Development of Randomized Trials in Adults with Medulloblastoma—The Example of EORTC 1634-BTG/NOA-23

From MDPI via Jisc Publications RouterHistory: accepted 2021-07-08, pub-electronic 2021-07-09Publication status: PublishedFunder: Deutsche Krebshilfe; Grant(s): 70113453Funder: Cancer Australia; Grant(s): 1165910Funder: CanTeen; Grant(s): noneFunder: KWF Kankerbestrijding; Grant(s): 2021-1/13555Funder: Ministère des Affaires Sociales et de la Santé; Grant(s): PHRC-K20-179Funder: Swiss Brain Tumor Foundation; Grant(s): none, none, noneMedulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials

Bevacizumab and radiotherapy for the treatment of glioblastoma: brothers in arms or unholy alliance?

Glioblastoma (GBM) represents the most frequent primary brain tumor in adults and carries a dismal prognosis despite aggressive, multimodal treatment regimens involving maximal resection, radiochemotherapy, and maintenance chemotherapy. Histologically, GBMs are characterized by a high degree of VEGF-mediated vascular proliferation. In consequence, new targeted anti-angiogenic therapies, such as the monoclonal anti-VEGF-A antibody bevacizumab, have proven effective in attenuating tumor (neo) angiogenesis and were shown to possess therapeutic activity in several phase II trials. However, the role of bevacizumab in the context of multimodal therapy approaches appears to be rather complex. This review will give insights into current concepts, limitations, and controversies regarding the molecular mechanisms and the clinical benefits of bevacizumab treatment in combination with radio(chemo) therapy - particularly in face of the results of recent phase III trials, which failed to demonstrate convincing improvements in overall survival (OS)

The acute superficial siderosis syndrome — clinical entity, imaging findings, and histopathology

Superficial siderosis is a consequence of repetitive bleeding into the subarachnoid space, leading to toxic iron and hemosiderin deposits on the surface of the brain and spine. The clinical and radiological phenotypes of superficial siderosis are known to manifest over long time intervals. In contrast, this study defines the “acute superficial siderosis syndrome” and illustrates typical imaging and histopathological findings of this entity. We describe the case of a 61-year-old male patient who was diagnosed with a melanoma metastasis in the right frontal cortex in February 2019. Within a few weeks he developed a progressive syndrome characterized by cerebellar ataxia, gait disturbance, signs of myelopathy, and radiculopathy. MRI revealed ongoing hemorrhage from the metastasis into the lateral ventricle and the subarachnoid space. A semiquantitative assessment of three subsequent MRI within an 8-week period documented the rapid development of superficial siderosis along the surface of the cerebellum, the brain stem, and the lower parts of the supratentorial regions on T2*-weighted sequences. The diagnosis of a superficial siderosis was histopathologically confirmed by identifying iron and hemosiderin deposits on the cortex along with astrogliosis. The recognition of this “acute superficial siderosis syndrome” triggered surgical removal of the hemorrhagic metastasis. Based on a single case presentation, we define the “acute superficial siderosis syndrome” as a clinical entity and describe the radiological and histopathological characteristics of this entity. Early recognition of this syndrome may allow timely elimination of the bleeding source, in order to prevent further clinical deterioration

Automatic identification of atypical clinical fMRI results (Aug, 10.1007/s00234-020-02510-z, 2020): Automatic identification of atypical clinical fMRI results (Neuroradiology, (2020), 62, 12, (1677-1688), 10.1007/s00234-020-02510-z)

The above article was published online with an incorrect affiliation

Automatic identification of atypical clinical fMRI results

Purpose Functional MRI is not routinely used for neurosurgical planning despite potential important advantages, due to difficulty of determining quality. We introduce a novel method for objective evaluation of fMRI scan quality, based on activation maps. A template matching analysis (TMA) is presented and tested on data from two clinical fMRI protocols, performed by healthy controls in seven clinical centers. Preliminary clinical utility is tested with data from low-grade glioma patients. Methods Data were collected from 42 healthy subjects from seven centers, with standardized finger tapping (FT) and verb generation (VG) tasks. Copies of these "typical" data were deliberately analyzed incorrectly to assess feasibility of identifying them as "atypical." Analyses of the VG task administered to 32 tumor patients assessed sensitivity of the TMA method to anatomical abnormalities. Results TMA identified all atypical activity maps for both tasks, at the cost of incorrectly classifying 3.6 (VG)-6.5% (FT) of typical maps as atypical. For patients, the average TMA was significantly higher than atypical healthy scans, despite localized anatomical abnormalities caused by a tumor. Conclusion This study supports feasibility of TMA for objective identification of atypical activation patterns for motor and verb generation fMRI protocols. TMA can facilitate the use and evaluation of clinical fMRI in hospital settings that have limited access to fMRI experts. In a clinical setting, this method could be applied to automatically flag fMRI scans showing atypical activation patterns for further investigation to determine whether atypicality is caused by poor scan data quality or abnormal functional topography

Short-term fasting in glioma patients: analysis of diet diaries and metabolic parameters of the ERGO2 trial

Purpose: The prospective, randomized ERGO2 trial investigated the effect of calorie-restricted ketogenic diet and intermittent fasting (KD-IF) on re-irradiation for recurrent brain tumors. The study did not meet its primary endpoint of improved progression-free survival in comparison to standard diet (SD). We here report the results of the quality of life/neurocognition and a detailed analysis of the diet diaries. Methods: 50 patients were randomized 1:1 to re-irradiation combined with either SD or KD-IF. The KD-IF schedule included 3 days of ketogenic diet (KD: 21–23 kcal/kg/d, carbohydrate intake limited to 50 g/d), followed by 3 days of fasting and again 3 days of KD. Follow-up included examination of cognition, quality of life and serum samples. Results: The 20 patients who completed KD-IF met the prespecified goals for calorie and carbohydrate restriction. Substantial decreases in leptin and insulin and an increase in uric acid were observed. The SD group, of note, had a lower calorie intake than expected (21 kcal/kg/d instead of 30 kcal/kg/d). Neither quality of life nor cognition were affected by the diet. Low glucose emerged as a significant prognostic parameter in a best responder analysis. Conclusion: The strict caloric goals of the ERGO2 trial were tolerated well by patients with recurrent brain cancer. The short diet schedule led to significant metabolic changes with low glucose emerging as a candidate marker of better prognosis. The unexpected lower calorie intake of the control group complicates the interpretation of the results. Clinicaltrials.gov number: NCT01754350; Registration: 21.12.2012

Erratum to: Gliomatosis cerebri: no evidence for a separate brain tumor entity

Erratum to: Acta Neuropathol DOI 10.1007/s00401‑015‑1495‑z. The original version of this article contained errors in the alignment of several entries in Tables 4 and 5. The corrected Tables 4 and 5 are given below. The original article has been updated accordingly

Gliomatosis cerebri: no evidence for a separate brain tumor entity

Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification