Colin M Harari, Adam R Burr, Brett A Morris, W. A. Tomé, PhD Adam Bayliss, A. Bhatia, P.T. Grogan, H. I. Robins, S. Howard, WI AveMadison
Patients with grade 2 glioma exhibit highly variable survival. Re-irradiation for recurrent disease has limited mature clinical data. We report treatment results of pulsed reduced dose rate (PRDR) radiation for patients with recurrent grade 2 glioma. A retrospective analysis of 58 patients treated with PRDR from 2000-2021 was performed. Radiation was delivered in 0.2 Gy pulses every three minutes encompassing tumor plus margin. Survival outcomes and prognostic factors on outcome were Kaplan Meier and Cox regression analyses. The median survival from date of initial surgery was 8.6 years (95% CI 5.5-11.8 yrs). 69% of patients showed malignant transformation to grade 3 (38%) or grade 4 (31%) glioma. Overall survival following PRDR was 12.6 months (95% CI 8.3-17.0 mo) and progression free survival was 6.2 months (95% CI 3.8-8.6 mo). Overall response rate based on post PRDR MRI was 36%. In patients who maintained grade 2 histology at recurrence, overall survival from PRDR was 22.0 months with five patients remaining disease free, the longest at 8.2 and 11.4 years. PRDR was generally well tolerated. To our knowledge, this is the largest reported series of patients with recurrent grade 2 gliomas treated with PRDR radiation for disease recurrence. We demonstrate promising survival and acceptable toxicity profiles following re-irradiation. In the cohort of patients who maintain grade 2 disease, prolonged survival (>5 years) is observed in selected patients. For the entire cohort, 1p19q co-deletion, KPS, and longer time from initial diagnosis to PRDR were associated with improved survival.
{"title":"Pulsed Reduced Dose Rate Re-Irradiation for Patients with Recurrent Grade 2 Gliomas","authors":"Colin M Harari, Adam R Burr, Brett A Morris, W. A. Tomé, PhD Adam Bayliss, A. Bhatia, P.T. Grogan, H. I. Robins, S. Howard, WI AveMadison","doi":"10.1093/noajnl/vdae073","DOIUrl":"https://doi.org/10.1093/noajnl/vdae073","url":null,"abstract":"\u0000 \u0000 \u0000 Patients with grade 2 glioma exhibit highly variable survival. Re-irradiation for recurrent disease has limited mature clinical data. We report treatment results of pulsed reduced dose rate (PRDR) radiation for patients with recurrent grade 2 glioma.\u0000 \u0000 \u0000 \u0000 A retrospective analysis of 58 patients treated with PRDR from 2000-2021 was performed. Radiation was delivered in 0.2 Gy pulses every three minutes encompassing tumor plus margin. Survival outcomes and prognostic factors on outcome were Kaplan Meier and Cox regression analyses.\u0000 \u0000 \u0000 \u0000 The median survival from date of initial surgery was 8.6 years (95% CI 5.5-11.8 yrs). 69% of patients showed malignant transformation to grade 3 (38%) or grade 4 (31%) glioma. Overall survival following PRDR was 12.6 months (95% CI 8.3-17.0 mo) and progression free survival was 6.2 months (95% CI 3.8-8.6 mo). Overall response rate based on post PRDR MRI was 36%. In patients who maintained grade 2 histology at recurrence, overall survival from PRDR was 22.0 months with five patients remaining disease free, the longest at 8.2 and 11.4 years. PRDR was generally well tolerated.\u0000 \u0000 \u0000 \u0000 To our knowledge, this is the largest reported series of patients with recurrent grade 2 gliomas treated with PRDR radiation for disease recurrence. We demonstrate promising survival and acceptable toxicity profiles following re-irradiation. In the cohort of patients who maintain grade 2 disease, prolonged survival (>5 years) is observed in selected patients. For the entire cohort, 1p19q co-deletion, KPS, and longer time from initial diagnosis to PRDR were associated with improved survival.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 45","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140993829","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}
Martha I Betancur, Ayden Case, Ekaterina Ilich, Nalini Mehta, Sean Meehan, Sabrina Pogrebivsky, S. T. Kier, Kevin Stevenson, Barun Brahma, Simon Gregory, Wei Chen, David M Ashley, Ravi Bellamkonda, Nassir Mokarram
A major hurdle to effectively treating glioblastoma (GBM) patients is the lack of longitudinal information about tumor progression, evolution, and treatment response. In this study, we report the use of a neural tract-inspired conduit containing aligned polymeric nanofibers (i.e., an aligned nanofiber device) to enable on-demand access to GBM tumors in two rodent models. Depending on the experiment, a humanized U87MG xenograft tumor and/or F98-GFP+ syngeneic rat tumor models were chosen to test the safety and functionality of the device in providing continuous sampling access to the tumor and its microenvironment. The aligned nanofiber device was safe and provided a high quantity of quality genomic materials suitable for omics analyses and yielded a sufficient number of live cells for in vitro expansion and screening. Transcriptomic and genomic analyses demonstrated continuity between material extracted from the device and that of the primary, intracortical tumor (in the in vivo model). The results establish the potential of this neural tract-inspired, aligned nanofiber device as an on-demand, safe, and minimally invasive access point which enables rapid, high-throughput, longitudinal assessment of tumor and its microenvironment, leading to more informed clinical treatment strategies.
