A. Picca, A. D. Di Stefano, J. Savatovsky, F. Ducray, O. Chinot, Elisabeth Cohen-Jonathan Moyal, P. Augereau, E. Le Rhun, Y. Schmitt, Nabila Rousseaux, Ariane Murielle Mbekwe Yepnang, Candice Estellat, Frédérique Charbonneau, Quentin Letourneur, D. Branger, D. Meyronet, Christine Fardeau, K. Mokhtari, Franck Bielle, A. Iavarone, Marc Sanson
Oncogenic FGFR-TACC fusions are present in 3-5% of high-grade gliomas (HGGs). Fexagratinib (AZD4547) is an oral FGFR1-3 inhibitor with preclinical activity in FGFR-TACC+ gliomas. We tested its safety and efficacy in patients with recurrent FGFR-TACC+ HGGs. TARGET (NCT02824133) is a phase I/II open-label multicenter study that included adult patients with FGFR-TACC+ HGGs relapsing after ≥1 line of standard chemoradiation. Patients received fexagratinib 80 mg bd on a continuous schedule until disease progression or inacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (PFS6). Twelve patients with recurrent IDH wildtype FGFR-TACC+ HGGs (all FGFR3-TACC3+) were included in the efficacy cohort (male/female ratio=1.4, median age=61.5 years). Most patients (67%) were included at the first relapse. The PFS6 was 25% (95% confidence interval 5-57%), with a median PFS of 1.4 months. All patients without progression at six months (n=3) were treated at first recurrence (versus 56% of those in progression) and remained progression-free for 14-23 months. The best response was RANO partial response in one patient (8%), stable disease in five (42%), and progressive disease in six (50%). Median survival was 17.5 months from inclusion. Grade 3 toxicities included lymphopenia, hyperglycaemia, stomatitis, nail changes, and alanine aminotransferase increase (n=1 each). No grade 4-5 toxicities were seen. A 32-gene signature was associated with benefit from FGFR inhibition in FGFR3-TACC3+ HGGs. Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3-TACC3+ HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required.
{"title":"TARGET: a phase I/II open-label multicentre study to assess safety and efficacy of fexagratinib in patients with relapsed/refractory FGFR fusion positive glioma","authors":"A. Picca, A. D. Di Stefano, J. Savatovsky, F. Ducray, O. Chinot, Elisabeth Cohen-Jonathan Moyal, P. Augereau, E. Le Rhun, Y. Schmitt, Nabila Rousseaux, Ariane Murielle Mbekwe Yepnang, Candice Estellat, Frédérique Charbonneau, Quentin Letourneur, D. Branger, D. Meyronet, Christine Fardeau, K. Mokhtari, Franck Bielle, A. Iavarone, Marc Sanson","doi":"10.1093/noajnl/vdae068","DOIUrl":"https://doi.org/10.1093/noajnl/vdae068","url":null,"abstract":"\u0000 \u0000 \u0000 Oncogenic FGFR-TACC fusions are present in 3-5% of high-grade gliomas (HGGs). Fexagratinib (AZD4547) is an oral FGFR1-3 inhibitor with preclinical activity in FGFR-TACC+ gliomas. We tested its safety and efficacy in patients with recurrent FGFR-TACC+ HGGs.\u0000 \u0000 \u0000 \u0000 TARGET (NCT02824133) is a phase I/II open-label multicenter study that included adult patients with FGFR-TACC+ HGGs relapsing after ≥1 line of standard chemoradiation. Patients received fexagratinib 80 mg bd on a continuous schedule until disease progression or inacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (PFS6).\u0000 \u0000 \u0000 \u0000 Twelve patients with recurrent IDH wildtype FGFR-TACC+ HGGs (all FGFR3-TACC3+) were included in the efficacy cohort (male/female ratio=1.4, median age=61.5 years). Most patients (67%) were included at the first relapse. The PFS6 was 25% (95% confidence interval 5-57%), with a median PFS of 1.4 months. All patients without progression at six months (n=3) were treated at first recurrence (versus 56% of those in progression) and remained progression-free for 14-23 months. The best response was RANO partial response in one patient (8%), stable disease in five (42%), and progressive disease in six (50%). Median survival was 17.5 months from inclusion. Grade 3 toxicities included lymphopenia, hyperglycaemia, stomatitis, nail changes, and alanine aminotransferase increase (n=1 each). No grade 4-5 toxicities were seen. A 32-gene signature was associated with benefit from FGFR inhibition in FGFR3-TACC3+ HGGs.\u0000 \u0000 \u0000 \u0000 Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3-TACC3+ HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required.\u0000","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141121448","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}
