A Controlled, Study of the Effect of Combination Antineoplaston Therapy [Atengenal (A10) and Astugenal (AS2-1)] on the QT/QTc Interval In Subjects With Newly Diagnosed Diffuse, Intrinsic, Brainstem Glioma

The primary objective of this protocol study is to investigate the effect of Antineoplaston therapy on the QT/QTc interval in study subjects age 3 to 21 years with newly-diagnosed, diffuse, intrinsic brainstem glioma. This investigation is to be conducted in parallel with a phase 3 efficacy and safety study of combination Antineoplaston therapy + radiation vs. radiation alone (BRI-BT-52).

开始日期2027-06-01

申办/合作机构

Burzynski Research Institute, Inc.

NCT02887040 / Not yet recruiting临床3期IIT

A Randomized Phase 3 Study of Combination Antineoplaston Therapy [Antineoplastons A10 (Atengenal) and AS2-1 (Astugenal)] Plus Radiation Therapy vs. Radiation Therapy Only in Subjects With Newly Diagnosed Diffuse, Intrinsic, Brainstem Glioma

Patients ≥ 3 years of age with newly-diagnosed, diffuse, intrinsic pontine glioma will be enrolled in this study. However, the primary objectives of this study are to 1) compare overall survival, the time from randomization to death from any cause, for study subjects 3-21 years of age with newly-diagnosed, diffuse, intrinsic pontine glioma who receive Antineoplaston therapy (Atengenal + Astugenal) + radiation therapy vs. radiation therapy alone and 2) describe the toxicity profile (all subjects) for Antineoplaston therapy + radiation therapy vs. radiation therapy alone.
A secondary objective is to compare progression-free survival for study subjects 3-21 years of age with newly-diagnosed, diffuse, intrinsic pontine glioma treated with Antineoplaston therapy + radiation therapy vs. radiation therapy alone.

开始日期2025-06-01

申办/合作机构

Burzynski Research Institute, Inc.

NCT05956821 / Recruiting临床1/2期IIT

Phase I/II Trial of Repeat Dosing of Super-Selective Intraarterial Infusion of Erbitux (Cetuximab) and Avastin (Bevacizumab) for Treatment of Relapsed/Refractory Intracranial Glioma in Patients Under 22 Years of Age

This study assesses the safety and efficacy of repeat monthly dosing of super-selective intra-arterial cerebral infusion (SIACI) of cetuximab and bevacizumab in patients < 22 years of age.

开始日期2024-12-01

申办/合作机构

University of Miami

100 项与脑干胶质瘤相关的临床结果

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100 项与脑干胶质瘤相关的转化医学

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0 项与脑干胶质瘤相关的专利（医药）

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项与脑干胶质瘤相关的文献（医药）

2024-11-01·Magnetic Resonance Imaging

A multi-task generative model for simultaneous post-contrast MR image synthesis and brainstem glioma segmentation

Article

作者: Zhang, Yajing ; Qi, Jin ; Xiong, Xiangyu ; Liu, Yaou ; Huang, Yanxin

OBJECTIVESThis study aims to generate post-contrast MR images reducing the exposure of gadolinium-based contrast agents (GBCAs) for brainstem glioma (BSG) detection, simultaneously delineating the BSG lesion, and providing high-resolution contrast information.METHODSA retrospective cohort of 30 patients diagnosed with brainstem glioma was included. Multi-contrast images, including pre-contrast T1 weighted (pre-T1w), T2 weighted (T2w), arterial spin labeling (ASL) and post-contrast T1w images, were collected. A multi-task generative model was developed to synthesize post-contrast T1w images and simultaneously segment BSG masks from the multi-contrast inputs. Performance evaluation was conducted using peak signal-to-noise ratio (PSNR), structural similarity index (SSIM), and mean absolute error (MAE) metrics. A perceptual study was also undertaken to assess diagnostic quality.RESULTSThe proposed model achieved SSIM of 0.86 ± 0.04, PSNR of 26.33 ± 0.05 and MAE of 57.20 ± 20.50 for post-contrast T1w image synthesis. Automated delineation of the BSG lesions achieved Dice similarity coefficient (DSC) score of 0.88 ± 0.27.CONCLUSIONSThe proposed model can synthesize high-quality post-contrast T1w images and accurately segment the BSG region, yielding satisfactory DSC scores.CLINICAL RELEVANCE STATEMENTThe synthesized post-contrast MR image presented in this study has the potential to reduce the usage of gadolinium-based contrast agents, which may pose risks to patients. Moreover, the automated segmentation method proposed in this paper aids radiologists in accurately identifying the brainstem glioma lesion, facilitating the diagnostic process.

