Cancer Frequency in MuSK Myasthenia Gravis and Histological Evidence of Paraneoplastic Etiology.

Cancer frequency in muscle-specific kinase myasthenia gravis (MuSK-MG) has not yet been explored and the mechanisms leading to the formation of MuSK IgG remain elusive. We aimed to explore cancer frequency in MuSK-MG patients and to assess MuSK expression in cancer cells from 2 tumors occurred in this cohort. Immunohistochemistry on tumor specimens revealed the expression of MuSK in the cancer cells from primary mediastinal B cell lymphoma and endometrial carcinoma. Twenty-one males and 73 females were enrolled. Fifteen cancers occurred in 13 of 94 patients (13.8%). Patients with cancer were significantly older at time of MuSK-MG onset. ANN NEUROL 2024;96:1020-1025.

PATZ1-Rearranged Tumors of the Central Nervous System: Characterization of a Pediatric Series of Seven Cases.

PATZ1-rearranged sarcomas are well-recognized tumors as part of the family of round cell sarcoma with EWSR1-non-ETS fusions. Whether PATZ1-rearranged central nervous system (CNS) tumors are a distinct tumor type is debatable. We thoroughly characterized a pediatric series of PATZ1-rearranged CNS tumors by chromosome microarray analysis (CMA), DNA methylation analysis, gene expression profiling and, when frozen tissue is available, optical genome mapping (OGM). The series consisted of 7 cases (M:F=1.3:1, 1-17 years, median 12). On MRI, the tumors were supratentorial in close relation to the lateral ventricles (intraventricular or iuxtaventricular), preferentially located in the occipital lobe. Two major histologic groups were identified: one (4 cases) with an overall glial appearance, indicated as "neuroepithelial" (NET) by analogy with the corresponding methylation class (MC); the other (3 cases) with a predominant spindle cell sarcoma morphology, indicated as "sarcomatous" (SM). A single distinct methylation cluster encompassing both groups was identified by multidimensional scaling analysis. Despite the epigenetic homogeneity, unsupervised clustering analysis of gene expression profiles revealed 2 distinct transcriptional subgroups correlating with the histologic phenotypes. Interestingly, genes implicated in epithelial-mesenchymal transition and extracellular matrix composition were enriched in the subgroup associated to the SM phenotype. The combined use of CMA and OGM enabled the identification of chromosome 22 chromothripsis in all cases suitable for the analyses, explaining the physical association of PATZ1 to EWSR1 or MN1. Six patients are currently disease-free (median follow-up 30 months, range 12-92). One patient of the SM group developed spinal metastases at 26 months from diagnosis and is currently receiving multimodal therapy (42 months). Our data suggest that PATZ1-CNS tumors are defined by chromosome 22 chromothripsis as causative of PATZ1 fusion, show peculiar MRI features (eg, relation to lateral ventricles, supratentorial frequently posterior site), and, although epigenetically homogenous, encompass 2 distinct histologic and transcriptional subgroups.

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Central nervous system pediatric multi-disciplinary tumor board: a single center experience.

BACKGROUND: The Multidisciplinary Tumor Board (MTB) is a collaborative platform involving specialists in oncology, surgery, radiology, pathology, and radiotherapy, and aims to optimize diagnostics and treatments. Despite MTB's widespread benefits, limited literature addresses its application in pediatric neuro-oncology. After a literature revision on pediatric neuro-oncology MTB, our study describes our institute's pediatric neuro-oncology MTB, focuses on evaluating its impact and the neuroradiologist's role in patient-centric approaches, considering recent genetic insights into pediatric brain tumors. MATERIALS AND METHODS: Literature Review concerning pediatric neuro-oncology MTB from January 2002 to June 2024. CLINICAL DATA: retrospective study of all patient files presented in the pediatric neuro-oncology MTB (pnMTB) between 2019 and 2022. Statistical analysis was mainly carried out by directly comparing the absolute or relative values of the respective parameters examined; qualitative variables compared mainly with the chi-square test, quantitative variables mainly with the t-test. RESULTS: Literature Review: 7 papers encompass a multidisciplinary approach for the pediatric CNS tumors. CLINICAL DATA: A total of 236 discussions were analyzed representing 107 patients. Median age was 14,3 years (range: 6 months - 17 years). The requests for case evaluations primarily came from the pediatric oncologists (83%) and neurosurgeons (14.8%), and they were mainly addressed to the neuroradiologists (70.3%). Proposals during pnMTB mainly involved imaging follow-up (47.8%) and management with chemotherapy (34.7%). Changes in patient treatment (CPT) occurred in 115 cases, and pediatric neuroradiologist intervention contributed to 72.4% of these changes. CONCLUSION: Thanks to their multidisciplinarity, high number of cases discussed, and usual respect for their proposals, the pnMTB has made it possible to improve the coordination among specialties involved in patient management, to apply the recent protocols, and to exchange knowledge among teams managing pediatric CNS tumors.