Tomasz Gruchala, Heather Smith, Osaama Khan, Lawrence Jennings, Lucas Santana-Santos, Erica Vormittag-Nocito, Craig M Horbinski
{"title":"Epithelial differentiation mimicking tumor-to-tumor metastasis in an IDH-wildtype glioblastoma","authors":"Tomasz Gruchala, Heather Smith, Osaama Khan, Lawrence Jennings, Lucas Santana-Santos, Erica Vormittag-Nocito, Craig M Horbinski","doi":"10.1093/noajnl/vdae081","DOIUrl":"https://doi.org/10.1093/noajnl/vdae081","url":null,"abstract":"","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141126476","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}
William B McKean, Jingye Yang, Kenneth Boucher, D. Shrieve, Gita Suneja, Karen Salzman, Randy Jensen, H. Colman, Adam L Cohen
Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-κB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas. Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3 + 3 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry. The MTD of minocycline was 150 mg twice per day (N = 20); one patient (5%) experienced CTCAE grade 3+ nausea and dizziness, and two patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-κB activation, were correlated with the microglia marker IBA-1. Minocycline at 150 mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-κB activation correlates with microglia levels in high-grade glioma.
{"title":"D-TERMINED, a Phase 1 Trial in Newly Diagnosed High-Grade Glioma With Temozolomide, Radiation, and Minocycline Followed by Adjuvant Minocycline/Temozolomide","authors":"William B McKean, Jingye Yang, Kenneth Boucher, D. Shrieve, Gita Suneja, Karen Salzman, Randy Jensen, H. Colman, Adam L Cohen","doi":"10.1093/noajnl/vdae063","DOIUrl":"https://doi.org/10.1093/noajnl/vdae063","url":null,"abstract":"\u0000 \u0000 \u0000 Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-κB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas.\u0000 \u0000 \u0000 \u0000 Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3 + 3 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry.\u0000 \u0000 \u0000 \u0000 The MTD of minocycline was 150 mg twice per day (N = 20); one patient (5%) experienced CTCAE grade 3+ nausea and dizziness, and two patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-κB activation, were correlated with the microglia marker IBA-1.\u0000 \u0000 \u0000 \u0000 Minocycline at 150 mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-κB activation correlates with microglia levels in high-grade glioma.\u0000","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140667683","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}
Background: The ONO-4059-02 phase 1/2 study showed favorable efficacy and acceptable safety profile of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, for relapsed/refractory primary central nervous system lymphoma (PCNSL). Here, we report the long-term efficacy and safety after a 3-year follow-up.
Methods: Eligible patients were aged ≥ 20 years with histologically diagnosed PCNSL and KPS of ≥ 70. Patients received oral tirabrutinib once daily at 320 or 480 mg, or 480 mg under fasted conditions.
Results: Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapsed and refractory, respectively. The 320, 480, and 480 mg fasted groups included 20, 7, and 17 patients, respectively. The median follow-up was 37.1 months. The overall response rate was 63.6% (95% CI: 47.8-77.6) with complete response (CR), unconfirmed CR, and partial response in 9, 7, and 12 patients, respectively. The median duration of response (DOR) was 9.2 months, with a DOR rate of 19.8%; the median progression-free survival (PFS) and median overall survival (OS) were 2.9 months and not reached, respectively, with PFS and OS rates of 13.9% and 56.7%, respectively. Adverse events occurred in 38 patients (86.4%): grade ≥ 3 in 23 (52.3%) including 1 patient with grade 5 events. KPS and quality of life (QoL) scores were well maintained among patients receiving long-term treatment.
Conclusions: The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile, while KPS and QoL scores were maintained.