{"title":"A Neural Tract-Inspired Conduit for Facile, On-Demand Biopsy of Glioblastoma","authors":"Martha I Betancur, Ayden Case, Ekaterina Ilich, Nalini Mehta, Sean Meehan, Sabrina Pogrebivsky, S. T. Kier, Kevin Stevenson, Barun Brahma, Simon Gregory, Wei Chen, David M Ashley, Ravi Bellamkonda, Nassir Mokarram","doi":"10.1093/noajnl/vdae064","DOIUrl":"https://doi.org/10.1093/noajnl/vdae064","url":null,"abstract":"\u0000 \u0000 \u0000 A major hurdle to effectively treating glioblastoma (GBM) patients is the lack of longitudinal information about tumor progression, evolution, and treatment response.\u0000 \u0000 \u0000 \u0000 In this study, we report the use of a neural tract-inspired conduit containing aligned polymeric nanofibers (i.e., an aligned nanofiber device) to enable on-demand access to GBM tumors in two rodent models. Depending on the experiment, a humanized U87MG xenograft tumor and/or F98-GFP+ syngeneic rat tumor models were chosen to test the safety and functionality of the device in providing continuous sampling access to the tumor and its microenvironment.\u0000 \u0000 \u0000 \u0000 The aligned nanofiber device was safe and provided a high quantity of quality genomic materials suitable for omics analyses and yielded a sufficient number of live cells for in vitro expansion and screening. Transcriptomic and genomic analyses demonstrated continuity between material extracted from the device and that of the primary, intracortical tumor (in the in vivo model).\u0000 \u0000 \u0000 \u0000 The results establish the potential of this neural tract-inspired, aligned nanofiber device as an on-demand, safe, and minimally invasive access point which enables rapid, high-throughput, longitudinal assessment of tumor and its microenvironment, leading to more informed clinical treatment strategies.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 47","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141000776","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}
R. Otsuji, N. Hata, Hidetaka Yamamoto, Daisuke Kuga, R. Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Naoki Noguchi, Aki Sako, Osamu Togao, T. Yoshitake, Akira Nakamizo, M. Mizoguchi, Koji Yoshimoto
Homozygous deletion of the tumor suppression genes cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is a strong adverse prognostic factor in IDH-mutant gliomas, particularly astrocytoma. However, the impact of hemizygous deletion of CDKN2A/B is unknown. Furthermore, the influence of CDKN2A/B status in IDH-mutant and 1p/19q-codeleted oligodendroglioma remains controversial. We examined the impact of CDKN2A/B status classification, including hemizygous deletions, on the prognosis of IDH-mutant gliomas. We enrolled 101 adults with IDH-mutant glioma between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation-dependent probe amplification (MLPA). Immunohistochemical analysis of p16/MTAP and promoter methylation analysis with methylation-specific MLPA was performed for cases with CDKN2A/B deletion. Kaplan−Meier plots and Cox proportion hazards model analyses were performed to evaluate the impact on overall (OS) and progression-free survival. Of 101 cases, 12 and 4 were classified as hemizygous and homozygous deletion, respectively. Immunohistochemistry revealed p16-negative and MTAP retention in cases with hemizygous deletion, whereas homozygous deletions had p16-negative and MTAP loss. In astrocytoma, OS was shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral groups (median OS: 38.5, 59.5, and 93.1 months, respectively). Multivariate analysis revealed hazard ratios of 9.30 (p=0.0191) and 2.44 (p=0.0943) for homozygous and hemizygous deletions, respectively. CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytoma. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combination with conventional molecular diagnosis.