Pediatric craniopharyngiomas: magnetic resonance imaging assessment for hypothalamus-pituitary axis dysfunction and outcome prediction.

BACKGROUND: In adamantinomatous craniopharyngiomas, tumor topographical categories, cystic component volume, and magnetic resonance signal intensity may impact prognosis. OBJECTIVE: To identify magnetic resonance imaging (MRI) variables associated with pituitary-hypothalamic axis dysfunction and predictive of outcome in children with cystic adamantinomatous craniopharyngiomas. MATERIALS AND METHODS: We evaluated 40 preoperative MRIs of adamantinomatous craniopharyngiomas to classify tumor topography, volume, and signal intensity of the cystic components and peritumoral edema. Volumes and normalized signal intensity minimum values were extracted from coronal T2-weighted images (nT2min). Radiological variables were compared to pituitary-hypothalamic axis dysfunction-related clinical data and surgical outcomes. RESULTS: Adamantinomatous craniopharyngiomas were categorized into five topographic classes (12 patients, sellar-suprasellar; seven patients, pseudo-intraventricular; six patients, strict intraventricular; 14 patients, secondary intraventricular; one patient, not strict intraventricular). All cases exhibited a predominant (30 patients, 80%) or total (10 patients, 20%) cystic tumor component and displayed low nT2min percentage values compared to cerebrospinal fluid (42.3% [interquartile range 28.4-54.6%]). Significant associations between tumor topographic classes and pituitary dysfunction (P<0.001), and between peritumoral edema and hypothalamic dysfunction (P<0.001) were found. Considering extent of surgical removal and tumor relapse, volume of the cystic tumor component displayed a positive correlation (P=0.002; r=0.48; P=0.02; r=0.36), while nT2min intensity values exhibited a negative correlation (P=0.01; r= - 0.40; P=0.028; r= - 0.34). CONCLUSION: Severe hypothalamic-pituitary axis dysfunction is associated with tumors along the pituitary stalk and peritumoral edema. Tumor invasion of the third ventricle, tight adherence to the hypothalamus, larger volumes, and lower nT2min intensity of the tumor cystic component are independent predictors of extent of adamantinomatous craniopharyngioma excision and recurrence.

Giant Congenital Hemangioma of the Skull: Prenatal Diagnosis and Multimodal Endovascular and Surgical Management.

Introduction: calvarial capillary hemangiomas are vascular tumors rarely seen in newborns. Differential diagnosis may be not straightforward on imaging studies and the management depends on patient and lesion characteristics. Case report: we present the case of a large congenital intracranial extra-axial lesion detected by routine prenatal US screening, a giant calvarial congenital hemangioma, treated with a multimodal strategy. Neonatal MR showed a hemorrhagic solid lesion, causing compression of brain tissue. Conservative treatment was attempted, but a one-month follow-up MR showed growth of the lesion with increased mass effect. Pre-operative endovascular embolization and surgical resection were performed. The pathology was consistent with intraosseous capillary hemangioma. The post-operative course was uneventful. At the 8-month follow-up, the patient had no clinical deficits and MR showed complete resection of the lesion. At the 13-month follow-up, the patient was asymptomatic, showing normal neurological examination and psychophysical development. Conclusions: although wait-and-see policy is feasible for small and asymptomatic lesions, radical resection is indicated when the mass is large, thus causing severe mass effect on the brain. Hypervascularization of the tumor may be responsible for hemorrhagic complications and severe anemia. On these grounds, endovascular treatment is feasible and effective to reduce hemorrhagic complications.

MRI and Trouillas' grading system of pituitary tumors: the usefulness of T2 signal intensity volumetric values.