{"title":"Three-year follow-up analysis of phase 1/2 study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma.","authors":"Hajime Yonezawa, Yoshitaka Narita, Motoo Nagane, Kazuhiko Mishima, Yasuhito Terui, Yoshiki Arakawa, Katsunori Asai, Noriko Fukuhara, Kazuhiko Sugiyama, Naoki Shinojima, Arata Aoi, Ryo Nishikawa","doi":"10.1093/noajnl/vdae037","DOIUrl":"https://doi.org/10.1093/noajnl/vdae037","url":null,"abstract":"<p><strong>Background: </strong>The ONO-4059-02 phase 1/2 study showed favorable efficacy and acceptable safety profile of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, for relapsed/refractory primary central nervous system lymphoma (PCNSL). Here, we report the long-term efficacy and safety after a 3-year follow-up.</p><p><strong>Methods: </strong>Eligible patients were aged ≥ 20 years with histologically diagnosed PCNSL and KPS of ≥ 70. Patients received oral tirabrutinib once daily at 320 or 480 mg, or 480 mg under fasted conditions.</p><p><strong>Results: </strong>Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapsed and refractory, respectively. The 320, 480, and 480 mg fasted groups included 20, 7, and 17 patients, respectively. The median follow-up was 37.1 months. The overall response rate was 63.6% (95% CI: 47.8-77.6) with complete response (CR), unconfirmed CR, and partial response in 9, 7, and 12 patients, respectively. The median duration of response (DOR) was 9.2 months, with a DOR rate of 19.8%; the median progression-free survival (PFS) and median overall survival (OS) were 2.9 months and not reached, respectively, with PFS and OS rates of 13.9% and 56.7%, respectively. Adverse events occurred in 38 patients (86.4%): grade ≥ 3 in 23 (52.3%) including 1 patient with grade 5 events. KPS and quality of life (QoL) scores were well maintained among patients receiving long-term treatment.</p><p><strong>Conclusions: </strong>The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile, while KPS and QoL scores were maintained.</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11059299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kohei Tsujino, Hideki Kashiwagi, Kai Nishimura, Yoshiki Fujikawa, Ryozo Kayama, Yusuke Fukuo, R. Hiramatsu, N. Nonoguchi, T. Takata, Hiroki Tanaka, Minoru Suzuki, N. Hu, K. Ono, M. Wanibuchi, Kei Nakai, Hiroyuki Nakamura, Shinji Kawabata
Boron Neutron Capture Therapy (BNCT) is a precise particle radiation therapy known for its unique cellular targeting ability. The development of innovative boron carriers is crucial for the advancement of BNCT technologies. Our previous study demonstrated the potential of PBC-IP administered via Convection-Enhanced Delivery (CED) in an F98 rat glioma model. This approach significantly extended rat survival in neutron irradiation experiments, with half achieving long-term survival, akin to a cure, in a rat brain tumor model. Our commitment to clinical applicability has spurred additional non-clinical pharmacodynamic research, including an investigation into the effects of cannula position and the time elapsed post-CED administration. In comprehensive in vivo experiments conducted on an F98 rat brain tumor model, we meticulously examined the boron distribution and neutron irradiation experiments at various sites and multiple time intervals following CED administration. The PBC-IP showed substantial efficacy for BNCT, revealing minimal differences in tumor boron concentration between central and peripheral CED administration, although a gradual decline in intratumoral boron concentration post-administration was observed. Therapeutic efficacy remained robust, particularly when employing cannula insertion at the tumor margin, compared to central injections. Even delayed neutron irradiation showed notable effectiveness, albeit with a slightly reduced survival period. These findings underscore the robust clinical potential of CED-administered PBC-IP in the treatment of malignant gliomas, offering adaptability across an array of treatment protocols. This study represents a significant leap forward in the quest to enhance BNCT for the management of malignant gliomas, opening promising avenues for clinical translation.
