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  • 1
    Online Resource
    Online Resource
    Molecular profiling-based decision for targeted therapies in IDH wild-type glioblastoma
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Advances Vol. 2, No. 1 ( 2020-01-01)
    Details
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 2, No. 1 ( 2020-01-01)
    Abstract: Molecular profiling allows tumor classification as well as assessment of diagnostic, prognostic, and treatment-related molecular changes. Translation into clinical practice and relevance for patients has not been demonstrated yet. Methods We analyzed clinical and molecular data of isocitrate dehydrogenase wild-type glioblastoma patients with sufficient clinical follow-up from the Heidelberg Neuro-Oncology Center and with molecular analysis of tumor tissue that consisted of DNA methylation array data, genome-scale copy number variations, gene panel sequencing, and partly mTOR immunohistochemistry between October 2014 and April 2018. Results Of 536 patients screened, molecular assessment was performed in 253 patients (47%) in a prospective routine clinical setting with further clinical appointments. Therapy decision was directly based on the molecular assessment in 97 (38%) patients. Of these, genetic information from MGMT (n = 68), EGFR (n = 7), CDKN2A/B (n = 8), alterations of the PI3K–AKT–mTOR pathway (n = 5), and BRAF (n = 3) have been the most frequently used for decision making with a positive overall survival signal for patients with glioblastoma harboring an unmethylated MGMT promoter treated according to the molecular assignment. Based on detected molecular alterations and possible targeted therapies, we generated an automated web-based prioritization algorithm. Conclusion Molecular decision making in clinical practice was mainly driven by MGMT promoter status in elderly patients and study inclusion criteria. A reasonable number of patients have been treated based on other molecular aberrations. This study prepares for complex molecular decisions in a routine clinical decision making.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdz060
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 3009682-0
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  • 2
    Online Resource
    Online Resource
    Clinical Effectiveness of Newborn Screening for Spinal Muscular Atrophy : A Nonrandomized Controlled Trial
    American Medical Association (AMA) ; 2024
    In:  JAMA Pediatrics Vol. 178, No. 6 ( 2024-06-01), p. 540-
    Details
    In: JAMA Pediatrics, American Medical Association (AMA), Vol. 178, No. 6 ( 2024-06-01), p. 540-
    Abstract: There is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking. Objective To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset. Design, Setting, and Participants This nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months. Exposure Patients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system. Main Outcomes The primary end point was the achievement of motor milestones. Results A total of 234 children (123 [52.6%] female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%). Conclusions and Relevance This nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group. Trial Registration German Clinical Trials Register: DRKS00012699
    Type of Medium: Online Resource
    ISSN: 2168-6203
    URL: Article
    DOI: 10.1001/jamapediatrics.2024.0492
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2024
    detail.hit.zdb_id: 2701223-2
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  • 3
    Online Resource
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    Bevacizumab Alone or in Combination with Irinotecan in Recurrent WHO Grade II and Grade III Gliomas
    S. Karger AG ; 2013
    In:  European Neurology Vol. 69, No. 2 ( 2013), p. 95-101
    Details
    In: European Neurology, S. Karger AG, Vol. 69, No. 2 ( 2013), p. 95-101
    Abstract: 〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 The repertoire of salvage regimens for patients with WHO grade II and III gliomas recurring or progressing after surgery, radiotherapy and temozolomide chemotherapy is limited. Based on promising response and progression-free survival (PFS) data in recurrent glioblastoma, the use of bevacizumab (BEV) has been extended to recurrent grade II/III gliomas. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 We retrospectively assessed the safety and efficacy of BEV alone or combined with irinotecan in 39 patients with recurrent grade II/III gliomas. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Both BEV monotherapy and its combination with irinotecan were well tolerated. Response rates were 26% as monotherapy and 33% in combination using Macdonald and RANO criteria. The median PFS was 4.2 months and the PFS rate at 6 months 29% for BEV alone, and 4.7 months and 42% for the combination. The median overall survival was 14.8 months for BEV monotherapy and 8.1 months for the combination. Outcome after failure of BEV was better when patients continued BEV beyond progression. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 BEV has limited activity in recurrent grade II/III gliomas. The additional value of irinotecan remains questionable. Prospective studies with BEV-free control groups are required to better define the role of BEV among the limited options in patients with recurrent grade II/III gliomas.