PURPOSE: To classify pituitary macroadenomas according to the Trouillas' grading system; to compare this grading system with T2 values of volumetric signal intensity to determine T2 values able to predict the final grade. METHODS: A total of 106 patients with macroadenomas were grouped according to the grading system score combining proliferation and invasiveness criteria of Trouillas' classification. Normalized volumetric signal intensity values were extracted from coronal T2-weighted images (nT2mean, nT2Max, nT2min) and were compared with the final grading score system. RESULTS: Thirty-three patients were in grade 1a (non-invasive, non-proliferative tumors), 17 patients in grade 1b (non-invasive, proliferative tumors), 36 patients in grade 2a (invasive, non-proliferative tumors), and 20 patients in grade 2b (invasive, proliferative tumors). No patient was in grade 3 (metastatic tumors). nT2Max and nT2min were the best quantitative values to discriminate invasive from non-invasive grades; in invasive grades, nT2Max intensity values were higher, and nT2min intensity values were lower than in non-invasive grades. Receiver operating characteristic analysis of nT2 values showed that nT2min values had a better diagnostic performance than nT2Max values because they allowed differentiating with a moderate accuracy invasive tumors (2a or 2b grades) from both non-invasive proliferative tumors (1b) and non-invasive-non proliferative tumors (1a) (2a vs 1b: AUCnT2min = 0.78, 2b vs 1b: AUCnT2min = 0.72, 2a vs 1a: AUCnT2min = 0.72, 2b vs 1a AUCnT2min = 0.69). CONCLUSION: Volumetric nT2Max and nT2min values of MRI might be practical and non-invasive markers for assessing tumor invasiveness although nT2 min signal intensity values have more effects in discriminating tumor's invasive behavior.

Magnetic resonance imaging-derived parameters to predict response to regorafenib in recurrent glioblastoma.

PURPOSE: Regorafenib is a multikinase inhibitor, approved as a preferred regimen for recurrent glioblastoma (rGB). Although its effects on prolonging survival could seem modest, it is still unclear whether a subset of patients, potentially identifiable by imaging biomarkers, might experience a more substantial positive effect. Our aim was to evaluate the potential value of magnetic resonance imaging-derived parameters as non-invasive biomarkers to predict response to regorafenib in patients with rGB. METHODS: 20 patients with rGB underwent conventional and advanced MRI at diagnosis (before surgery), at recurrence and at first follow-up (3 months) during regorafenib. Maximum relative cerebral blood volume (rCBVmax) value, intra-tumoral susceptibility signals (ITSS), apparent diffusion coefficient (ADC) values, and contrast-enhancing tumor volumes were tested for correlation with response to treatment, progression-free survival (PFS), and overall survival (OS). Response at first follow-up was assessed according to Response Assessment in Neuro-Oncology (RANO) criteria. RESULTS: 8/20 patients showed stable disease at first follow-up. rCBVmax values of the primary glioblastoma (before surgery) significantly correlated to treatment response; specifically, patients with stable disease displayed higher rCBVmax compared to progressive disease (p = 0.04, 2-group t test). Moreover, patients with stable disease showed longer PFS (p = 0.02, 2-group t test) and OS (p = 0.04, 2-group t test). ITSS, ADC values, and contrast-enhancing tumor volumes showed no correlation with treatment response, PFS nor OS. CONCLUSION: Our results suggest that rCBVmax of the glioblastoma at diagnosis could serve as a non-invasive biomarker of treatment response to regorafenib in patients with rGB.

Spinal Epidural Atypical Meningioma: Case Report and Review of the Literature.

Spinal atypical meningiomas are rare, and those whose main extension is in the epidural space are anecdotal. Here, we report a case of a young woman presenting with sensory disturbances and a radiological diagnosis of a dorsal epidural sleeve-like mass. The surgical resection of the lesion allowed the decompression of the spinal cord and led to the histopathological diagnosis of atypical meningioma. At the 3-month follow-up, her neurological recovery was complete. Because of the gross total removal of the lesion, adjuvant radiotherapy was not performed: At the 2-year follow-up, no recurrence of disease was detected. A comprehensive literature review was performed, and just two more case reports on epidural atypical meningiomas were found in the English literature. Through this case report and literature review, we described a rare manifestation of spinal meningioma that entered into a differential diagnosis for extradural spinal lesions, such as secondary malignancies.

Aggressive PitNETs and Potential Target Therapies: A Systematic Review of Molecular and Genetic Pathways.