{"title":"Nonclinical pharmacodynamics of boron neutron capture therapy using direct intratumoral administration of a folate receptor targeting novel boron carrier","authors":"Kohei Tsujino, Hideki Kashiwagi, Kai Nishimura, Yoshiki Fujikawa, Ryozo Kayama, Yusuke Fukuo, R. Hiramatsu, N. Nonoguchi, T. Takata, Hiroki Tanaka, Minoru Suzuki, N. Hu, K. Ono, M. Wanibuchi, Kei Nakai, Hiroyuki Nakamura, Shinji Kawabata","doi":"10.1093/noajnl/vdae062","DOIUrl":"https://doi.org/10.1093/noajnl/vdae062","url":null,"abstract":"\u0000 \u0000 \u0000 Boron Neutron Capture Therapy (BNCT) is a precise particle radiation therapy known for its unique cellular targeting ability. The development of innovative boron carriers is crucial for the advancement of BNCT technologies. Our previous study demonstrated the potential of PBC-IP administered via Convection-Enhanced Delivery (CED) in an F98 rat glioma model. This approach significantly extended rat survival in neutron irradiation experiments, with half achieving long-term survival, akin to a cure, in a rat brain tumor model. Our commitment to clinical applicability has spurred additional non-clinical pharmacodynamic research, including an investigation into the effects of cannula position and the time elapsed post-CED administration.\u0000 \u0000 \u0000 \u0000 In comprehensive in vivo experiments conducted on an F98 rat brain tumor model, we meticulously examined the boron distribution and neutron irradiation experiments at various sites and multiple time intervals following CED administration.\u0000 \u0000 \u0000 \u0000 The PBC-IP showed substantial efficacy for BNCT, revealing minimal differences in tumor boron concentration between central and peripheral CED administration, although a gradual decline in intratumoral boron concentration post-administration was observed. Therapeutic efficacy remained robust, particularly when employing cannula insertion at the tumor margin, compared to central injections. Even delayed neutron irradiation showed notable effectiveness, albeit with a slightly reduced survival period. These findings underscore the robust clinical potential of CED-administered PBC-IP in the treatment of malignant gliomas, offering adaptability across an array of treatment protocols.\u0000 \u0000 \u0000 \u0000 This study represents a significant leap forward in the quest to enhance BNCT for the management of malignant gliomas, opening promising avenues for clinical translation.\u0000","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140677780","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}
Han T N Nguyen, Bailey H. Duhon, Hsuan-Chih Kuo, Melanie Fisher, Olivia M Brickey, Lisa Zhang, José J. Otero, Daniel M. Prevedello, O. Adunka, Yin Ren
The progression of vestibular schwannoma (VS) is intricately linked with interactions between schwannoma cells and the extracellular matrix. Surgical resection of VS is associated with substantial risks as tumors are adherent to the brainstem and cranial nerves. We evaluate the role of matrix metalloproteinase 9 (MMP9) in VS and explore its potential as a biomarker to classify adherent VS. Transcriptomic analysis of a murine schwannoma allograft model and immunohistochemical analysis of 17 human VS were performed. MMP9 abundance was assessed in mouse and human schwannoma cell lines. Transwell studies were performed to evaluate the effect of MMP9 on schwannoma invasion in vitro. Plasma biomarkers were identified from a multiplexed proteomic analysis in 45 prospective VS patients and validated in primary culture. The therapeutic efficacy of MMP9 inhibition was evaluated in a mouse schwannoma model. MMP9 was the most highly upregulated protease in mouse schwannomas and was significantly enriched in adherent VS, particularly around tumor vasculature. High levels of MMP9 were found in plasma of patients with adherent VS. MMP9 outperformed clinical and radiographic variables to classify adherent VS with outstanding discriminatory ability. Human schwannoma cells secreted MMP9 in response to TNF-α which promoted cellular invasion and adhesion protein expression in vitro. Lastly, MMP9 inhibition decreased mouse schwannoma growth in vivo. We identify MMP9 as a pre-operative biomarker to classify adherent VS. MMP9 may represent a new therapeutic target in adherent VS associated with poor surgical outcomes that lack other viable treatment options.
