIs to compute the volume of the lesions. For the volumetric criteria, progressive disease was defined as at least a 30% increase in volume, and partial response was characterized by a 20% volume reduction. Our study showed that the proposed volumetric criteria outperformed the RANO-BM criteria in several aspects: 1) Evaluating every lesion, while RANO-BM failed to evaluate 9.2% of them. 2) Classifying response effectively in 140 lesions, compared to only 72 lesions classified by RANO-BM. 3) Identifying BM recurrences a median of 3.3 months earlier than RANO-BM criteria. Our study demonstrates the superiority of volumetric criteria in improving the response assessment of BMs compared to the RANO-BM criteria. Our proposed criteria allow for evaluation of every lesion, regardless of its size or shape, better classification, and enable earlier identification of progressive disease. Volumetric criteria provide a standardized, reliable, and objective tool for assessing treatment response.
{"title":"Volumetric Analysis: Rethinking Brain Metastases Response Assessment","authors":"B. Ocaña-Tienda, J. Pérez-Beteta, J. A. Romero-Rosales, B. Asenjo, A. Ortiz de Mendivil, Luis Alberto Pérez Romasanta, Jose David Albillo Labarra, Fátima Nagib, María Vidal Denis, B. Luque, Estanislao Arana, Víctor M. Pérez-García","doi":"10.1093/noajnl/vdad161","DOIUrl":"https://doi.org/10.1093/noajnl/vdad161","url":null,"abstract":"\u0000 \u0000 \u0000 The Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) criteria are the gold standard for assessing brain metastases (BMs) treatment response. However, they are limited by their reliance on one dimension, despite the routine use of high-resolution T1-weighted MRI scans for BMs, which allows for 3D measurements. Our study aimed to investigate whether volumetric measurements could improve the response assessment in patients with BMs.\u0000 \u0000 \u0000 \u0000 We retrospectively evaluated a dataset comprising 783 BMs and analyzed the response of 185 of them from 132 patients who underwent stereotactic radiotherapy between 2007 and 2021 at five hospitals. We used T1-weighted MRIs to compute the volume of the lesions. For the volumetric criteria, progressive disease was defined as at least a 30% increase in volume, and partial response was characterized by a 20% volume reduction.\u0000 \u0000 \u0000 \u0000 Our study showed that the proposed volumetric criteria outperformed the RANO-BM criteria in several aspects: 1) Evaluating every lesion, while RANO-BM failed to evaluate 9.2% of them. 2) Classifying response effectively in 140 lesions, compared to only 72 lesions classified by RANO-BM. 3) Identifying BM recurrences a median of 3.3 months earlier than RANO-BM criteria.\u0000 \u0000 \u0000 \u0000 Our study demonstrates the superiority of volumetric criteria in improving the response assessment of BMs compared to the RANO-BM criteria. Our proposed criteria allow for evaluation of every lesion, regardless of its size or shape, better classification, and enable earlier identification of progressive disease. Volumetric criteria provide a standardized, reliable, and objective tool for assessing treatment response.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"5 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138584771","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}
Patients with relapsed or progressive glioblastoma only rarely respond to salvage therapies. Nevertheless, comprehensive genomic profiling can provide insight that can identify promising approaches. Signaling pathway analyses have revealed synthetic lethal partnerships which create the possibility of targeting vulnerabilities arising from loss of tumor suppressor genes. For synthetic lethal vulnerabilities that are not present in normal tissues, lethal cytotoxicity against cancer cells can be achieved without the necessity of causing normal tissue toxicity. This case reports describes a patient with progressive glioblastoma with homozygous deletion of chromosome 9p21. Vulnerabilities created by CDKN2A and MTAP loss were exploited with pemetrexed, bevacizumab, and candesartan (PBC) to achieve a clinically meaningful remission by targeting multiple synthetic lethal nodes. Synthetic lethality can reveal the basis for exceptional responsiveness, thus extending the utility of molecular profiling and fulfilling the promise of precision medicine.
