Proteomic profiling of cerebrospinal fluid reveals TKT as a potential biomarker for medulloblastoma.

Cerebrospinal fluid (CSF) plays an important role in brain tumors, including medulloblastoma (MBL). Recent advancements in mass spectrometry systems and 'Omics' data analysis methods enable unbiased, high proteome depth research. We conducted proteomic profiling of the total CSF in MBL patients with the purpose of finding a potential diagnostic biomarker for MBL. We quantified 1112 proteins per CSF sample. Feature selection identified four elevated soluble proteins (SPTBN1, HSP90AA1, TKT, and NME1-NME2) in MBL CSF. Validation with ELISA confirmed that TKT was significantly elevated in MBL. Additionally, TKT-positive extracellular vesicles were significantly enriched in MBL CSF and correlated with the burden of leptomeningeal seeding. Our results provide insights into the proteomics data of the total CSF of MBL patients. Furthermore, we identified the significance of TKT within the total CSF and its presence within circulating EVs in the CSF. We suggest that TKT may serve as a biomarker for MBL.

Epigenetic reprogramming enables NF1A/B oncogenic role in SHH medulloblastoma.

In this issue of Developmental Cell, Shiraishi et al. investigate the epigenetic changes occurring during the formation of SHH medulloblastoma and show that an epigenomic shift renders Nuclear Factor I family of transcription factors oncogenic.

Geometric target margin strategy of proton craniospinal irradiation for pediatric medulloblastoma.

In proton craniospinal irradiation (CSI) for skeletally immature pediatric patients, a treatment plan should be developed to ensure that the dose is uniformly delivered to all vertebrae, considering the effects on bone growth balance. The technical (t) clinical target volume (CTV) is conventionally set by manually expanding the CTV from the entire intracranial space and thecal sac, based on the physician's experience. However, there are differences in contouring methods among physicians. Therefore, we aimed to propose a new geometric target margin strategy. Nine pediatric patients with medulloblastoma who underwent proton CSI were enrolled. We measured the following water equivalent lengths for each vertebra in each patient: body surface to the dorsal spinal canal, vertebral limbus, ventral spinal canal and spinous processes. A simulated tCTV (stCTV) was created by assigning geometric margins to the spinal canal using the measurement results such that the vertebral limb and dose distribution coincided with a margin assigned to account for the uncertainty of the proton beam range. The stCTV with a growth factor (correlation between body surface area and age) and tCTV were compared and evaluated. The median values of each index for cervical, thoracic and lumber spine were: the Hausdorff distance, 9.14, 9.84 and 9.77 mm; mean distance-to-agreement, 3.26, 2.65 and 2.64 mm; Dice coefficient, 0.84, 0.81 and 0.82 and Jaccard coefficient, 0.50, 0.60 and 0.62, respectively. The geometric target margin setting method used in this study was useful for creating an stCTV to ensure consistent and uniform planning.

AB026. A rare case report: multiple hemangioblastoma.

BACKGROUND: Hemangioblastomas (HBLs) are uncommon tumors of the central nervous system (CNS), corresponding to 1% to 2.5% of all intracranial tumors. They can present sporadically or in patients with von Hippel-Lindau (VHL) disease along with a variety of benign and malignant tumors, and are most often located in the cerebellum, brainstem, and spinal cord. Although surgical resection is currently considered the main therapeutic option for symptomatic lesions, evidence supporting the application of microsurgery has not been systematically assessed. However, post-operative outcomes can vary depending on factors including disease location, number of lesions, and tumor characteristics that make complete resections difficult. The objective of this case report is to document a rare case of multiple HBL in a 45-year-old man, highlighting the need for further research, the absence of a standardized treatment protocol for appropriate management strategies. CASE DESCRIPTION: A 45-year-old man presented to the outpatient neurology department with a chief complaint of gradual weakness of the left side of his body, walking unsteadily, and seizure. Neurological examination revealed a positive dysmetria sign. According to his medical records, he was diagnosed with multiple HBL since August 2022 and subsequently underwent two times partial tumor resections, and a ventriculoperitoneal (VP)-shunt due to hydrocephalus. The latest magnetic resonance imaging examination shows improvement in the original tumor. He is currently receiving symptomatic therapy with complaints have improved. CONCLUSIONS: This case report highlights a rare occurrence of multiple HBL in a 45-year-old man. Surgical management of HBL was the most common modality and was suggested as an effective and optimal treatment, but the recurrence possibility of the cystic wall tumor must also be considered in the choice of treatment.