2024-09-05·Blood

Rapid tumor DNA analysis of cerebrospinal fluid accelerates treatment of central nervous system lymphoma

Article

作者: Kessler, Tobias ; Gallagher, Aidan ; Batten, Julie ; Iser, Florian ; Dietrich, Jorg ; Georgantas, N Zeke ; Martinez-Lage, Maria ; Jones, Pamela S. ; Nahed, Brian V. ; Pisapia, Michelle ; Meyerson, Matthew L ; Batchelor, Tracy T ; Nayyar, Naema ; Thierauf, Julia ; Gupta, Mihir ; Bradley, Joseph D. ; Brastianos, Priscilla K. ; Meyerson, Matthew ; Curry, William ; Jones, SooAe ; Nahed, Brian Vala ; Cahill, Daniel P ; Massaad, Elie ; Brastianos, Priscilla ; Bradley, Joseph ; Barker, Fred G ; Carter, Bob ; Lennerz, Jochen K. ; Maron, Garrett ; Romero, Javier M. ; Carter, Bob S. ; Cahill, Daniel P. ; Ritterhouse, Lauren L ; Jordan, Justin T. ; Wang, Nancy ; Tateishi, Kensuke ; Georgantas, N. Zeke ; Maron, Garrett E. ; Curry, William T. ; Batchelor, Tracy T. ; Sun, Ying ; Ritterhouse, Lauren L. ; Burns, Evan J. ; Gupta, Rajiv ; Burns, Evan ; Forst, Deborah Anne ; Barker, Fred G. ; Lennerz, Jochen K ; Jordan, Justin T ; Forst, Deborah A. ; Jones, Pamela Stuart ; Romero, Javier ; Shankar, Ganesh M ; Jones, SooAe S. ; Shankar, Ganesh M. ; Gordon, Amanda ; Batten, Julie M.

AbstractDelays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown cause. Participants underwent genotyping of CSF-derived DNA using a quantitative polymerase chain reaction–based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF, and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma, and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7 of 33 cases (21.2%) of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median, 3 vs 12 days; P = .027). This assay was then implemented in a Clinical Laboratory Improvement Amendments environment, with 2-day median turnaround for diagnosis of CNS lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.

2024-09-01·Journal of Neuro-Oncology

Characteristics of H3K27M-mutant diffuse gliomas with a non-midline location

Article

作者: Hench, Jürgen ; Cartalat, Stéphanie ; Barritault, Marc ; Ducray, François ; Poncet, Delphine ; Seyve, Antoine ; McLeer, Anne ; Picart, Thiebaud ; Sturm, Dominik ; Guidara, Souhir ; Frank, Stephan ; Ferrari, Anthony ; Meyronet, David ; Leonce, Camille ; Bringuier, Pierre-Paul