{"title":"Hemizygous deletion of CDKN2A/B with p16 immuno-negative and methylthioadenosine phosphorylase retention predicts poor prognosis in IDH-mutant adult glioma","authors":"R. Otsuji, N. Hata, Hidetaka Yamamoto, Daisuke Kuga, R. Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Naoki Noguchi, Aki Sako, Osamu Togao, T. Yoshitake, Akira Nakamizo, M. Mizoguchi, Koji Yoshimoto","doi":"10.1093/noajnl/vdae069","DOIUrl":"https://doi.org/10.1093/noajnl/vdae069","url":null,"abstract":"\u0000 \u0000 \u0000 Homozygous deletion of the tumor suppression genes cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is a strong adverse prognostic factor in IDH-mutant gliomas, particularly astrocytoma. However, the impact of hemizygous deletion of CDKN2A/B is unknown. Furthermore, the influence of CDKN2A/B status in IDH-mutant and 1p/19q-codeleted oligodendroglioma remains controversial. We examined the impact of CDKN2A/B status classification, including hemizygous deletions, on the prognosis of IDH-mutant gliomas.\u0000 \u0000 \u0000 \u0000 We enrolled 101 adults with IDH-mutant glioma between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation-dependent probe amplification (MLPA). Immunohistochemical analysis of p16/MTAP and promoter methylation analysis with methylation-specific MLPA was performed for cases with CDKN2A/B deletion. Kaplan−Meier plots and Cox proportion hazards model analyses were performed to evaluate the impact on overall (OS) and progression-free survival.\u0000 \u0000 \u0000 \u0000 Of 101 cases, 12 and 4 were classified as hemizygous and homozygous deletion, respectively. Immunohistochemistry revealed p16-negative and MTAP retention in cases with hemizygous deletion, whereas homozygous deletions had p16-negative and MTAP loss. In astrocytoma, OS was shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral groups (median OS: 38.5, 59.5, and 93.1 months, respectively). Multivariate analysis revealed hazard ratios of 9.30 (p=0.0191) and 2.44 (p=0.0943) for homozygous and hemizygous deletions, respectively.\u0000 \u0000 \u0000 \u0000 CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytoma. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combination with conventional molecular diagnosis.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 16","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141001206","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. D. Robinson, J. de Boisanger, F. M. G. Pearl, G. Critchley, N. Rosenfelder, G. Giamas
Brain metastases remain a challenging and feared complication for patients with cancer and research in this area has lagged behind research into metastases to other organs. Due to their location and the risks associated with neurosurgical biopsies, the biology underpinning brain metastases response to treatment and evolution over time remains poorly understood. Liquid biopsies are proposed to overcome many of the limitations present with tissue biopsies, providing a better representation of tumour heterogeneity, facilitating repeated sampling, and providing a non-invasive assessment of tumour biology. Several different liquid biopsy approaches have been investigated including circulating tumour cells, circulating tumour DNA, extracellular vesicles, and tumour educated platelets; however, these have generally been less effective in assessing brain metastases compared to metastases to other organs requiring improved techniques to investigate these approaches, studies combining different liquid biopsy approaches and/or novel liquid biopsy approaches. Through this review we highlight the current state of the art and define key unanswered questions related to brain metastases liquid biopsies.