AB087. Rectosigmoid approach for cerebellopontine angle tumors: what have we learned so far?

BACKGROUND: The cerebellopontine angle (CPA) is a multifaceted triangular region bordered by the brainstem medially, the cerebellum superiorly and posteriorly, and the temporal bone laterally. Tumors located in the CPA comprise 5% to 10% of all intracranial neoplasms, with vestibular schwannomas being the most prevalent, followed by meningiomas and epidermoid tumors. Various surgical approaches exist for removing these lesions, which consistently present challenges for neurosurgeons in effectively managing them. This study presents a case of a CPA tumor successfully treated via the retrosigmoid approach, followed by an assessment of the approach's efficacy and surgical outcomes. METHODS: A comprehensive literature search was conducted using electronic databases, including PubMed, ScienceDirect, and Google Scholar, to gather studies on surgically managed CPA tumors. In addition to reviewing the literature, we present a case study of a patient with CPA tumor who underwent surgery using the retrosigmoid approach. RESULTS: The literature review revealed that the retrosigmoid approach emerged as a commonly utilized technique, particularly for tumors in the CPA region. Analysis of the collected data indicated that the retrosigmoid approach offers several advantages, including excellent exposure of the CPA, minimal brain retraction, and reduced risk of injury to critical neurovascular structures. Moreover, studies consistently reported favorable surgical outcomes, with low rates of morbidity and mortality associated with this approach. In our case study, we successfully employed the retrosigmoid approach to resect a CPA tumor in a patient presenting with typical symptoms of spasticity in all four extremities and progressive hearing loss. CONCLUSIONS: In conclusion, the retrosigmoid approach remains a valuable surgical technique for the management of CPA tumors. This approach enhances the exposure of the CPA and increases the surgical angle of maneuverability. In most literature, the retrosigmoid approach provides adequate access that is safe and effective, with a low rate of postoperative complications. However, further prospective studies and comparative analyses are warranted to validate these findings and refine surgical techniques for optimizing patient outcomes.

Consensus guidelines for the management of pediatric medulloblastoma in low and middle-income countries.

The management of medulloblastoma, a pediatric brain tumor, has evolved significantly with the advent of genomic subgrouping, yet morbidity and mortality remain high in LMICs like Pakistan due to inadequate multidisciplinary care infrastructure. This paper aims to establish evidence-based guidelines tailored to the constraints of such countries. An expert panel comprising neuro-oncologists, neurosurgeons, radiologists, radiation oncologists, neuropathologists, and pediatricians collaborated to develop these guidelines, considering the specific challenges of pediatric brain tumor care in Pakistan. The recommendations cover various aspects of medulloblastoma treatment, including pre-surgical workup, neurosurgery, neuropathology, chemotherapy, radiation therapy, and supportive care. They offer both minimum required and additional optional protocols for more advanced centers, ensuring comprehensive patient management with attention to complications and complexities encountered in Pakistan. The paper's consensus guidelines strive for uniformity in healthcare delivery and address significant gaps in diagnosis, treatment, and follow-up of pediatric medulloblastoma patients.

Consensus guidelines for the management of posterior fossa tumour for low- and middle-income countries.

The posterior fossa is a limited compartment therefore lesions compressing its structures can result in devastating outcomes. It can cause significant neurological deficit due to mass effect on critical structures and hydrocephalus. Due to the nature of the infratentorial region, urgent surgical intervention is often the first-line option. Surgical neuro-oncologists guide patients and caregivers through the course of this disease and to inform them about the various options for management and long-term outcome optimisation. There is currently conflicting data; however, institutional experiences can guide us towards achieving improvements in surgical outcomes and quality of life. Advances in molecular classifications coupled with highdose radiation treatment improve our capacity for improving overall survival in these patients. Common childhood tumours are ependymomas, medulloblastomas, and juvenile pilocytic astrocytomas, while adults often present with metastases, and less commonly, cerebellar haemangioblastomas and gliomas. This paper outlines management strategies with consideration for multidisciplinary care and resourcelimited settings.