前庭裂隙瘤（VS）的发展与裂隙瘤细胞和细胞外基质之间的相互作用密切相关。由于肿瘤与脑干和颅神经粘连，前庭裂隙瘤的手术切除存在很大风险。我们评估了基质金属蛋白酶9（MMP9）在VS中的作用，并探讨了其作为生物标记物对粘附性VS进行分类的潜力。 我们对小鼠分裂瘤异体移植模型进行了转录组分析，并对 17 例人类 VS 进行了免疫组化分析。在小鼠和人类裂隙瘤细胞系中评估了 MMP9 的丰度。进行了透孔研究，以评估 MMP9 对体外侵袭 schwannoma 的影响。通过对 45 名前瞻性 VS 患者进行多重蛋白质组分析，确定了血浆生物标志物，并在原代培养中进行了验证。在小鼠血吸虫瘤模型中评估了抑制 MMP9 的疗效。 MMP9是小鼠裂隙瘤中上调率最高的蛋白酶，在粘附的VS中明显富集，尤其是在肿瘤血管周围。在粘连性 VS 患者的血浆中发现了高水平的 MMP9。在对粘连性 VS 进行分类时，MMP9 的鉴别能力优于临床和放射学变量。人类裂隙瘤细胞在 TNF-α 的作用下分泌 MMP9，从而促进了体外细胞侵袭和粘附蛋白的表达。最后，MMP9抑制剂可减少小鼠裂隙瘤在体内的生长。 我们发现 MMP9 是一种术前生物标记物，可用于对粘附的 VS 进行分类。对于手术效果不佳、缺乏其他可行治疗方案的粘连性 VS，MMP9 可能是一个新的治疗靶点。
{"title":"Matrix metalloproteinase 9: an emerging biomarker for classification of adherent vestibular schwannoma","authors":"Han T N Nguyen, Bailey H. Duhon, Hsuan-Chih Kuo, Melanie Fisher, Olivia M Brickey, Lisa Zhang, José J. Otero, Daniel M. Prevedello, O. Adunka, Yin Ren","doi":"10.1093/noajnl/vdae058","DOIUrl":"https://doi.org/10.1093/noajnl/vdae058","url":null,"abstract":"\u0000 \u0000 \u0000 The progression of vestibular schwannoma (VS) is intricately linked with interactions between schwannoma cells and the extracellular matrix. Surgical resection of VS is associated with substantial risks as tumors are adherent to the brainstem and cranial nerves. We evaluate the role of matrix metalloproteinase 9 (MMP9) in VS and explore its potential as a biomarker to classify adherent VS.\u0000 \u0000 \u0000 \u0000 Transcriptomic analysis of a murine schwannoma allograft model and immunohistochemical analysis of 17 human VS were performed. MMP9 abundance was assessed in mouse and human schwannoma cell lines. Transwell studies were performed to evaluate the effect of MMP9 on schwannoma invasion in vitro. Plasma biomarkers were identified from a multiplexed proteomic analysis in 45 prospective VS patients and validated in primary culture. The therapeutic efficacy of MMP9 inhibition was evaluated in a mouse schwannoma model.\u0000 \u0000 \u0000 \u0000 MMP9 was the most highly upregulated protease in mouse schwannomas and was significantly enriched in adherent VS, particularly around tumor vasculature. High levels of MMP9 were found in plasma of patients with adherent VS. MMP9 outperformed clinical and radiographic variables to classify adherent VS with outstanding discriminatory ability. Human schwannoma cells secreted MMP9 in response to TNF-α which promoted cellular invasion and adhesion protein expression in vitro. Lastly, MMP9 inhibition decreased mouse schwannoma growth in vivo.\u0000 \u0000 \u0000 \u0000 We identify MMP9 as a pre-operative biomarker to classify adherent VS. MMP9 may represent a new therapeutic target in adherent VS associated with poor surgical outcomes that lack other viable treatment options.\u0000","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140681961","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}
Quirin D. Strotzer, Thomas Wagner, Pia Angstwurm, K. Hense, Lucca Scheuermeyer, E. Noeva, Johannes Dinkel, Christian Stroszczynski, Claudia Fellner, M. Riemenschneider, K. Rosengarth, T. Pukrop, Isabel Wiesinger, Christina Wendl, A. Schicho
Growing research demonstrates the ability to predict histology or genetic information of various malignancies using radiomic features extracted from imaging data. This study aimed to investigate MRI-based radiomics in predicting the primary tumor of brain metastases through internal and external validation, using oversampling techniques to address class imbalance. This IRB-approved retrospective multicenter study included brain metastases from lung cancer, melanoma, breast cancer, colorectal cancer, and a combined heterogenous group of other primary entities (five-class classification). Local data were acquired between 2003 and 2021 from 231 patients (545 metastases). External validation was performed with 82 patients (280 metastases) and 258 patients (809 metastases) from the publicly available Stanford BrainMetShare and the University of California San Francisco Brain Metastases Stereotactic Radiosurgery datasets, respectively. Pre-processing included brain extraction, bias correction, co-registration, intensity normalization, and semi-manual binary tumor segmentation. 2528 radiomic features were extracted from T1w (± contrast), FLAIR, and wavelet transforms for each sequence (eight decompositions). Random forest classifiers were trained with selected features on original and oversampled data (five-fold cross-validation) and evaluated on internal/external holdout test sets using accuracy, precision, recall, F1-score, and AUC. Oversampling did not improve the overall unsatisfactory performance on the internal and external test sets. Incorrect data partitioning (oversampling before train/validation/test split) lead to a massive overestimation of model performance. Radiomics models' capability to predict histologic or genomic data from imaging should be critically assessed; external validation is essential.