PURPOSEDiffuse midline gliomas (DMG) with H3K27 alterations (H3K27M-DMG) are a highly aggressive form of brain cancer. In rare cases, H3K27 mutations have been observed in diffuse non-midline gliomas (DNMG). It is currently unclear how these tumors should be classified. Herein, we analyze the characteristics of DNMG with H3K27M mutations.METHODSWe reviewed the clinical, radiological and histological characteristics of all patients with an H3K27M mutated diffuse glioma diagnosed in our institution, between 2016 and 2023, to identify cases with a non-midline location. We then performed a molecular characterization (DNA methylation profiling, whole genome and transcriptome sequencing or targeted sequencing) of patients with an H3K27M-mutant DNMG and reviewed previously reported cases.RESULTSAmong 51 patients (18 children and 33 adults) diagnosed with an H3K27M diffuse glioma, we identified two patients (4%) who had a non-midline location. Including our two patients, 39 patients were reported in the literature with an H3K27M-mutant DNMG. Tumors were most frequently located in the temporal lobe (48%), affected adolescents and adults, and were associated with a poor outcome (median overall survival was 10.3 months (0.1-84)). Median age at diagnosis was 19.1 years. Tumors frequently harbored TP53 mutations (74%), ATRX mutations (71%) and PDGFRA mutations or amplifications (44%). In DNA methylation analysis, H3K27M-mutant DNMG clustered within or close to the reference group of H3K27M-mutant DMG. Compared to their midline counterpart, non-midline gliomas with H3K27M mutations seemed more frequently associated with PDGFRA alterations.CONCLUSIONDNMG with H3K27M mutations share many similarities with their midline counterpart, suggesting that they correspond to a rare anatomical presentation of these tumors. This is of paramount importance, as they may benefit from new therapeutic approaches such as ONC201.

项与脑干胶质瘤相关的新闻（医药）

2024-06-21

·生物谷

Cancer & Metabol：儿童脑瘤或会依赖不同的代谢途径来诱发其对疗法的耐受性

本文研究结果表明，DMG-H3K27M细胞依赖于高度活跃的嘌呤合成，包括从头合成和回收合成途径等，然而，高度活跃的游离嘌呤碱基进入到成熟的鸟苷酸盐中就能绕过抑制从头合成的途径。弥漫性中线胶质瘤（DMG，Diffuse midline gliomas）包括弥漫性内在脑桥胶质瘤（DIPGs，diffuse intrinsic pontine gliomas），其是一种罕见的脑癌形式，这些肿瘤通常会在组氨酸H3上携带突变，从而将赖氨酸27转化成为蛋氨酸（H3K27M），DMG-H3K27M的主要特征就是代谢改变以及对标准的护理辐射产生一定的耐受性，但目前研究人员并不清楚H3K27M是如何介导对辐射的代谢反应以及随之而来的疗法耐受性的。近日，一篇发表在国际杂志Cancer & Metabolism上题为“Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma”的研究报告中，来自密歇根大学Rogel癌症研究中心等机构的科学家们通过研究距离理解儿童DIPG肿瘤的作用机理又近了一步。DIPG是一种最具侵袭性的儿童脑瘤，由于手术不可行且放疗后的复发率较高，因此这种脑瘤往往难以治疗。这种肿瘤通常由H3K27M驱动组蛋白突变进行定义，研究者Daniel Wahl博士表示，我们想通过研究理解这一突变如何影响DIPG的肿瘤代谢以及对放疗的耐受性，这些问题能将我们直接引向嘌呤代谢。此前研究人员通过研究探索了嘌呤是如何在成人脚趾母细胞瘤中进行代谢的，包括在一项临床试验中，研究人员想观察阻断嘌呤的代谢如何帮助改善疗法的成功率。儿童脑瘤或会依赖不同的代谢途径来诱发其对疗法的耐受性图片来源：Cancer & Metabolism (2024). DOI:10.1186/s40170-024-00341-7 这项研究中，研究人员尝试了一种类似的方法来抑制嘌呤的合成，尽管其在DIPG细胞中的效果很好，但在动物模型研究中却并不那么令人印象深刻。研究者Wahl解释道，与很多成人脚趾母细胞瘤不同的是，DIPG肿瘤似乎依赖于两种不同的通路来制造嘌呤，我们将它比作是一条由两个入口坡道的道路，在成人GBMs中，其中一条入口坡道似乎被阻断了，其几乎就好像正在建设之中；如果利用药物来阻断第二条坡道，这对于肿瘤而言或许就真的是一个问题了，但在这些儿童脑瘤中，这两种坡道似乎都是敞开的，因此，仅仅阻断其中一种坡道的药物或许并不能真正减缓DIPGs的进展。尽管没有药物能阻断第二种坡道，但研究人员却能通过遗传沉默的技术来阻断嘌呤在细胞内产生，当他们这样做的时候，放疗的效果或许就很好。研究者表示，更好地理解这些肿瘤如何躲避疗法意味着他们就能更好地开发新型策略并在自己的游戏中击败它们，并改善这些患儿的治疗前景。下一步，研究人员还想基于这些研究发现，更好地理解为何儿童DIPG肿瘤依赖于一种不同于成人肿瘤的途径，以及如何开发阻断这种肿瘤进展的策略；通过进行额外的工作，研究人员希望能在未来改善患者的治疗。综上，本文研究结果表明，DMG-H3K27M细胞依赖于高度活跃的嘌呤合成，包括从头合成和回收合成途径等，然而，高度活跃的游离嘌呤碱基进入到成熟的鸟苷酸盐中就能绕过抑制从头合成的途径；因此，抑制嘌呤的回收或许能作为一种新型策略来克服DMG-H3K27M肿瘤对疗法的耐受性。（生物谷Bioon.com）参考文献： Erik R. Peterson, Peter Sajjakulnukit, Andrew J. Scott, et al. Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma, Cancer & Metabolism (2024). DOI:10.1186/s40170-024-00341-7