Innovative solutions? Belzutifan therapy for hemangioblastomas in Von Hippel-Lindau disease: A systematic review and single-arm meta-analysis.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder that predisposes patients to develop multiple cysts and tumors, such as hemangioblastomas (HBs) and clear cell renal cell carcinoma (ccRCC), due to mutations in the VHL tumor suppressor gene. While treatment of HBs varies based on their characteristics and has improved patient survival, it still involves high morbidity and mortality, leading to ongoing debates and studies to refine therapy strategies. Recent developments include the emergence of Belzutifan, a novel inhibitor targeting hypoxia-inducible factor 2α (HIF-2α), which has shown promising results in ongoing trials, particularly for patients not immediately requiring surgery. METHODS: This systematic review and meta-analysis aimed to comprehensively evaluate the efficacy and safety of Belzutifan for treating HBs associated with VHL disease. Search was conducted across Medline, Embase, Cochrane, and Web of Science databases. Statistical Analysis was performed, with proportions and 95 % confidence intervals. Statistical analyses were carried out using R Studio. RESULTS: Ten studies were selected, comprising 553 patients. The population mean age was 40 (24-65), and 50 % of the population was formed by males. In terms of proportion, 6 analyses were performed: Disease Stability of 31 % [95 %CI:14 %-47 %; I2 = 2 %]; Disease Progression of 2 %[95 %CI:0 %-9 %; I2 = 0 %]; Partial Response of 75 % [95 %CI:54 %-96 %; I2 = 58 %]. Complete response of 1 % [95 %CI:0 %-7 %; I2 = 0 %];and Side effects, anemia 81 % rate [95 % CI:54 %-100 %; I2 = 94 %], and fatigue rate of 79 % [95 % CI:54 %-100 %;I2 = 94 %]. CONCLUSION: Results indicate that Belzutifan effectively stabilizes disease, reduces tumor progression, and achieves significant therapeutic responses, although side effects like anemia and fatigue were noted.

Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma.

Sonic hedgehog subgroup of medulloblastoma (SHH-MB) is characterized by aberrant activation of the SHH signaling pathway. An inhibition of the positive SHH regulator Smoothened (SMO) has demonstrated promising clinical efficacy. Yet, primary and acquired resistance to SMO inhibitors limit their efficacy. An understanding of underlying molecular mechanisms of resistance to therapy is warranted to bridge this unmet need. Here, we make use of genome-wide CRISPR-Cas9 knockout screens in murine SMB21 and human DAOY cells, in order to unravel genetic dependencies and drug-related genetic interactors that could serve as alternative therapeutic targets for SHH-MB. Our screens reinforce SMB21 cells as a faithful model system for SHH-MB, as opposed to DAOY cells, and identify members of the epigenetic machinery including DNA methyltransferase 1 (DNMT1) as druggable targets in SHH-dependent tumors. We show that Dnmt1 plays a crucial role in normal murine cerebellar development and is required for SHH-MB growth in vivo. Additionally, DNMT1 pharmacological inhibition alone and in combination with SMO inhibition effectively inhibits tumor growth in murine and human SHH-MB cell models and prolongs survival of SHH-MB mouse models by inhibiting SHH signaling output downstream of SMO. In conclusion, our data highlight the potential of inhibiting epigenetic regulators as a novel therapeutic avenue in SMO-inhibitor sensitive as well as resistant SHH-MBs.

nnU-Net-based Segmentation of Tumor Subcompartments in Pediatric Medulloblastoma Using Multiparametric MRI: A Multi-institutional Study.