{"title":"Limited Capability of MRI Radiomics to Predict Primary Tumor Histology of Brain Metastases in External Validation","authors":"Quirin D. Strotzer, Thomas Wagner, Pia Angstwurm, K. Hense, Lucca Scheuermeyer, E. Noeva, Johannes Dinkel, Christian Stroszczynski, Claudia Fellner, M. Riemenschneider, K. Rosengarth, T. Pukrop, Isabel Wiesinger, Christina Wendl, A. Schicho","doi":"10.1093/noajnl/vdae060","DOIUrl":"https://doi.org/10.1093/noajnl/vdae060","url":null,"abstract":"\u0000 \u0000 \u0000 Growing research demonstrates the ability to predict histology or genetic information of various malignancies using radiomic features extracted from imaging data. This study aimed to investigate MRI-based radiomics in predicting the primary tumor of brain metastases through internal and external validation, using oversampling techniques to address class imbalance.\u0000 \u0000 \u0000 \u0000 This IRB-approved retrospective multicenter study included brain metastases from lung cancer, melanoma, breast cancer, colorectal cancer, and a combined heterogenous group of other primary entities (five-class classification). Local data were acquired between 2003 and 2021 from 231 patients (545 metastases). External validation was performed with 82 patients (280 metastases) and 258 patients (809 metastases) from the publicly available Stanford BrainMetShare and the University of California San Francisco Brain Metastases Stereotactic Radiosurgery datasets, respectively. Pre-processing included brain extraction, bias correction, co-registration, intensity normalization, and semi-manual binary tumor segmentation. 2528 radiomic features were extracted from T1w (± contrast), FLAIR, and wavelet transforms for each sequence (eight decompositions). Random forest classifiers were trained with selected features on original and oversampled data (five-fold cross-validation) and evaluated on internal/external holdout test sets using accuracy, precision, recall, F1-score, and AUC.\u0000 \u0000 \u0000 \u0000 Oversampling did not improve the overall unsatisfactory performance on the internal and external test sets. Incorrect data partitioning (oversampling before train/validation/test split) lead to a massive overestimation of model performance.\u0000 \u0000 \u0000 \u0000 Radiomics models' capability to predict histologic or genomic data from imaging should be critically assessed; external validation is essential.\u0000","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140679872","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}
Husain Shakil, A. Malhotra, J. Badhiwala, Vishu Karthikeyan, Ahmad Essa, Yingshi He, M. Fehlings, A. Saghal, Nicolas Dea, Alex Kiss, Christopher Witiw, Donald A. Redelmeier, Jefferson R Wilson
Spinal metastases are a significant complication of advanced cancer. In this study we assess temporal trends in the incidence and timing of spinal metastases and examine underlying patient demographics and primary cancer associations. In this population-based retrospective cohort study, health data from 2007 to 2019 in Ontario, Canada were analyzed (n = 37, 375 patients identified with spine metastases). Primary outcomes were annual incidence of spinal metastasis, and time to metastasis after primary diagnosis. The age-standardized incidence of spinal metastases increased from 229 to 302 cases per million over the 13-year study period. The average annual percent change (AAPC) in incidence was 2.2% (95% CI 1.4 to 3.0%) with patients aged ≥85 years demonstrating the largest increase (AAPC 5.2%; 95% CI 2.3 to 8.3%). Lung cancer had the greatest annual incidence, while prostate cancer had the greatest increase in annual incidence (AAPC 6.5; 95% CI 4.1 to 9.0%). Lung cancer patients were found to have the highest risk of spine metastasis with 10.3% (95% CI 10.1 to 10.5%) of patients being diagnosed at 10-years. Gastrointestinal cancer patients were found to have the lowest risk of spine metastasis with 1.0% (95% CI 0.9 to 1.0%) of patients being diagnosed at 10-years. The incidence of spinal metastases has increased in recent years particularly among older patients. The incidence and timing vary substantially among different primary cancer types. These findings contribute to the understanding of disease trends and emphasize a growing population of patients that require subspecialty care.