{"title":"Network targeting combination therapy (NTCT) of synthetic lethal (SL) vulnerabilities in 9p21 deficient glioblastoma (GBM): a case report","authors":"Michael P Castro, Kristin Dittmar","doi":"10.1093/noajnl/vdad162","DOIUrl":"https://doi.org/10.1093/noajnl/vdad162","url":null,"abstract":"\u0000 Patients with relapsed or progressive glioblastoma only rarely respond to salvage therapies. Nevertheless, comprehensive genomic profiling can provide insight that can identify promising approaches. Signaling pathway analyses have revealed synthetic lethal partnerships which create the possibility of targeting vulnerabilities arising from loss of tumor suppressor genes. For synthetic lethal vulnerabilities that are not present in normal tissues, lethal cytotoxicity against cancer cells can be achieved without the necessity of causing normal tissue toxicity. This case reports describes a patient with progressive glioblastoma with homozygous deletion of chromosome 9p21. Vulnerabilities created by CDKN2A and MTAP loss were exploited with pemetrexed, bevacizumab, and candesartan (PBC) to achieve a clinically meaningful remission by targeting multiple synthetic lethal nodes. Synthetic lethality can reveal the basis for exceptional responsiveness, thus extending the utility of molecular profiling and fulfilling the promise of precision medicine.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"12 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138982006","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}
Erica L Macke, Anthony R Miller, Eileen Stonerock, Randal Olshefski, Kristin N Zajo, Tracy A Bedrosian, Elaine R Mardis, Yassmine M N Akkari, C. Cottrell, K. Schieffer
Retinoblastoma is an ocular cancer associated with genomic variation in the RB1 gene. In individuals with bilateral retinoblastoma, a germline variant in RB1 is identified in virtually all cases. We describe herein an individual with bilateral retinoblastoma for whom multiple clinical lab assays performed by outside commercial laboratories failed to identify a germline RB1 variant. Paired tumor/normal exome sequencing, long-read whole genome sequencing, and long-read isoform sequencing performed on a translational research basis ultimately identified a germline likely de novo LINE-1 mediated deletion resulting in a premature stop of translation of RB1 as the underlying genetic cause of retinoblastoma in this individual. Based on these research findings, the LINE-1 mediated deletion was confirmed via Sanger sequencing in our clinical laboratory and results reported into the patient medical record to allow for appropriate genetic counseling.
{"title":"A LINE-1 Mediated Deletion Resulting in Germline Retinoblastoma Predisposition","authors":"Erica L Macke, Anthony R Miller, Eileen Stonerock, Randal Olshefski, Kristin N Zajo, Tracy A Bedrosian, Elaine R Mardis, Yassmine M N Akkari, C. Cottrell, K. Schieffer","doi":"10.1093/noajnl/vdad163","DOIUrl":"https://doi.org/10.1093/noajnl/vdad163","url":null,"abstract":"\u0000 Retinoblastoma is an ocular cancer associated with genomic variation in the RB1 gene. In individuals with bilateral retinoblastoma, a germline variant in RB1 is identified in virtually all cases. We describe herein an individual with bilateral retinoblastoma for whom multiple clinical lab assays performed by outside commercial laboratories failed to identify a germline RB1 variant. Paired tumor/normal exome sequencing, long-read whole genome sequencing, and long-read isoform sequencing performed on a translational research basis ultimately identified a germline likely de novo LINE-1 mediated deletion resulting in a premature stop of translation of RB1 as the underlying genetic cause of retinoblastoma in this individual. Based on these research findings, the LINE-1 mediated deletion was confirmed via Sanger sequencing in our clinical laboratory and results reported into the patient medical record to allow for appropriate genetic counseling.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"7 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138584881","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}
S. Puri, R. Malani, Anna W Chalmers, K. Kerrigan, Shiven B. Patel, Kelly Monynahan, L. Cannon, Barbara Blouw, Wallace Akerley
Leptomeningeal Disease (LMD) is a devastating complication for patients with advanced cancer. Diagnosis and monitoring the response to therapy remains challenging due to limited sensitivity and specificity of standard-of-care (SOC) diagnostic modalities, including cerebrospinal fluid (CSF) cytology, MRI, and clinical evaluation. These hindrances contribute to the poor survival of LMD patients. CNSide is a CLIA-validated test that detects and characterizes CSF-derived tumor cells and cell-free (cf) DNA. We performed a retrospective analysis on the utility of CNSide to analyze CSF obtained from advanced non-small cell lung cancer (aNSCLC) patients with suspected LMD treated at the Huntsman Cancer Institute in Salt Lake City, Utah. CNSide was used to evaluate CSF from fifteen patients with aNSCLC. CSF tumor cell quantification was performed throughout treatment for five patients. CSF tumor cells and cfDNA were characterized for actionable mutations. In LMD-positive patients, CNSide detected CSF tumor cells in 88% (22/25) samples vs. 40% (10/25) for cytology (matched samples). CSF tumor cell numbers tracked response to therapy in five patients where CNSide was used to quantify tumor cells throughout treatment. In 75% (9/12) of the patients genetic alterations were detected in CSF, with majority representing gene mutations and amplifications with therapeutic potential. The median survival for LMD patients was 16.1 m (5.2- NR). We show that CNSide can supplement the management of LMD in conjunction with SOC methods for the diagnosis, monitoring response to therapy, and identifying actionable mutations unique to the CSF in patients with LMD.