{"title":"A brain metastasis liquid biopsy – Where are we now?","authors":"S. D. Robinson, J. de Boisanger, F. M. G. Pearl, G. Critchley, N. Rosenfelder, G. Giamas","doi":"10.1093/noajnl/vdae066","DOIUrl":"https://doi.org/10.1093/noajnl/vdae066","url":null,"abstract":"\u0000 Brain metastases remain a challenging and feared complication for patients with cancer and research in this area has lagged behind research into metastases to other organs. Due to their location and the risks associated with neurosurgical biopsies, the biology underpinning brain metastases response to treatment and evolution over time remains poorly understood. Liquid biopsies are proposed to overcome many of the limitations present with tissue biopsies, providing a better representation of tumour heterogeneity, facilitating repeated sampling, and providing a non-invasive assessment of tumour biology. Several different liquid biopsy approaches have been investigated including circulating tumour cells, circulating tumour DNA, extracellular vesicles, and tumour educated platelets; however, these have generally been less effective in assessing brain metastases compared to metastases to other organs requiring improved techniques to investigate these approaches, studies combining different liquid biopsy approaches and/or novel liquid biopsy approaches. Through this review we highlight the current state of the art and define key unanswered questions related to brain metastases liquid biopsies.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"5 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141021188","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}
Martha Foltyn-Dumitru, Marianne Schell, Felix Sahm, T. Kessler, Wolfgang Wick, Martin Bendszus, Aditya Rastogi, G. Brugnara, Phillipp Vollmuth
This study investigates the influence of diffusion-weighted MRI (DWI) on radiomic-based prediction of glioma types according to molecular status and assesses the impact of DWI intensity normalization on model generalizability. Radiomic features, compliant with IBSI standards, were extracted from preoperative MRI of 549 patients with diffuse glioma, known IDH, and 1p19q-status. Anatomical sequences (T1, T1c, T2, FLAIR) underwent N4-Bias Field Correction (N4) and WhiteStripe normalization (N4/WS). Apparent diffusion coefficient (ADC) maps were normalized using N4 or N4/z-score. Nine machine-learning algorithms were trained for multiclass prediction of glioma types (IDH-mutant 1p/19q codeleted, IDH-mutant 1p/19q non-codeleted, IDH-wildtype). Four approaches were compared: anatomical, anatomical + ADC naive, anatomical + ADC N4, and anatomical + ADC N4/z-score. The UCSF-glioma dataset (n=409) was used for external validation. Naïve-Bayes algorithms yielded overall the best performance on the internal test-set. Adding ADC radiomics significantly improved AUC from 0.79 to 0.86 (p= .011) for the IDH-wildtype subgroup, but not for the other two glioma subgroups (p>0.05). In the external UCSF dataset, the addition of ADC radiomics yielded a significantly higher AUC for the IDH-wildtype subgroup (p≤ .001): 0.80 (N4/WS anatomical alone), 0.81 (anatomical + ADC naive), 0.81 (anatomical + ADC N4) and 0.88 (anatomical + ADC N4/z-score) as well as for the IDH-mutant 1p/19q non-codeleted subgroup (p< .012 each). ADC radiomics can enhance the performance of conventional MRI-based radiomic models, particularly for IDH-wildtype glioma. The benefit of intensity normalization of ADC maps depends on the type and context of the used data.
{"title":"Advancing non-invasive glioma classification with diffusion radiomics: Exploring the impact of signal intensity normalization","authors":"Martha Foltyn-Dumitru, Marianne Schell, Felix Sahm, T. Kessler, Wolfgang Wick, Martin Bendszus, Aditya Rastogi, G. Brugnara, Phillipp Vollmuth","doi":"10.1093/noajnl/vdae043","DOIUrl":"https://doi.org/10.1093/noajnl/vdae043","url":null,"abstract":"\u0000 \u0000 \u0000 This study investigates the influence of diffusion-weighted MRI (DWI) on radiomic-based prediction of glioma types according to molecular status and assesses the impact of DWI intensity normalization on model generalizability.\u0000 \u0000 \u0000 \u0000 Radiomic features, compliant with IBSI standards, were extracted from preoperative MRI of 549 patients with diffuse glioma, known IDH, and 1p19q-status. Anatomical sequences (T1, T1c, T2, FLAIR) underwent N4-Bias Field Correction (N4) and WhiteStripe normalization (N4/WS). Apparent diffusion coefficient (ADC) maps were normalized using N4 or N4/z-score. Nine machine-learning algorithms were trained for multiclass prediction of glioma types (IDH-mutant 1p/19q codeleted, IDH-mutant 1p/19q non-codeleted, IDH-wildtype). Four approaches were compared: anatomical, anatomical + ADC naive, anatomical + ADC N4, and anatomical + ADC N4/z-score. The UCSF-glioma dataset (n=409) was used for external validation.