Purpose To evaluate nnU-Net-based segmentation models for automated delineation of medulloblastoma tumors on multi-institutional MRI scans. Materials and Methods This retrospective study included 78 pediatric patients (52 male, 26 female), with ages ranging from 2 to 18 years, with medulloblastomas, from three different sites (28 from hospital A, 18 from hospital B, and 32 from hospital C), who had data available from three clinical MRI protocols (gadolinium-enhanced T1-weighted, T2-weighted, and fluid-attenuated inversion recovery). The scans were retrospectively collected from the year 2000 until May 2019. Reference standard annotations of the tumor habitat, including enhancing tumor, edema, and cystic core plus nonenhancing tumor subcompartments, were performed by two experienced neuroradiologists. Preprocessing included registration to age-appropriate atlases, skull stripping, bias correction, and intensity matching. The two models were trained as follows: (a) the transfer learning nnU-Net model was pretrained on an adult glioma cohort (n = 484) and fine-tuned on medulloblastoma studies using Models Genesis and (b) the direct deep learning nnU-Net model was trained directly on the medulloblastoma datasets, across fivefold cross-validation. Model robustness was evaluated on the three datasets when using different combinations of training and test sets, with data from two sites at a time used for training and data from the third site used for testing. Results Analysis on the three test sites yielded Dice scores of 0.81, 0.86, and 0.86 and 0.80, 0.86, and 0.85 for tumor habitat; 0.68, 0.84, and 0.77 and 0.67, 0.83, and 0.76 for enhancing tumor; 0.56, 0.71, and 0.69 and 0.56, 0.71, and 0.70 for edema; and 0.32, 0.48, and 0.43 and 0.29, 0.44, and 0.41 for cystic core plus nonenhancing tumor for the transfer learning and direct nnU-Net models, respectively. The models were largely robust to site-specific variations. Conclusion nnU-Net segmentation models hold promise for accurate, robust automated delineation of medulloblastoma tumor subcompartments, potentially leading to more effective radiation therapy planning in pediatric medulloblastoma. Keywords: Pediatrics, MR Imaging, Segmentation, Transfer Learning, Medulloblastoma, nnU-Net, MRI Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Rudie and Correia de Verdier in this issue.

Identification of tumor rejection antigens and the immunologic landscape of medulloblastoma.

BACKGROUND: The current standard of care treatments for medulloblastoma are insufficient as these do not take tumor heterogeneity into account. Newer, safer, patient-specific treatment approaches are required to treat high-risk medulloblastoma patients who are not cured by the standard therapies. Immunotherapy is a promising treatment modality that could be key to improving survival and avoiding morbidity. For an effective immune response, appropriate tumor antigens must be targeted. While medulloblastoma patients with subgroup-specific genetic substitutions have been previously reported, the immunogenicity of these genetic alterations remains unknown. The aim of this study is to identify potential tumor rejection antigens for the development of antigen-directed cellular therapies for medulloblastoma. METHODS: We developed a cancer immunogenomics pipeline and performed a comprehensive analysis of medulloblastoma subgroup-specific transcription profiles (n = 170, 18 WNT, 46 SHH, 41 Group 3, and 65 Group 4 patient tumors) available through International Cancer Genome Consortium (ICGC) and European Genome-Phenome Archive (EGA). We performed in silico antigen prediction across a broad array of antigen classes including neoantigens, tumor-associated antigens (TAAs), and fusion proteins. Furthermore, we evaluated the antigen processing and presentation pathway in tumor cells and the immune infiltrating cell landscape using the latest computational deconvolution methods. RESULTS: Medulloblastoma patients were found to express multiple private and shared immunogenic antigens. The proportion of predicted TAAs was higher than neoantigens and gene fusions for all molecular subgroups, except for sonic hedgehog (SHH), which had a higher neoantigen burden. Importantly, cancer-testis antigens, as well as previously unappreciated neurodevelopmental antigens, were found to be expressed by most patients across all medulloblastoma subgroups. Despite being immunologically cold, medulloblastoma subgroups were found to have distinct immune cell gene signatures. CONCLUSIONS: Using a custom antigen prediction pipeline, we identified potential tumor rejection antigens with important implications for the development of immunotherapy for medulloblastoma.

Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells.

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

Leading medulloblastoma to a differentiation end.

Effective and less toxic therapies for medulloblastoma have proved to be highly elusive. In this issue of Cancer Cell, Yang et al. show that thyroid hormone treatment leads to the activation of neurogenic differentiation factor 1 (NeuroD1) and differentiation of medulloblastoma cells through reversing EZH2-mediated transcriptional repression of NeuroD1.

Acute acquired comitant esotropia associated with Lhermitte-Duclos disease: a case report.