轻脑膜病(LMD)是晚期癌症患者的一种毁灭性并发症。由于标准诊断模式(包括脑脊液(CSF)细胞学、MRI和临床评估)的敏感性和特异性有限，诊断和监测对治疗的反应仍然具有挑战性。这些障碍导致LMD患者的生存率较低。CNSide是一种经过clia验证的检测方法，可检测和表征csf来源的肿瘤细胞和无细胞(cf) DNA。我们对在犹他州盐湖城亨茨曼癌症研究所(Huntsman cancer Institute)接受疑似LMD治疗的晚期非小细胞肺癌(aNSCLC)患者的脑脊液进行了回顾性分析。CNSide用于评估15例aNSCLC患者的CSF。在整个治疗过程中对5例患者进行脑脊液肿瘤细胞定量。脑脊液肿瘤细胞和cfDNA以可操作突变为特征。在lmd阳性患者中，CNSide在88%(22/25)样本中检测到脑脊液肿瘤细胞，而在细胞学(匹配样本)中检测到脑脊液肿瘤细胞的比例为40%(10/25)。脑脊液肿瘤细胞数追踪了5例患者对治疗的反应，在整个治疗过程中，CNSide用于量化肿瘤细胞。75%(9/12)的患者在脑脊液中检测到基因改变，其中大多数代表具有治疗潜力的基因突变和扩增。LMD患者的中位生存期为16.1 m (5.2- NR)。我们表明，CNSide可以与SOC方法一起补充LMD的诊断，监测对治疗的反应，并识别LMD患者CSF特有的可操作突变。
{"title":"Keeping a Track on Leptomeningeal Disease in Non-Small Cell Lung Cancer: A Single Institution Experience with CNSideTM","authors":"S. Puri, R. Malani, Anna W Chalmers, K. Kerrigan, Shiven B. Patel, Kelly Monynahan, L. Cannon, Barbara Blouw, Wallace Akerley","doi":"10.1093/noajnl/vdad150","DOIUrl":"https://doi.org/10.1093/noajnl/vdad150","url":null,"abstract":"\u0000 \u0000 \u0000 Leptomeningeal Disease (LMD) is a devastating complication for patients with advanced cancer. Diagnosis and monitoring the response to therapy remains challenging due to limited sensitivity and specificity of standard-of-care (SOC) diagnostic modalities, including cerebrospinal fluid (CSF) cytology, MRI, and clinical evaluation. These hindrances contribute to the poor survival of LMD patients. CNSide is a CLIA-validated test that detects and characterizes CSF-derived tumor cells and cell-free (cf) DNA. We performed a retrospective analysis on the utility of CNSide to analyze CSF obtained from advanced non-small cell lung cancer (aNSCLC) patients with suspected LMD treated at the Huntsman Cancer Institute in Salt Lake City, Utah.\u0000 \u0000 \u0000 \u0000 CNSide was used to evaluate CSF from fifteen patients with aNSCLC. CSF tumor cell quantification was performed throughout treatment for five patients. CSF tumor cells and cfDNA were characterized for actionable mutations.\u0000 \u0000 \u0000 \u0000 In LMD-positive patients, CNSide detected CSF tumor cells in 88% (22/25) samples vs. 40% (10/25) for cytology (matched samples). CSF tumor cell numbers tracked response to therapy in five patients where CNSide was used to quantify tumor cells throughout treatment. In 75% (9/12) of the patients genetic alterations were detected in CSF, with majority representing gene mutations and amplifications with therapeutic potential. The median survival for LMD patients was 16.1 m (5.2- NR).\u0000 \u0000 \u0000 \u0000 We show that CNSide can supplement the management of LMD in conjunction with SOC methods for the diagnosis, monitoring response to therapy, and identifying actionable mutations unique to the CSF in patients with LMD.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"2 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138585857","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}
Lindy Zhang, K. Lemberg, A. Calizo, Ravi Varadhan, Alan H Siegel, Christian F. Meyer, J. Blakeley, C. A. Pratilas
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas originating from cellular components within the nerve sheath. The incidence of MPNST is highest in people with neurofibromatosis type 1 (NF1), and MPNST is the leading cause of death for these individuals. Complete surgical resection is the only curative therapeutic option, but is often unfeasible due to tumor location, size, or presence of metastases. Evidence-based choices of chemotherapy for recurrent/ refractory MPNST remain elusive. To address this gap, we conducted a retrospective analysis of our institutional experience in treating patients with relapsed MPNST in order to describe patient outcomes related to salvage regimens. We conducted a retrospective electronic health record analysis of patients with MPNST who were treated at Johns Hopkins Hospital from January 2010 to June 2021. We calculated time to progression (TTP) based on salvage chemotherapy regimens. Sixty-five patients were included in the analysis. Upfront therapy included single or combined modalities of surgery, chemotherapy, or