    Type of Medium: Online Resource
    ISSN: 0014-3022 , 1421-9913
    URL: Article
    DOI: 10.1159/000343811
    RVK:
    XA 10000
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2013
    detail.hit.zdb_id: 209426-5
    detail.hit.zdb_id: 1482237-4
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  • 4
    Online Resource
    Online Resource
    Nonmeasurable Speckled Contrast-Enhancing Lesions Appearing During Course of Disease Are Associated With IDH Mutation in High-Grade Astrocytoma Patients
    Elsevier BV ; 2018
    In:  International Journal of Radiation Oncology*Biology*Physics Vol. 102, No. 5 ( 2018-12), p. 1472-1480
    Details
    In: International Journal of Radiation Oncology*Biology*Physics, Elsevier BV, Vol. 102, No. 5 ( 2018-12), p. 1472-1480
    Type of Medium: Online Resource
    ISSN: 0360-3016
    URL: Article
    DOI: 10.1016/j.ijrobp.2018.07.2004
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
    detail.hit.zdb_id: 197614-X
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  • 5
    Online Resource
    Online Resource
    AMPLIFY-NEOVAC: a randomized, 3-arm multicenter phase I trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with an immune checkpoint inhibitor targeting programmed death-ligand 1 in isocitrate dehydrogenase 1 mutant gliomas
    Springer Science and Business Media LLC ; 2022
    In:  Neurological Research and Practice Vol. 4, No. 1 ( 2022-12)
    Details
    In: Neurological Research and Practice, Springer Science and Business Media LLC, Vol. 4, No. 1 ( 2022-12)
    Abstract: Isocitrate dehydrogenase (IDH) mutations are disease-defining mutations in IDH-mutant astrocytomas and IDH-mutant and 1p/19q-codeleted oligodendrogliomas. In more than 80% of these tumors, point mutations in IDH type 1 (IDH1) lead to expression of the tumor-specific protein IDH1R132H. IDH1R132H harbors a major histocompatibility complex class II (MHCII)-restricted neoantigen that was safely and successfully targeted in a first-in human clinical phase 1 trial evaluating an IDH1R132H 20-mer peptide vaccine (IDH1-vac) in newly diagnosed astrocytomas concomitant to standard of care (SOC). Methods AMPLIFY-NEOVAC is a randomized, 3-arm, window-of-opportunity, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with avelumab (AVE), an immune checkpoint inhibitor (ICI) targeting programmed death-ligand 1 (PD-L1). The target population includes patients with resectable IDH1R132H-mutant recurrent astrocytoma or oligodendroglioma after SOC. Neoadjuvant and adjuvant immunotherapy will be administered to 48 evaluable patients. In arm 1, 12 patients will receive IDH1-vac; in arm 2, 12 patients will receive the combination of IDH1-vac and AVE, and in arm 3, 24 patients will receive AVE only. Until disease progression according to immunotherapy response assessment for neuro-oncology (iRANO) criteria, treatment will be administered over a period of maximum 43 weeks (primary treatment phase) followed by facultative maintenance treatment. Perspective IDH1R132H 20-mer peptide is a shared clonal driver mutation-derived neoepitope in diffuse gliomas. IDH1-vac safely targets IDH1R132H in newly diagnosed astrocytomas. AMPLIFY-NEOVAC aims at (1) demonstrating safety of enhanced peripheral IDH1-vac-induced T cell responses by combined therapy with AVE compared to IDH1-vac only and (2) investigating intra-glioma abundance and phenotypes of IDH1-vac induced T cells in exploratory post-treatment tissue analyses. In an exploratory analysis, both will be correlated with clinical outcome. Trial registration NCT03893903.
    Type of Medium: Online Resource
    ISSN: 2524-3489
    URL: Article
    DOI: 10.1186/s42466-022-00184-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2947493-0
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  • 6
    Online Resource
    Online Resource
    INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomas
    Springer Science and Business Media LLC ; 2023
    In:  Neurological Research and Practice Vol. 5, No. 1 ( 2023-10-19)
    Details
    In: Neurological Research and Practice, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2023-10-19)
    Abstract: Diffuse midline gliomas (DMG) are universally lethal central nervous system tumors that carry almost unanimously the clonal driver mutation histone-3 K27M (H3K27M). The single amino acid substitution of lysine to methionine harbors a neoantigen that is presented in tumor tissue. The long peptide vaccine H3K27M-vac targeting this major histocompatibility complex class II (MHC class II)-restricted neoantigen induces mutation-specific immune responses that suppress the growth of H3K27M + flank tumors in an MHC-humanized rodent model. Methods INTERCEPT H3 is a non-controlled open label, single arm, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of H3K27M-vac in combination with standard radiotherapy and the immune checkpoint inhibitor atezolizumab (ATE). 15 adult patients with newly diagnosed K27M-mutant histone-3.1 (H3.1K27M) or histone-3.3 (H3.3K27M) DMG will be enrolled in this trial. The 27mer peptide vaccine H3K27M-vac will be administered concomitantly to standard radiotherapy (RT) followed by combinatorial treatment with the programmed death‐ligand 1 (PD-L1) targeting antibody ATE. The first three vaccines will be administered bi-weekly (q2w) followed by a dose at the beginning of recovery after RT and six-weekly administrations of doses 5 to 11 thereafter. In a safety lead-in, the first three patients (pts. 1–3) will be enrolled sequentially. Perspective H3K27M-vac is a neoepitope targeting long peptide vaccine derived from the clonal driver mutation H3K27M in DMG. The INTERCEPT H3 trial aims at demonstrating (1) safety and (2) immunogenicity of repeated fixed dose vaccinations of H3K27M-vac administered with RT and ATE in adult patients with newly diagnosed H3K27M-mutant DMG. Trial registration NCT04808245.