\u0000 \u0000 \u0000 \u0000 Naïve-Bayes algorithms yielded overall the best performance on the internal test-set. Adding ADC radiomics significantly improved AUC from 0.79 to 0.86 (p= .011) for the IDH-wildtype subgroup, but not for the other two glioma subgroups (p>0.05). In the external UCSF dataset, the addition of ADC radiomics yielded a significantly higher AUC for the IDH-wildtype subgroup (p≤ .001): 0.80 (N4/WS anatomical alone), 0.81 (anatomical + ADC naive), 0.81 (anatomical + ADC N4) and 0.88 (anatomical + ADC N4/z-score) as well as for the IDH-mutant 1p/19q non-codeleted subgroup (p< .012 each).\u0000 \u0000 \u0000 \u0000 ADC radiomics can enhance the performance of conventional MRI-based radiomic models, particularly for IDH-wildtype glioma. The benefit of intensity normalization of ADC maps depends on the type and context of the used data.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 43","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140217098","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}
K. Holíková, I. Selingerová, P. Pospíšil, M. Bulik, L. Hynková, Ivana Koloušková, Lucie Hnidáková, P. Burkoň, M. Slávik, Jiří Šáňa, Tomas Holecek, Jiří Vaníček, P. Šlampa, R. Jancalek, Tomas Kazda
Changes in the hippocampus after brain metastases radiotherapy can significantly impact neurocognitive functions. Numerous studies document hippocampal atrophy correlating with the radiation dose. This study aims to elucidate volumetric changes in patients undergoing whole-brain radiotherapy (WBRT) or targeted stereotactic radiotherapy (SRT) and to explore volumetric changes in the individual subregions of the hippocampus. Ten patients indicated to WBRT and 18 to SRT underwent brain magnetic resonance before radiotherapy and after four months. A structural T1-weighted sequence was used for volumetric analysis, and the software FreeSurfer was employed as the tool for the volumetry evaluation of 19 individual hippocampal subregions. The volume of the whole hippocampus, segmented by the software, was larger than the volume outlined by the radiation oncologist. No significant differences in volume changes were observed in the right hippocampus. In the left hippocampus, the only subregion with a smaller volume after WBRT was the granular cells and molecular layers of the dentate gyrus (GC-ML-DG) region (median change -5mm3, median volume 137 vs. 135 mm3; p=0.027), the region of the presumed location of neuronal progenitors. Our study enriches the theory that the loss of neural stem cells is involved in cognitive decline after radiotherapy, contributes to the understanding of cognitive impairment, and advocates for the need for SRT whenever possible to preserve cognitive functions in patients undergoing brain radiotherapy.
{"title":"Hippocampal subfield volumetric changes after radiotherapy for brain metastases","authors":"K. Holíková, I. Selingerová, P. Pospíšil, M. Bulik, L. Hynková, Ivana Koloušková, Lucie Hnidáková, P. Burkoň, M. Slávik, Jiří Šáňa, Tomas Holecek, Jiří Vaníček, P. Šlampa, R. Jancalek, Tomas Kazda","doi":"10.1093/noajnl/vdae040","DOIUrl":"https://doi.org/10.1093/noajnl/vdae040","url":null,"abstract":"\u0000 \u0000 \u0000 Changes in the hippocampus after brain metastases radiotherapy can significantly impact neurocognitive functions. Numerous studies document hippocampal atrophy correlating with the radiation dose. This study aims to elucidate volumetric changes in patients undergoing whole-brain radiotherapy (WBRT) or targeted stereotactic radiotherapy (SRT) and to explore volumetric changes in the individual subregions of the hippocampus.\u0000 \u0000 \u0000 \u0000 Ten patients indicated to WBRT and 18 to SRT underwent brain magnetic resonance before radiotherapy and after four months. A structural T1-weighted sequence was used for volumetric analysis, and the software FreeSurfer was employed as the tool for the volumetry evaluation of 19 individual hippocampal subregions.\u0000 \u0000 \u0000 \u0000 The volume of the whole hippocampus, segmented by the software, was larger than the volume outlined by the radiation oncologist. No significant differences in volume changes were observed in the right hippocampus. In the left hippocampus, the only subregion with a smaller volume after WBRT was the granular cells and molecular layers of the dentate gyrus (GC-ML-DG) region (median change -5mm3, median volume 137 vs. 135 mm3; p=0.027), the region of the presumed location of neuronal progenitors.\u0000 \u0000 \u0000 \u0000 Our study enriches the theory that the loss of neural stem cells is involved in cognitive decline after radiotherapy, contributes to the understanding of cognitive impairment, and advocates for the need for SRT whenever possible to preserve cognitive functions in patients undergoing brain radiotherapy.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"30 1‐2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140224852","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}