radiotherapy. Forty-eight patients received at least one line of chemotherapy, which included 23 different regimens (excluding active clinical studies). Most patients (n=42, 87.5%) received a combination of doxorubicin, ifosfamide, or etoposide as first-line chemotherapy. Salvage chemotherapy regimens and their TTP varied greatly, with irinotecan/ temozolomide-based regimens having the longest average TTP (255.5 days, among 4 patients). Patients with advanced or metastatic MPNST often succumb to their disease despite multiple lines of therapy. These data may be used as comparative information in decision-making for future patients and clinical trials.
{"title":"Analysis of treatment sequence and outcomes in patients with relapsed malignant peripheral nerve sheath tumors","authors":"Lindy Zhang, K. Lemberg, A. Calizo, Ravi Varadhan, Alan H Siegel, Christian F. Meyer, J. Blakeley, C. A. Pratilas","doi":"10.1093/noajnl/vdad156","DOIUrl":"https://doi.org/10.1093/noajnl/vdad156","url":null,"abstract":"\u0000 \u0000 \u0000 Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas originating from cellular components within the nerve sheath. The incidence of MPNST is highest in people with neurofibromatosis type 1 (NF1), and MPNST is the leading cause of death for these individuals. Complete surgical resection is the only curative therapeutic option, but is often unfeasible due to tumor location, size, or presence of metastases. Evidence-based choices of chemotherapy for recurrent/ refractory MPNST remain elusive. To address this gap, we conducted a retrospective analysis of our institutional experience in treating patients with relapsed MPNST in order to describe patient outcomes related to salvage regimens.\u0000 \u0000 \u0000 \u0000 We conducted a retrospective electronic health record analysis of patients with MPNST who were treated at Johns Hopkins Hospital from January 2010 to June 2021. We calculated time to progression (TTP) based on salvage chemotherapy regimens.\u0000 \u0000 \u0000 \u0000 Sixty-five patients were included in the analysis. Upfront therapy included single or combined modalities of surgery, chemotherapy, or radiotherapy. Forty-eight patients received at least one line of chemotherapy, which included 23 different regimens (excluding active clinical studies). Most patients (n=42, 87.5%) received a combination of doxorubicin, ifosfamide, or etoposide as first-line chemotherapy. Salvage chemotherapy regimens and their TTP varied greatly, with irinotecan/ temozolomide-based regimens having the longest average TTP (255.5 days, among 4 patients).\u0000 \u0000 \u0000 \u0000 Patients with advanced or metastatic MPNST often succumb to their disease despite multiple lines of therapy. These data may be used as comparative information in decision-making for future patients and clinical trials.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"119 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138607391","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 : 2023-12-01DOI: 10.1093/noajnl/vdad141.024
Taijun Hana, Satoshi Takahashi, Yuki Kawaguchi, S. Oya
Abstract INTRODUCTION Brain tumors affect approximately 20,000 individuals annually in Japan, with some cases requiring urgent treatment. However, the medical knowledge of non-medical individuals (the general public) is often limited, resulting in delays in seeking treatment even when neurological symptoms are evident. Having appropriate advisors who can encourage medical consultations could potentially improve this situation. While Natural Language Processing AI (NLP-AI) is widely used, its full integration into healthcare remains a work in progress. ChatGPT, a prominent NLP-AI, possesses extensive knowledge and is accessible 24/7 online. We explored the potential of leveraging its advanced capabilities and accessibility in the field of brain tumor management. METHODS To evaluate its ability to guide hospital visits effectively, we simulated various symptoms associated with primary brain tumors and consulted ChatGPT(GPT3.5) as patients. We