BACKGROUND: Acute acquired comitant esotropia caused by prolonged near work, such as the use of digital devices, has been frequently reported in recent years. However, intracranial examination is necessary even for patients with nonparalytic comitant esotropia. Lhermitte-Duclos disease is a rare tumor that grows in layers in the cerebellum. Among those with this disease, cases of esotropia have been reported due to abduction limitation of the eye, but there have been no reports of comitant esotropia. Here, we report the case of a young woman with acute acquired comitant esotropia who was found to have Lhermitte-Duclos disease. CASE PRESENTATION: A 16-year-old Japanese female patient, whose ethnicity was Asian, was referred to our hospital for acute acquired comitant esotropia. Fundus examination revealed papilledema in both eyes, and magnetic resonance imaging of the head revealed a cerebellar tumor in the right cerebellum with obstructive hydrocephalus. She underwent partial tumor resection, and a histopathological diagnosis of Lhermitte-Duclos disease was obtained. However, comitant esotropia status remained unchanged, and she underwent strabismus surgery. Finally, diplopia disappeared completely. CONCLUSION: Neurological and intracranial imaging examinations are essential when acute acquired comitant esotropia is observed. Acute acquired comitant esotropia by Lhermitte-Duclos disease did not improve with partial tumor resection and required strabismus surgery, but good surgical results were obtained.

Systematic transcriptomic analysis of childhood medulloblastoma identifies N6-methyladenosine-dependent lncRNA signatures associated with molecular subtype, immune cell infiltration, and prognosis.

Medulloblastoma, the most common malignant pediatric brain tumor, is classified into four main molecular subgroups, but group 3 and group 4 tumors are difficult to subclassify and have a poor prognosis. Rapid point-of-care diagnostic and prognostic assays are needed to improve medulloblastoma risk stratification and management. N6-methyladenosine (m6A) is a common RNA modification and long non-coding RNAs (lncRNAs) play a central role in tumor progression, but their impact on gene expression and associated clinical outcomes in medulloblastoma are unknown. Here we analyzed 469 medulloblastoma tumor transcriptomes to identify lncRNAs co-expressed with m6A regulators. Using LASSO-Cox analysis, we identified a five-gene m6A-associated lncRNA signature (M6LSig) significantly associated with overall survival, which was combined in a prognostic clinical nomogram. Using expression of the 67 m6A-associated lncRNAs, a subgroup classification model was generated using the XGBoost machine learning algorithm, which had a classification accuracy > 90%, including for group 3 and 4 samples. All M6LSig genes were significantly correlated with at least one immune cell type abundance in the tumor microenvironment, and the risk score was positively correlated with CD4+ naïve T cell abundance and negatively correlated with follicular helper T cells and eosinophils. Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings.

The predictive value of intraoperative facial motor evoked potentials in cerebellopontine angle tumor surgery.

OBJECTIVE: Our aim is to explore the value of intraoperative facial motor evoked potentials (FMEP) for facial outcomes in cerebellopontine angle (CPA) tumor surgery to provide an evidence-based consensus standard for future clinical practice and prospective studies. METHODS: Electronic databases were searched from inception to June 2023. Study quality was assessed with the QUADAS-2 tool. Bivariate and random-effects models for meta-analysis and meta-regression generated summary receiver operating characteristic curves (ROC) and forest plots for estimates of sensitivity and specificity. RESULTS: We included 17 studies (1,206 participants). Sensitivity was lower in the immediate (IM) post-operative (0.76, 95% CI 0.65-0.84) compared to follow-up (FU) period (0.82, 95% CI 0.74-0.88) while specificity was similar in both groups (IM, 0.94, 95% CI 0.89-0.97; FU, 0.93, 95% CI 0.87-0.96). Data driven estimates improved FMEP performance but require confirmation from future studies. Amplitude cutoff criteria and studies that scored new deficits as worse than House-Brackmann (HB) grade 2 yielded best sensitivities. CONCLUSIONS: FMEP demonstrated statistically significant accuracy for facial function monitoring. Implementation of FMEPs varied widely across studies. SIGNIFICANCE: Our study is the first systematic review with meta-analysis to demonstrate that intraoperative FMEP is valuable in CPA tumor surgery for facial outcomes. Meta-regression identified the methods that were most useful in the application of FMEPs.