2024-03-06

·生物制药小编

绝命脑癌的一线生机

弥漫性中线神经胶质瘤（DMG）是一种极其难治的脑瘤，属于最严重的4级胶质瘤，且主要发病于儿童，诊断后平均预期寿命仅为10个月，5年生存率不到1%。此前受到广泛报道的郑州女孩心蕊就是罹患这一疾病而过世。由于主要发病于患者三脑室、丘脑、脑干、脊髓等位置，手术治疗很难达成。放疗是目前的主要手段，化疗带来的获益似乎有限。然而即便如此，复发实际上也是不可避免的，近年来也没有其他系统性疗法被证明是有效的，仅有几项初步临床展现出了一线可能的希望。本文将对目前可能有希望的疗法进行简单总结。ONC-201ONC-201是Chimerix公司的一款药物，本身是一种多巴胺受体D2/D3抑制剂和线粒体酪蛋白水解蛋白酶P（CIpP）变构激动剂。因为多巴胺受体抑制剂的性质，最初是打算将用于精神相关疾病的，但研究人员发现这种小分子还可以穿透血脑屏障，因此他们就将其用于脑瘤开发。适应症也因此选择了脑瘤中占据不小比例的胶质母细胞瘤（GBM）作为适应症，但临床最终失败，并没能改善患者的无进展生存期（PFS）。好在天无绝人之路。在这项试验的两个GBM组中，四名偶然入选的H3K27M突变患者中有两名表现出多处病变的持续消退。后续的多项在H3K27M突变患者中的临床轶事和肿瘤消退也证明了其疗效。这就使得研究人员将注意力转移到H3K27M突变上。而刚好H3K27M突变DMG肿瘤细胞侵袭性更高，具有更差的预后。因此研究人员就将适应症开发集中在了H3K27M突变DMG上。而DMG上的临床开发也并没有辜负他们的期待，ONC201单药治疗H3K27M-DMG患者展现出相当有希望的疗效，在非复发患者中已经超过了化疗的金标准——ONC201治疗患者的诊断中位OS为21.7月，而外部化疗对照组仅为12个月。近期，发表于Journal of Clinical Oncology为ONC-201补充了在复发H3K27M-DMG患者的初步疗效，其机制此前也得到了阐述。ONC-201作为多巴胺受体抑制剂之外的额外作用，它可以过度激活ClpP，导致线粒体蛋白质组成分的选择性降解，并随后激活整合的应激反应和细胞凋亡，最终造成线粒体降解来实现靶向H3K27M突变蛋白质的方式诱导肿瘤细胞凋亡。GD2-CAR-TGD2-CAR-T同样是H3K27M突变DMG的可能解决方案，二硫根神经节苷脂（GD2）是一种二唾液酸神经节苷脂，主要在神经母细胞瘤、黑素瘤、骨肉瘤、肺癌和乳腺癌等肿瘤中高表达。通过调控MAPK、PI3K/Akt和FAK/paxillin等信号通路，能够促进肿瘤细胞增殖、迁移，维持肿瘤干性，以及促进化疗耐药等。而这种蛋白同时高表达于H3K27M突变的癌细胞，所以GD2-CAR-T也可以用于针对这种疾病，不过与ONC-201不同的是，这毕竟是一种CAR-T，脑内用药副作用和风险有些大。因此目前的临床主要用于儿童和青壮年脑桥和脊髓DMG患者，而丘脑或小脑肿瘤患者就会被排除入组，因为这些位置过于关键，具有极大风险。2022年披露的一项临床结果表明，4例患者中有3例表现出临床和影像学改善，患者神经细胞有所改善。该研究主要展现了临床转化过程中应对炎症等CAR-T副作用的相关处理方式。目前仍然在伦敦大学和斯坦福大学等几个机构中探索最佳剂量、途径和方案，并确定GD2-CAR T细胞疗法在H3K27M + DMG患者中的疗效。总结总的来说，目前较为有希望的治疗方案主要是ONC-201和GD2-CAR-T，其他治疗方案如溶瘤病毒，ADC，BBB穿梭肽，TILs，抗体等方式大多位于临床早期或临床前研究。