Christopher P Millward, A. Islim, Terri S Armstrong, H. Barrington, Sabrina Bell, A. Brodbelt, H. Bulbeck, L. Dirven, Paul L Grundy, Mohsen Javadpour, Sumirat M. Keshwara, Shelli D Koszdin, Anthony G Marson, Michael W McDermott, T. Meling, Kathy Oliver, P. Plaha, M. Preusser, Thomas Santarius, N. Srikandarajah, M. Taphoorn, Carole Turner, C. Watts, M. Weller, Paula R Williamson, Gelareh Zadeh, A. Z. Zamanipoor Najafabadi, M. Jenkinson
The clinical management of patients with incidental intracranial meningioma varies markedly and is often based on clinician choice and observational data. Heterogeneous outcome measurement has likely hampered knowledge progress by preventing comparative analysis of similar cohorts of patients. This systematic review aimed to summarise the outcomes measured and reported in observational studies. A systematic literature search was performed to identify published full-texts describing active monitoring of adult cohorts with incidental and untreated intracranial meningioma (PubMed, EMBASE, MEDLINE, and CINAHL via EBSCO, completed 24th Jan 22). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were deduplicated and the resulting unique outcomes grouped under standardised outcome terms. These were classified using the taxonomy proposed by the ‘Core Outcome Measures in Effectiveness Trials’ (COMET) initiative. Thirty-three published articles and one ongoing study were included describing 32 unique studies: study designs were retrospective n=27 and prospective n=5. In total, 268 verbatim outcomes were reported, of which 77 were defined. Following de-duplication, 178 unique verbatim outcomes remained and were grouped into 53 standardised outcome terms. These were classified using the COMET taxonomy into 9 outcome domains and 3 core areas. Outcome measurement across observational studies of incidental and untreated intracranial meningioma is heterogeneous. The standardised outcome terms identified will be prioritised through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set (COS) for use in future observational studies.
{"title":"The outcomes measured and reported in observational studies of incidental and untreated intracranial meningioma: a systematic review","authors":"Christopher P Millward, A. Islim, Terri S Armstrong, H. Barrington, Sabrina Bell, A. Brodbelt, H. Bulbeck, L. Dirven, Paul L Grundy, Mohsen Javadpour, Sumirat M. Keshwara, Shelli D Koszdin, Anthony G Marson, Michael W McDermott, T. Meling, Kathy Oliver, P. Plaha, M. Preusser, Thomas Santarius, N. Srikandarajah, M. Taphoorn, Carole Turner, C. Watts, M. Weller, Paula R Williamson, Gelareh Zadeh, A. Z. Zamanipoor Najafabadi, M. Jenkinson","doi":"10.1093/noajnl/vdae042","DOIUrl":"https://doi.org/10.1093/noajnl/vdae042","url":null,"abstract":"\u0000 \u0000 \u0000 The clinical management of patients with incidental intracranial meningioma varies markedly and is often based on clinician choice and observational data. Heterogeneous outcome measurement has likely hampered knowledge progress by preventing comparative analysis of similar cohorts of patients. This systematic review aimed to summarise the outcomes measured and reported in observational studies.\u0000 \u0000 \u0000 \u0000 A systematic literature search was performed to identify published full-texts describing active monitoring of adult cohorts with incidental and untreated intracranial meningioma (PubMed, EMBASE, MEDLINE, and CINAHL via EBSCO, completed 24th Jan 22). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were deduplicated and the resulting unique outcomes grouped under standardised outcome terms. These were classified using the taxonomy proposed by the ‘Core Outcome Measures in Effectiveness Trials’ (COMET) initiative.\u0000 \u0000 \u0000 \u0000 Thirty-three published articles and one ongoing study were included describing 32 unique studies: study designs were retrospective n=27 and prospective n=5. In total, 268 verbatim outcomes were reported, of which 77 were defined. Following de-duplication, 178 unique verbatim outcomes remained and were grouped into 53 standardised outcome terms. These were classified using the COMET taxonomy into 9 outcome domains and 3 core areas.\u0000 \u0000 \u0000 \u0000 Outcome measurement across observational studies of incidental and untreated intracranial meningioma is heterogeneous. The standardised outcome terms identified will be prioritised through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set (COS) for use in future observational studies.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"22 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140229923","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}