{"title":"Contemporary Trends in the Incidence and Timing of Spinal Metastases: A Population-Based Study","authors":"Husain Shakil, A. Malhotra, J. Badhiwala, Vishu Karthikeyan, Ahmad Essa, Yingshi He, M. Fehlings, A. Saghal, Nicolas Dea, Alex Kiss, Christopher Witiw, Donald A. Redelmeier, Jefferson R Wilson","doi":"10.1093/noajnl/vdae051","DOIUrl":"https://doi.org/10.1093/noajnl/vdae051","url":null,"abstract":"\u0000 \u0000 \u0000 Spinal metastases are a significant complication of advanced cancer. In this study we assess temporal trends in the incidence and timing of spinal metastases and examine underlying patient demographics and primary cancer associations.\u0000 \u0000 \u0000 \u0000 In this population-based retrospective cohort study, health data from 2007 to 2019 in Ontario, Canada were analyzed (n = 37, 375 patients identified with spine metastases). Primary outcomes were annual incidence of spinal metastasis, and time to metastasis after primary diagnosis.\u0000 \u0000 \u0000 \u0000 The age-standardized incidence of spinal metastases increased from 229 to 302 cases per million over the 13-year study period. The average annual percent change (AAPC) in incidence was 2.2% (95% CI 1.4 to 3.0%) with patients aged ≥85 years demonstrating the largest increase (AAPC 5.2%; 95% CI 2.3 to 8.3%). Lung cancer had the greatest annual incidence, while prostate cancer had the greatest increase in annual incidence (AAPC 6.5; 95% CI 4.1 to 9.0%). Lung cancer patients were found to have the highest risk of spine metastasis with 10.3% (95% CI 10.1 to 10.5%) of patients being diagnosed at 10-years. Gastrointestinal cancer patients were found to have the lowest risk of spine metastasis with 1.0% (95% CI 0.9 to 1.0%) of patients being diagnosed at 10-years.\u0000 \u0000 \u0000 \u0000 The incidence of spinal metastases has increased in recent years particularly among older patients. The incidence and timing vary substantially among different primary cancer types. These findings contribute to the understanding of disease trends and emphasize a growing population of patients that require subspecialty care.\u0000","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140686780","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}
Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas (ODG), and IDH-wildtype glioblastomas (GBM). GBM display genome instability, which may result from two genetic events leading to massive chromosome alterations: chromothripsis (CT) and whole-genome duplication (WGD). These events are scarcely described in IDH-mutant gliomas. The better prognosis of the latter may be related to their genome stability compared to GBM. Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening. Survival data were compared using the Kaplan-Meier method. At initial diagnosis, 37 GBM (18.7%) displayed CT versus 5 IDH-mutant gliomas (4.7%) (p = 0.0008), the latter were all high-grade (grade 3 or 4) astrocytomas. WGD was detected at initial diagnosis in 18 GBM (9.3%) and 9 IDH-mutant gliomas (5 astrocytomas and 4 oligodendrogliomas, either low- or high-grade) (8.5%). Neither CT nor WGD was associated with overall survival in GBM or in IDH-mutant gliomas. CT is less frequent in IDH-mutant gliomas compared to GBM. The absence of CT in ODG and grade 2 astrocytomas might, in part, explain their genome stability and better prognosis, while CT might underlie aggressive biological behavior in some high-grade astrocytomas. WGD is a rare and early event occurring equally in IDH-mutant gliomas and GBM.
{"title":"CT is rare in IDH-mutant gliomas compared to IDH-wildtype glioblastomas whereas whole-genome duplication is equally frequent in both tumor types","authors":"Baptiste Sourty, Laëtitia Basset, Alix Fontaine, Emmanuel Garcion, Audrey Rousseau","doi":"10.1093/noajnl/vdae059","DOIUrl":"https://doi.org/10.1093/noajnl/vdae059","url":null,"abstract":"\u0000 \u0000 \u0000 Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas (ODG), and IDH-wildtype glioblastomas (GBM). GBM display genome instability, which may result from two genetic events leading to massive chromosome alterations: chromothripsis (CT) and whole-genome duplication (WGD). These events are scarcely described in IDH-mutant gliomas. The better prognosis of the latter may be related to their genome stability compared to GBM.\u0000 \u0000 \u0000 \u0000 Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening. Survival data were compared using the Kaplan-Meier method.\u0000 \u0000 \u0000 \u0000 At initial diagnosis, 37 GBM (18.7%) displayed CT versus 5 IDH-mutant gliomas (4.7%) (p = 0.0008), the latter were all high-grade (grade 3 or 4) astrocytomas. WGD was detected at initial diagnosis in 18 GBM (9.3%) and 9 IDH-mutant gliomas (5 astrocytomas and 4 oligodendrogliomas, either low- or high-grade) (8.5%). Neither CT nor WGD was associated with overall survival in GBM or in IDH-mutant gliomas.\u0000 \u0000 \u0000 \u0000 CT is less frequent in IDH-mutant gliomas compared to GBM. The absence of CT in ODG and grade 2 astrocytomas might, in part, explain their genome stability and better prognosis, while CT might underlie aggressive biological behavior in some high-grade astrocytomas. WGD is a rare and early event occurring equally in IDH-mutant gliomas and GBM.\u0000","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140686713","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}