Recently, advances in molecular biology and bioinformatics have allowed a more thorough understanding of tumorigenesis in aggressive PitNETs (pituitary neuroendocrine tumors) through the identification of specific essential genes, crucial molecular pathways, regulators, and effects of the tumoral microenvironment. Target therapies have been developed to cure oncology patients refractory to traditional treatments, introducing the concept of precision medicine. Preliminary data on PitNETs are derived from preclinical studies conducted on cell cultures, animal models, and a few case reports or small case series. This study comprehensively reviews the principal pathways involved in aggressive PitNETs, describing the potential target therapies. A search was conducted on Pubmed, Scopus, and Web of Science for English papers published between 1 January 2004, and 15 June 2023. 254 were selected, and the topics related to aggressive PitNETs were recorded and discussed in detail: epigenetic aspects, membrane proteins and receptors, metalloprotease, molecular pathways, PPRK, and the immune microenvironment. A comprehensive comprehension of the molecular mechanisms linked to PitNETs' aggressiveness and invasiveness is crucial. Despite promising preliminary findings, additional research and clinical trials are necessary to confirm the indications and effectiveness of target therapies for PitNETs.

Paediatric astroblastoma-like neuroepithelial tumour of the spinal cord with a MAMLD1-BEND2 rearrangement.

Astroblastomas are neuroepithelial tumours defined by the presence of MN1 rearrangement and are typically located in the cerebral hemispheres. Rare cases of astroblastoma-like tumours carrying an EWSR1-BEND2 fusion have been recently described in the brain stem and spinal cord. We report a paediatric case of neuroepithelial astroblastoma-like tumour occurring in the spine and carrying a novel MAMLD1-BEND2 fusion. We believe that our case aligns with the rare astroblastoma-like tumours with EWSR1-BEND2 fusion, in terms of non-hemispheric location, pathology, methylation profile and activation of BEND2 transcription. Whether they may represent a distinct entity or a variant of MN1-altered astroblastoma is not clear.

Characterization of high-grade pineal region lesions: the usefulness of apparent diffusion coefficient volumetric values.

BACKGROUND: High-grade pineal region tumors are rare and heterogeneous types of primary central nervous system neoplasms; radiological differential diagnosis is challenging but it is important because it has a therapeutic relevance. PURPOSE: To discriminate among high-grade pineal region tumors by combining apparent diffusion coefficient (ADC) volumetric values and qualitative features in order to predict their histology. MATERIAL AND METHODS: Twenty-two patients with high-grade pineal region tumors were assessed by qualitative and quantitative analysis. Margins, T2-weighted signal intensity, contrast enhancement, hemorrhage, calcifications, different volumetric ADC fractions (ADCmean, ADCmax, ADCmin) were evaluated and were compared to the histopathologic findings (cell count and proliferation index). RESULTS: Our qualitative imaging data showed that only margins were different among different tumors and each tumor type showed peculiar age onset. ADCmean was found the best quantitative value to discriminate high-grade tumors of the pineal region. ADCmean correlated with proliferation index but not with cell count. ADCmean values were lower in tumors with higher proliferation rate and a significant difference in ADCmean values were found between germinomas and pineoblastomas, between germinomas and papillary tumors and between papillary tumors and pineoblastomas. Moreover, the cut-off value of 0.865 × 10-3 mm2/s for ADCmean (ADC mean threshold value) could differentiate germinoma from pineoblastomas with the best combination of sensitivity and specificity. CONCLUSION: The ADCmean value measured on the whole tumor, reflecting tumor proliferative activity, may be a practical and non-invasive marker for predicting tumor histology in high-grade pineal region lesions and might be useful in preoperative assessment.

Dissecting Stemness in Aggressive Intracranial Meningiomas: Prognostic Role of SOX2 Expression.

Meningiomas are mostly benign tumors that, at times, can behave aggressively, displaying recurrence despite gross-total resection (GTR) and progression to overt malignancy. Such cases represent a clinical challenge, particularly because they are difficult to recognize at first diagnosis. SOX2 (Sex-determining region Y-box2) is a transcription factor with a key role in stem cell maintenance and has been associated with tumorigenesis in a variety of cancers. The purpose of the present work was to dissect the role of SOX2 in predicting the aggressiveness of meningioma. We analyzed progressive/recurrent WHO grade 1−2 meningiomas and WHO grade 3 meningiomas; as controls, non-recurring WHO grade 1 and grade 2 meningioma patients were enrolled. SOX2 expression was evaluated using both immunohistochemistry (IHC) and RT-PCR. The final analysis included 87 patients. IHC was able to reliably assess SOX2 expression, as shown by the good correlation with mRNA levels (Spearman R = 0.0398, p = 0.001, AUC 0.87). SOX2 expression was an intrinsic characteristic of any single tumor and did not change following recurrence or progression. Importantly, SOX2 expression at first surgery was strongly related to meningioma clinical behavior, histological grade and risk of recurrence. Finally, survival data suggest a prognostic role of SOX2 expression in the whole series, both for overall and for recurrence-free survival (p < 0.0001 and p = 0.0001, respectively). Thus, SOX2 assessment could be of great help to clinicians in informing adjuvant treatments during follow-up.