    Type of Medium: Online Resource
    ISSN: 2524-3489
    URL: Article
    DOI: 10.1186/s42466-023-00282-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2947493-0
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  • 7
    Online Resource
    Online Resource
    Prophylactic anticoagulation in patients with glioblastoma or brain metastases and atrial fibrillation: an increased risk for intracranial hemorrhage?
    Springer Science and Business Media LLC ; 2021
    In:  Journal of Neuro-Oncology Vol. 152, No. 3 ( 2021-05), p. 483-490
    Details
    In: Journal of Neuro-Oncology, Springer Science and Business Media LLC, Vol. 152, No. 3 ( 2021-05), p. 483-490
    Abstract: Patients with glioblastoma (GBM) or brain metastases (MET) and atrial fibrillation (AF) might be at an increased risk of intracranial hemorrhage (ICH) due to anticoagulation (AC). Our aim was to assess this risk. Methods Our institution’s database (from 2005 to 2017) was screened for patients with GBM or MET and AF with an indication for AC according to their CHA 2 DS 2 VASc stroke risk score (≥ 2). Required follow-up was at least 3 months. AC was either performed with heparins, phenprocoumon or non-Vitamin K antagonist oral anticoagulants. Applying the propensity score approach, patient cohorts (matched according to primary tumor, age, sex) were generated (GBM [or MET] with AF ± AC, GBM [or MET] without AF/AC, no GBM [or MET] but AF on AC). ICH was defined as clinical det erioration caused by new blood on imaging. A log rank test was performed to compare the risk for ICH between the three groups. Results In total, 104 patients were identified of which 49 with GBM (37% on AC) and 37 with MET (46% on AC) were successfully matched. Median follow up was 8.6 and 7.2 months, respectively. ICH occurred in 10.2% of GBM + AF and 12.2% GBM-AF, whereas 8% of patients with AF on AC suffered ICH (p = 0.076). 13.5% of patients with MET + AF had ICHs, in the controls it was 16% for MET-AF and 8% for AF on AC (p = 0.11). Conclusion AC did not seem to influence the incidence of ICH in patients with glioblastoma or brain metastases within follow up of just under 9 months.
    Type of Medium: Online Resource
    ISSN: 0167-594X , 1573-7373
    URL: Article
    DOI: 10.1007/s11060-021-03716-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 604875-4
    detail.hit.zdb_id: 2007293-4
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  • 8
    Online Resource
    Online Resource
    RADT-40. FINAL RESULTS OF THE PROSPECTIVE PHASE 2 MARCIE TRIAL: EFFICACY AND TOXICITY OF POSTOPERATIVE BIMODAL RADIOTHERAPY WITH C12-BOOST IN PATIENTS WITH ATYPICAL MENINGIOMAS FOLLOWING SUBTOTAL RESECTION
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_5 ( 2023-11-10), p. v57-v58
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_5 ( 2023-11-10), p. v57-v58
    Abstract: Radiotherapy is recommended by current EANO guidelines for patients with atypical meningiomas (WHO grade 2) following subtotal resection. While meningiomas are generally considered radioresistant, novel radiotherapeutic modalities using carbon ions present an increased relative biological effectiveness (RBE) compared to photons, while reducing the radiation exposure for adjacent organs at risk by exploiting the Bragg peak. Our prospective phase 2 trial investigated bimodal radiotherapy using a carbon-ion boost in patients with atypical meningiomas following subtotal resection. A total of 33 patients were enrolled from 07/2012 until 07/2020. The study was prematurely terminated in 07/2020 after recruiting 33 of the initially planned 40 patients due to one grade 5 toxicity. Study treatment comprised a carbon ion boost (18 Gy [RBE] in 6 fractions) targeted to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was progression-free survival, and secondary endpoints included overall survival, safety and toxicities. With a median follow-up of 42 months, the 3-year estimates of progression-free survival (PFS), local PFS and overall survival were 80.3%, 86.7% and 89.8%, respectively. Radiation-induced contrast enhancements (RICE) was encountered in 45%, particularly in cases of periventricularly-located meningiomas. Patients exhibiting (transient) RICE were either asymptomatic (40%) or presented immediate improvement (47%) after the administration of corticosteroids or/and bevacizumab. Treatment-associated complications were encountered in 2 patients with radiation necrosis: 1 patient died due to postoperative complications in an external center after resection of radiation necrosis, and the other received an aggregated 21 cycles of bevacizumab. As a result, the study was prematurely terminated. Post-hoc integrated molecular-morphologic scoring identified patients at risk of tumor progression. Study treatment may be considered for selected patients with molecular high-risk meningiomas to achieve high tumor control rates. Patients’ risk to develop radiation-induced side effects depends on the location of the treatment volume.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad179.0229