L. Alder, Gloria Broadwater, Michelle Green, Amanda E. D. Van Swearingen, Eric S Lipp, Jeffrey Melson Clarke, Carey Anders, S. Sammons
While serum circulating tumor DNA (ctDNA) is routine, data from patients with brain metastases (BrMs) is limited. We assessed genomic alterations in ctDNA from patients with solid tumor BrMs in three groups: isolated BrMs with stable extracranial disease (iCNS), concurrent brain and extracranial progression (cCNS), and extracranial progression with no active BrMs (eCNS). We also compared ctDNA alterations between patients with and without BrMs. Patients with a Guardant360 ctDNA profile with (n=253) and without BrMs (n=449) from the Duke Molecular Registry between 01/2014 – 12/2020 were identified. Actionable alterations were defined as FDA-recognized or standard of care biomarkers. Disease status was determined via investigator assessment within 30 days of ctDNA collection. Among the 253 patients with BrMs: 29 (12%) had iCNS, 160 (63%) cCNS, and 64 (25%) eCNS. Breast (BC) (12.0%) and non-small cell lung cancer (NSCLC) (76.4%) were the most common tumor types. ESR1 (60% vs 25%, p< 0.001) and BRCA2 (17% vs 5%, p=0.022) were more frequent in BC BrMs. In NSCLC BrMs, EGFR alterations were most frequent in the iCNS group (iCNS: 67%, cCNS: 40%, eCNS:37%, p=0.08 and in patients with BrMs (36% vs 17%, p<0.001). Sequencing from both brain tissue and ctDNA were available for 8 patients; 7 (87.5%) had identical alterations. This study illustrates the feasibility of detecting alterations from ctDNA among patients with BrMs. A higher frequency of actionable mutations was observed in ctDNA in patients with BrMs. Additional studies comparing ctDNA and alterations in BrMs tissue are needed to determine if ctDNA can be considered a surrogate to support treatment decisions.
{"title":"Unique Genomic Alterations in the Circulating Tumor DNA of Patients With Solid Tumors Brain Metastases","authors":"L. Alder, Gloria Broadwater, Michelle Green, Amanda E. D. Van Swearingen, Eric S Lipp, Jeffrey Melson Clarke, Carey Anders, S. Sammons","doi":"10.1093/noajnl/vdae052","DOIUrl":"https://doi.org/10.1093/noajnl/vdae052","url":null,"abstract":"\u0000 \u0000 \u0000 While serum circulating tumor DNA (ctDNA) is routine, data from patients with brain metastases (BrMs) is limited. We assessed genomic alterations in ctDNA from patients with solid tumor BrMs in three groups: isolated BrMs with stable extracranial disease (iCNS), concurrent brain and extracranial progression (cCNS), and extracranial progression with no active BrMs (eCNS). We also compared ctDNA alterations between patients with and without BrMs.\u0000 \u0000 \u0000 \u0000 Patients with a Guardant360 ctDNA profile with (n=253) and without BrMs (n=449) from the Duke Molecular Registry between 01/2014 – 12/2020 were identified. Actionable alterations were defined as FDA-recognized or standard of care biomarkers. Disease status was determined via investigator assessment within 30 days of ctDNA collection.\u0000 \u0000 \u0000 \u0000 Among the 253 patients with BrMs: 29 (12%) had iCNS, 160 (63%) cCNS, and 64 (25%) eCNS. Breast (BC) (12.0%) and non-small cell lung cancer (NSCLC) (76.4%) were the most common tumor types. ESR1 (60% vs 25%, p< 0.001) and BRCA2 (17% vs 5%, p=0.022) were more frequent in BC BrMs. In NSCLC BrMs, EGFR alterations were most frequent in the iCNS group (iCNS: 67%, cCNS: 40%, eCNS:37%, p=0.08 and in patients with BrMs (36% vs 17%, p<0.001). Sequencing from both brain tissue and ctDNA were available for 8 patients; 7 (87.5%) had identical alterations.\u0000 \u0000 \u0000 \u0000 This study illustrates the feasibility of detecting alterations from ctDNA among patients with BrMs. A higher frequency of actionable mutations was observed in ctDNA in patients with BrMs. Additional studies comparing ctDNA and alterations in BrMs tissue are needed to determine if ctDNA can be considered a surrogate to support treatment decisions.\u0000","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140693607","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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