在我国人口基数巨大的情况下，可以期待该领域药物的开发能够为患者带来更多机遇。参考来源：1.Venneti S, Kawakibi AR, Ji S, Waszak SM, Sweha SR, Mota M, Pun M, Deogharkar A, Chung C, Tarapore RS, Ramage S, Chi A, Wen PY, Arrillaga-Romany I, Batchelor TT, Butowski NA, Sumrall A, Shonka N, Harrison RA, de Groot J, Mehta M, Hall MD, Daghistani D, Cloughesy TF, Ellingson BM, Beccaria K, Varlet P, Kim MM, Umemura Y, Garton H, Franson A, Schwartz J, Jain R, Kachman M, Baum H, Burant CF, Mottl SL, Cartaxo RT, John V, Messinger D, Qin T, Peterson E, Sajjakulnukit P, Ravi K, Waugh A, Walling D, Ding Y, Xia Z, Schwendeman A, Hawes D, Yang F, Judkins AR, Wahl D, Lyssiotis CA, de la Nava D, Alonso MM, Eze A, Spitzer J, Schmidt SV, Duchatel RJ, Dun MD, Cain JE, Jiang L, Stopka SA, Baquer G, Regan MS, Filbin MG, Agar NYR, Zhao L, Kumar-Sinha C, Mody R, Chinnaiyan A, Kurokawa R, Pratt D, Yadav VN, Grill J, Kline C, Mueller S, Resnick A, Nazarian J, Allen JE, Odia Y, Gardner SL, Koschmann C. Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways. Cancer Discov. 2023 Nov 1;13(11):2370-2393. doi: 10.1158/2159-8290.CD-23-0131.2.Isabel Arrillaga-Romany et al, ONC201 (Dordaviprone) in Recurrent H3 K27M–Mutant Diffuse Midline Glioma, Journal of Clinical Oncology (2024). DOI: 10.1200/JCO.23.011343.Miguel Llordes G, Medina Pérez VM, Curto Simón B, Castells-Yus I, Vázquez Sufuentes S, Schuhmacher AJ. Epidemiology, Diagnostic Strategies, and Therapeutic Advances in Diffuse Midline Glioma. J Clin Med. 2023 Aug 12;12(16):5261. doi: 10.3390/jcm12165261.