Expanding the spectrum of "mesenchymal" tumors of the central nervous system.

In this review, we summarize the clinical, histopathological, and molecular features of central nervous system (CNS) tumors with BCOR internal tandem duplication, intracranial mesenchymal tumor with FET/CREB fusion, CNS CIC-rearranged sarcomas and primary intracranial sarcoma DICER1-mutant, now included in the 2021 WHO classification of CNS tumors. Possible relationships between tumors occurring in the CNS and their systemic counterparts are discussed.

ALK-rearranged histiocytosis: Report of two cases with involvement of the central nervous system.

AIMS: Histiocytoses are a heterogeneous group of localized or disseminated diseases. Clinical presentation and patients' outcome vary greatly, ranging from mild to life-threatening disorders. Rare cases of systemic or localized histiocytosis harboring ALK rearrangement have been reported. METHODS: Two cases of CNS histiocytosis were thoroughly investigated by implementing multiple molecular tests, i.e. FISH, RT-qPCR, NGS analysis. RESULTS: In a 10-month old girl (patient #1), MRI showed two left hemispheric lesions and a right fronto-mesial lesion histologically consisting of a moderately cellular infiltrative proliferation, composed by CD68(PGM1)+/CD163+ spindle cells. ALK 5'/3'-imbalance and a KIF5B(exon 24)-ALK(exon 20) fusion were documented by RT-qPCR and NGS analysis, respectively. A subsequent CT scan showed multiple hepatic and pulmonary lesions. The patient was started on chemotherapy (vinblastine) associated to an ALK-inhibitor (Alectinib) with remarkable response. In a 11-year-old girl (patient #2), MRI showed a right frontal 1.5 cm lesion. Neuropathological examination revealed a histiocytic proliferation composed by medium sized CD68(PGM1)+/HLA-DR+ cells, showing moderate ALK1 positivity. ALK rearrangement and a KIF5B(exon 24)-ALK(exon 20) fusion were demonstrated also in this case. Subsequent CT, 18F-FDG-PET and MRI scans showed the presence of a single right femoral lesion, proved to be a fibrous cortical defect. CONCLUSIONS: In ALK-histiocytoses, CNS involvement may occur as part of a systemic disease or, rarely, as its only primary disease localization, which could remain otherwise asymptomatic. The diagnosis often relies on neuropathological examination of brain biopsy, which may pose a diagnostic challenge due to the variable histopathological features. An integrated histological and molecular approach in such cases is recommended.

Unusual case of long survival patient with leptomeningeal carcinomatosis from breast cancer.

Leptomeningeal carcinomatosis (LC) is defined as infiltration of the leptomeninges by metastatic carcinoma and often represents the end stage of cancer disease. In breast cancer, LC is associated with a median survival of approximately 6-8 weeks without specific treatment. It could increase by only few months with personalized treatment plans. Usually, the median time of onset of leptomeningeal spread is 18 months and it is diagnosed in up to 70% of patients with active and progressive systemic disease. We present an uncommon case of LC in a patient with history of breast cancer with a 10 year-disease-free condition and an overall survival after LC diagnosis of 10 months. Central Nervous System (CNS) Magnetic Resonance Imaging (MRI) showed contrast enhancement of medullary cone and cauda. Despite the negativity of cytological analysis of Cerebral-Spinal Fluid (CSF), the patient underwent meningeal and radicular biopsy in November 2019. The neuropathological examination confirmed the diagnosis of LC. The patient was started on the aromatase inhibitor anastrozole. A whole body contrast Computed Tomography (CT) scan at three months follow-up was negative for further disease dissemination. The patient is currently under oncological and radiological follow-up after more than 10 months from diagnosis. Although nowadays diagnosis of LC is prompted by cytological examination of CSF, its negativity should not halt the diagnostic process. In the presence of a high clinical suspicion of LC, we suggest the biopsy of lesion.

Combining Magnetic Resonance Imaging with Systemic Monocyte Evaluation for the Implementation of GBM Management.