V. Hein, N. Baeza-Kallee, A. Bertucci, C. Colin, Aurélie Tchoghandjian, D. Figarella-Branger, E. Tabouret
Glioblastoma is the most frequent and aggressive primary brain tumor in adults. Currently, no curative treatment is available. Despite first line treatment composed by the association of surgery, radiotherapy and chemotherapy, relapse remains inevitable in a median delay of 6 to 10 months. Improving patient management and developing new therapeutic strategies are therefore a critical medical need in neuro-oncology. Gangliosides are sialic acid-containing glycosphingolipids, the most abundant in the nervous system, representing attractive therapeutic targets. The ganglioside GD3 is highly expressed in neuroectoderm-derived tumors such as melanoma and neuroblastoma, but also in gliomas. Moreover, interesting results, including our own, have reported the involvement of GD3 in the stemness of glioblastoma cells. In this review, we will first describe the characteristics of the ganglioside GD3 and its enzyme, the GD3 synthase (GD3S), including their biosynthesis and metabolism. Then, we will detail their expression and role in gliomas. Finally, we will summarize the current knowledge regarding the therapeutic development opportunities against GD3 and GD3S.
{"title":"GD3 ganglioside is a promising therapeutic target for glioma patients","authors":"V. Hein, N. Baeza-Kallee, A. Bertucci, C. Colin, Aurélie Tchoghandjian, D. Figarella-Branger, E. Tabouret","doi":"10.1093/noajnl/vdae038","DOIUrl":"https://doi.org/10.1093/noajnl/vdae038","url":null,"abstract":"\u0000 Glioblastoma is the most frequent and aggressive primary brain tumor in adults. Currently, no curative treatment is available. Despite first line treatment composed by the association of surgery, radiotherapy and chemotherapy, relapse remains inevitable in a median delay of 6 to 10 months. Improving patient management and developing new therapeutic strategies are therefore a critical medical need in neuro-oncology. Gangliosides are sialic acid-containing glycosphingolipids, the most abundant in the nervous system, representing attractive therapeutic targets. The ganglioside GD3 is highly expressed in neuroectoderm-derived tumors such as melanoma and neuroblastoma, but also in gliomas. Moreover, interesting results, including our own, have reported the involvement of GD3 in the stemness of glioblastoma cells. In this review, we will first describe the characteristics of the ganglioside GD3 and its enzyme, the GD3 synthase (GD3S), including their biosynthesis and metabolism. Then, we will detail their expression and role in gliomas. Finally, we will summarize the current knowledge regarding the therapeutic development opportunities against GD3 and GD3S.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"19 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140230784","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}
J. J. Jones, Kate Jones, Stephen Q. Wong, James Whittle, David Goode, Hong Nguyen, Josie Iaria, Stan Stylli, James Towner, Thomas Pieters, Frank Gaillard, Andrew H Kaye, K. J. Drummond, Andrew P Morokoff
Liquid biopsy based on circulating tumor DNA (ctDNA) is a novel tool in clinical oncology, however, its use has been limited in glioma to date, due to low levels of ctDNA. In this study we aimed to demonstrate that sequencing techniques optimised for liquid biopsy in glioma patients can detect ctDNA in plasma with high sensitivity and with potential clinical utility. We investigated ten glioma patients with tumor tissue available from at least two surgical operations, who had 49 longitudinally collected plasma samples available for analysis. Plasma samples were sequenced with CAPP-seq (AVENIO) and tissue samples with TSO500. Glioma-derived ctDNA mutations were detected in 93.8% of plasma samples. 25% of all mutations detected were observed in plasma only. Mutations of the mismatch repair (MMR) genes MSH2 and MSH6 were the most frequent circulating gene alterations seen after temozolomide treatment and were frequently observed to appear in plasma prior to their appearance in tumor tissue at the time of surgery for recurrence. This pilot study suggests that plasma ctDNA in glioma is feasible and may provide sensitive and complementary information to tissue biopsy. Furthermore, plasma ctDNA detection of new MMR gene mutations not present in the initial tissue biopsy may provide an early indication of the development of chemotherapy resistance. Additional clinical validation in larger cohorts is needed.