免疫疗法细胞疗法临床研究

2023-09-21

·Science Daily

Mutation-specific peptide vaccine against midline gliomas used in patients

Tumor vaccines can help the body fight cancer. These vaccines alert the patient's immune system to proteins that are carrying cancer-typical alterations. Physicians and cancer researchers have now treated adult patients with advanced midline gliomas, difficult-to-treat brain tumors, with a peptide vaccine for the first time. The vaccine mimicked a mutational change in a histone protein typical of this type of cancer. The vaccine proved to be safe and induced the desired immune responses directed against the brain tumor. Tumor vaccines can help the body fight cancer. These vaccines alert the patient's immune system to proteins that are carrying cancer-typical alterations. Physicians and cancer researchers from Heidelberg and Mannheim have now treated adult patients with advanced midline gliomas, difficult-to-treat brain tumors, with a peptide vaccine for the first time. The vaccine mimicked a mutational change in a histone protein typical of this type of cancer. The vaccine proved to be safe and induced the desired immune responses directed against the brain tumor. Crucial for the success of cancer vaccinations are protein structures by which the immune cells can recognize the cancer -- and which are not present (or only to a small extent) on healthy cells. Mutations in the tumor genome often lead to protein structures that are altered in a way typical of cancer. Diffuse midline gliomas are among the most aggressive brain tumors. They usually occur in children and young adults near the brain stem and are therefore difficult to access surgically. Chemotherapy or radiation therapy also have limited effectiveness. In this type of cancer, mutations characteristically occur in the gene encoding histone H3 (H3K27M), a packaging protein of DNA. The mutation gives rise to a novel protein structure -- a so-called neoepitope -- that can be recognized as foreign by the patient's immune system. "Such mutations, which occur in identical form in many patients, are rare in cancer. They literally lend themselves to the development of tumor vaccines because they occur in all cancer cells, since the mutated histone is causative for the development of midline gliomas. This means that vaccination against the mutated protein gets to the root of the problem," explains Michael Platten, Director of the Department of Neurology at the University Medical Center Mannheim and Head of Department at the German Cancer Research Center (DKFZ). The researchers led by Katharina Sahm and Michael Platten synthetically reconstructed the section of the histone H3 protein with the characteristic mutation. Using this peptide, they were able to curb the growth of H3K27M-mutated tumors in a mouse model. Encouraged by the results, the team decided to test the mutation-specific vaccine produced at the University of Tübingen in patients in a phase I-trial*, which is still ongoing. In parallel, the physicians, together with colleagues from Munich, Berlin, Bonn and Münster, treated eight adult patients with the peptide vaccine in time-limited individual curative trials. These patients, who could not be enrolled in the trial protocol, suffered from diffuse midline gliomas with H3K27M mutation that progressed after standard therapy. Some of the affected individuals received therapy with immune checkpoint inhibitors in addition to tumor vaccination. No serious side effects were observed in any of the vaccinated patients. Five of the eight treated patients developed specific immune responses against the mutant protein, which were dominated by CD4 T-helper cells. In one of the patients who had shown a strong immune response, the tumor regressed completely and she remained tumor-free for 31 months. The vaccine peptide, which is comparatively long at 27 amino acids, worked in patients with different HLA variants. HLA proteins are responsible for the presentation of the mutant peptide on the cell surface and differ from person to person depending on their genetic background. Supported by the HI-TRON Mainz -- Helmholtz Institute of the DKFZ, the researchers also observed that immune responses decreased over time, so repeated administration of the vaccine could support a sustained effect. "We cannot make any further statements about the efficacy of the vaccination based on these treatments. In any case, the current study has given us valuable information that will help us to further optimize the development of brain tumor vaccines in the future," explains the study's senior author Katharina Sahm, senior physician at the Neurological University Hospital Mannheim and DKFZ researcher. A phase I-trial is currently underway to test the vaccine against the H3K27M mutation in patients with newly diagnosed midline gliomas. Evaluation is expected to begin around 2025. The project was funded by the Translational Oncology funding program of German Cancer Aid (Deutsche Krebshilfe). * INTERCEPT-H3 trial:

疫苗临床结果免疫疗法临床1期