Magnetic resonance imaging (MRI) is the gold standard for glioblastoma (GBM) patient evaluation. Additional non-invasive diagnostic modalities are needed. GBM is heavily infiltrated with tumor-associated macrophages (TAMs) that can be found in peripheral blood. FKBP51s supports alternative-macrophage polarization. Herein, we assessed FKBP51s expression in circulating monocytes from 14 GBM patients. The M2 monocyte phenotype was investigated by qPCR and flow cytometry using antibodies against PD-L1, CD163, FKBP51s, and CD14. MRI assessed morphologic features of the tumors that were aligned to flow cytometry data. PD-L1 expression on circulating monocytes correlated with MRI tumor necrosis score. A wider expansion in circulating CD163/monocytes was measured. These monocytes resulted in a dramatic decrease in patients with an MRI diagnosis of complete but not partial surgical removal of the tumor. Importantly, in patients with residual tumor, most of the peripheral monocytes that in the preoperative stage were CD163/FKBP51s- had turned into CD163/FKBP51s+. After Stupp therapy, CD163/FKBP51s+ monocytes were almost absent in a case of pseudoprogression, while two patients with stable or true disease progression showed sustained levels in such circulating monocytes. Our work provides preliminary but meaningful and novel results that deserve to be confirmed in a larger patient cohort, in support of potential usefulness in GBM monitoring of CD163/FKBP51s/CD14 immunophenotype in adjunct to MRI.

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II-Report from the German/Swiss SIOP-LGG 2004 cohort.

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.

Role of susceptibility-weighted imaging and intratumoral susceptibility signals in grading and differentiating pediatric brain tumors at 1.5 T: a preliminary study.

PURPOSE: Susceptibility-weighted imaging (SWI) is useful for glioma grading and discriminating between brain tumor categories in adults, but its diagnostic value for pediatric brain tumors is unclear. Here we evaluated the usefulness of SWI for pediatric tumor grading and differentiation by assessing intratumoral susceptibility signal intensity (ITSS). METHODS: We retrospectively enrolled 96 children with histopathologically diagnosed brain tumors, who underwent routine brain MRI exam with SWI (1.5 T scanner). Each tumor was assigned an ITSS score by a radiology resident and an experienced neuroradiologist, and subsequently by consensus. Statistical analyses were performed to differentiate between low-grade (LG) and high-grade (HG) tumors, histological categories, and tumor locations. Inter-reader agreement was assessed using Cohen's kappa (κ). RESULTS: The interobserver agreement was 0.844 (0.953 between first reader and consensus, and 0.890 between second reader and consensus). Among all tumors, we found a statistically significant difference between LG and HG for ITSS scores of 0 and 2 (p = 0.002). This correlation was weaker among astrocytomas alone, and became significant when considering only off-midline astrocytomas (p = 0.05). Scores of 0 and 2 were a strong discriminating factor (p = 0.001) for astrocytomas (score 0) and for embryonal, choroid plexus, germ-cell, pineal, and ependymoma tumors (score 2). No medulloblastoma showed a score of 0. CONCLUSIONS: Our preliminary ITTS results in pediatric brain tumors somewhat differed from those obtained in adult populations. These findings highlight the potential valuable role of ITSS for tumor grading and discriminating between some tumor categories in the pediatric population.

Central nervous system high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)-case-based reviews.

INTRODUCTION: High-grade neuroepithelial tumor with BCOR alteration (HGNET BCOR) has been recently classified as a new category of tumors among those previously known as PNET. They are molecularly characterized by the mutation of the BCOR gene, a corepressor of BCL6 a gene (which has an important role in immune responses). Only case reports and very small series have been published so far; therefore, their behavior and management are still under investigation. The goal of the present case-based review is to provide a summary about the state of the art on these tumors. METHODS AND RESULTS: The pertinent review has been reviewed, and an exemplary case has been reported (15-month-old boy with large HGNET BCOR of the left cerebellopontine angle). So far, 24 cases have been described, with a 5.5 mean age at diagnosis and a 1.4 male/female ratio. The cerebellar hemisphere is the more frequently involved region. No metastases are usually detected at diagnosis, though they are common in case of tumor recurrence. There are no specific radiological or pathological features to differentiate HGNET BCOR from other brain malignant neuroepithelial tumors so that the differential diagnosis is obtained by DNA methylation profiling. The management possibly relies on surgery and (high dose) chemotherapy and radiotherapy but without a dedicated protocol yet. The overall survival after 48-month follow-up is 50%. A gross total resection, which is mandatory for a better outcome, is achievable in the majority of cases. CONCLUSIONS: The clinical research on HGNET BCOR is just at the beginning. New targets and wide-ranging clinical trials are needed to get an optimal management.