{"title":"Plasma ctDNA enables early detection of temozolomide resistance mutations in glioma","authors":"J. J. Jones, Kate Jones, Stephen Q. Wong, James Whittle, David Goode, Hong Nguyen, Josie Iaria, Stan Stylli, James Towner, Thomas Pieters, Frank Gaillard, Andrew H Kaye, K. J. Drummond, Andrew P Morokoff","doi":"10.1093/noajnl/vdae041","DOIUrl":"https://doi.org/10.1093/noajnl/vdae041","url":null,"abstract":"\u0000 \u0000 \u0000 Liquid biopsy based on circulating tumor DNA (ctDNA) is a novel tool in clinical oncology, however, its use has been limited in glioma to date, due to low levels of ctDNA. In this study we aimed to demonstrate that sequencing techniques optimised for liquid biopsy in glioma patients can detect ctDNA in plasma with high sensitivity and with potential clinical utility.\u0000 \u0000 \u0000 \u0000 We investigated ten glioma patients with tumor tissue available from at least two surgical operations, who had 49 longitudinally collected plasma samples available for analysis. Plasma samples were sequenced with CAPP-seq (AVENIO) and tissue samples with TSO500.\u0000 \u0000 \u0000 \u0000 Glioma-derived ctDNA mutations were detected in 93.8% of plasma samples. 25% of all mutations detected were observed in plasma only. Mutations of the mismatch repair (MMR) genes MSH2 and MSH6 were the most frequent circulating gene alterations seen after temozolomide treatment and were frequently observed to appear in plasma prior to their appearance in tumor tissue at the time of surgery for recurrence.\u0000 \u0000 \u0000 \u0000 This pilot study suggests that plasma ctDNA in glioma is feasible and may provide sensitive and complementary information to tissue biopsy. Furthermore, plasma ctDNA detection of new MMR gene mutations not present in the initial tissue biopsy may provide an early indication of the development of chemotherapy resistance. Additional clinical validation in larger cohorts is needed.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"41 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140230202","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}
A. Menzies, G. V. Long, Amiee Kohn, Hussein Tawbi, J. Weber, Keith Flaherty, Grant A. McArthur, P. Ascierto, Y. Pfluger, Karl D. Lewis, Katy K Tsai, Omid Hamid, Hans Prenen, Luis Fein, Erjian Wang, Carolin Guenzel, Fan Zhang, J. Kleha, A. di Pietro, Michael A. Davies
POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases. The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg BID plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg QD plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined. RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n=10), 1 achieved complete response and 5 achieved partial responses (PR); brain metastasis response rate [BMRR] was 60% [95% CI: 26.2, 87.8]). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data. Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2 and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.
{"title":"A phase 2 trial of encorafenib plus binimetinib evaluating high-dose and standard-dose regimens in patients with BRAF V600-mutant melanoma with brain metastasis","authors":"A. Menzies, G. V. Long, Amiee Kohn, Hussein Tawbi, J. Weber, Keith Flaherty, Grant A. McArthur, P. Ascierto, Y. Pfluger, Karl D. Lewis, Katy K Tsai, Omid Hamid, Hans Prenen, Luis Fein, Erjian Wang, Carolin Guenzel, Fan Zhang, J. Kleha, A. di Pietro, Michael A. Davies","doi":"10.1093/noajnl/vdae033","DOIUrl":"https://doi.org/10.1093/noajnl/vdae033","url":null,"abstract":"\u0000 \u0000 \u0000 POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases.\u0000 \u0000 \u0000 \u0000 The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg BID plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg QD plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined.\u0000 \u0000 \u0000 \u0000 RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n=10), 1 achieved complete response and 5 achieved partial responses (PR); brain metastasis response rate [BMRR] was 60% [95% CI: 26.2, 87.8]). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data.\u0000 \u0000 \u0000 \u0000 Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2 and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.\u0000","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"46 28","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140231672","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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