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2028601-6
    detail.hit.zdb_id: 2094060-9
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  • 9
    Online Resource
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    RADT-34. ANALYSIS OF A METHYLATION CLASS-GUIDED RADIOTHERAPY IN MENINGIOMA PATIENTS - AND THE PROSPECTIVE PHASE II MARCIE TRIAL WITH CARBON-ION BOOST RADIOTHERAPY
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii57-vii57
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii57-vii57
    Abstract: Meningiomas represent the most common primary brain tumor type, with a recurrence rate of approximately 20% following resection. Classification by molecular classes was demonstrated to be more accurate in identifying patients at high risk of disease progression in meningiomas, compared to WHO grading only. Novel radiotherapeutic modalities using protons or carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, enabling a higher local dose deposition while reducing the radiation dose for organs of risks. The prospective single-arm phase II - MARCIE trial investigated a bimodal radiotherapy using photons (50 Gy in 25 fractions) and a carbon-ions boost with 18 Gy (RBE) in 6 fractions. Local progression-free survival after 3 years was defined as primary endpoint. In total, 33 patients were recruited before termination of the trial. After 3 years, local progression free survival was estimated at 94.7% and overall survival at 89.8%. Serious adverse events in the form of radiation necrosis were observed in 3 cases, requiring a subsequent treatment with bevacizumab. Post-hoc DNA methylation profiling revealed that relapses occur more frequently in high-risk meningiomas following radiotherapy, compared to the intermediate risk-group, confirming the prognostic relevance of the methylation-based meningioma classifier.Subsequently, a retrospective matched-pair analysis was performed to compare irradiated (n & gt; 100) and non-irradiated meningiomas, stratified into the molecular risk groups (ben, int, high). The clinical benefit of postoperative radiotherapy and dose escalation with regard to the local control are currently being assessed for the respective molecular meningioma classes. Postoperative, bimodal radiotherapy with carbon-ion boost represent an auspicious treatment modality with an excellent local tumor control following resection. Molecular risk stratification is crucial in identifying patients who might benefit from postoperative radiotherapy.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.224
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2028601-6
    detail.hit.zdb_id: 2094060-9
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  • 10
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    Efficacy and toxicity of bimodal radiotherapy in WHO grade 2 meningiomas following subtotal resection with carbon ion boost: Prospective phase 2 MARCIE trial
    Oxford University Press (OUP) ; 2024
    In:  Neuro-Oncology Vol. 26, No. 4 ( 2024-04-05), p. 701-712
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 26, No. 4 ( 2024-04-05), p. 701-712
    Abstract: Novel radiotherapeutic modalities using carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, delivering a higher biological dose while reducing radiation exposure for adjacent organs. This prospective phase 2 trial investigated bimodal radiotherapy using photons with carbon-ion (C12)-boost in patients with WHO grade 2 meningiomas following subtotal resection (Simpson grade 4 or 5). Methods A total of 33 patients were enrolled from July 2012 until July 2020. The study treatment comprised a C12-boost (18 Gy [RBE] in 6 fractions) applied to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was the 3-year progression-free survival (PFS), and the secondary endpoints included overall survival, safety and treatment toxicities. Results With a median follow-up of 42 months, the 3-year estimates of PFS, local PFS and overall survival were 80.3%, 86.7%, and 89.8%, respectively. Radiation-induced contrast enhancement (RICE) was encountered in 45%, particularly in patients with periventricularly located meningiomas. Patients exhibiting RICE were mostly either asymptomatic (40%) or presented immediate neurological and radiological improvement (47%) after the administration of corticosteroids or bevacizumab in case of radiation necrosis (3/33). Treatment-associated complications occurred in 1 patient with radiation necrosis who died due to postoperative complications after resection of radiation necrosis. The study was prematurely terminated after recruiting 33 of the planned 40 patients. Conclusions Our study demonstrates a bimodal approach utilizing photons with C12-boost may achieve a superior local PFS to conventional photon RT, but must be balanced against the potential risks of toxicities.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad244
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
    detail.hit.zdb_id: 2028601-6
    detail.hit.zdb_id: 2094060-9
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