also assessed how ChatGPT handled unnecessary noise information (unrelated symptoms) during symptom consultations. RESULTS ChatGPT consistently recommended hospital visits for all simulated brain tumor patients and provided appropriate advice regarding the urgency and relevant medical department. Notably, even when patients expressed hesitation and refusal hospital visits, ChatGPT persistently persuaded them to visit the hospital despite the user(patient)'s intention. Despite the introduction of noise information, ChatGPT accurately identified and emphasized the importance of relevant symptoms, prompting appropriate medical attention. However, accuracy declined when excessive noise was present. Additionally, ChatGPT generated concise summaries of medical histories for presentation during hospital visits. DISCUSSION While AI is widely utilized in medical imaging, the comprehensive integration of conversational AI in healthcare is still in progress. ChatGPT, despite not being a healthcare professional, holds potential as an "advisor" with extensive medical knowledge, accessible for consultations at any time, to support brain tumor patients. However, challenges related to accountability and expanding knowledge capabilities remain to be addressed.
{"title":"10048-CO-2 CAN NATURAL LANGUAGE PROCESSING AI BE AN APPROPRIATE “ADVISER” FOR BRAIN TUMOR PATIENTS? CLINICAL APPLICATION AND ISSUES ON CHATGPT","authors":"Taijun Hana, Satoshi Takahashi, Yuki Kawaguchi, S. Oya","doi":"10.1093/noajnl/vdad141.024","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.024","url":null,"abstract":"Abstract INTRODUCTION Brain tumors affect approximately 20,000 individuals annually in Japan, with some cases requiring urgent treatment. However, the medical knowledge of non-medical individuals (the general public) is often limited, resulting in delays in seeking treatment even when neurological symptoms are evident. Having appropriate advisors who can encourage medical consultations could potentially improve this situation. While Natural Language Processing AI (NLP-AI) is widely used, its full integration into healthcare remains a work in progress. ChatGPT, a prominent NLP-AI, possesses extensive knowledge and is accessible 24/7 online. We explored the potential of leveraging its advanced capabilities and accessibility in the field of brain tumor management. METHODS To evaluate its ability to guide hospital visits effectively, we simulated various symptoms associated with primary brain tumors and consulted ChatGPT(GPT3.5) as patients. We also assessed how ChatGPT handled unnecessary noise information (unrelated symptoms) during symptom consultations. RESULTS ChatGPT consistently recommended hospital visits for all simulated brain tumor patients and provided appropriate advice regarding the urgency and relevant medical department. Notably, even when patients expressed hesitation and refusal hospital visits, ChatGPT persistently persuaded them to visit the hospital despite the user(patient)'s intention. Despite the introduction of noise information, ChatGPT accurately identified and emphasized the importance of relevant symptoms, prompting appropriate medical attention. However, accuracy declined when excessive noise was present. Additionally, ChatGPT generated concise summaries of medical histories for presentation during hospital visits. DISCUSSION While AI is widely utilized in medical imaging, the comprehensive integration of conversational AI in healthcare is still in progress. ChatGPT, despite not being a healthcare professional, holds potential as an \"advisor\" with extensive medical knowledge, accessible for consultations at any time, to support brain tumor patients. However, challenges related to accountability and expanding knowledge capabilities remain to be addressed.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 753","pages":"v6 - v7"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138610564","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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