Hjernetegn.dk-The Danish Central Nervous System Tumor Awareness Initiative Digital Decision Support Tool: Design and Implementation Report.

BACKGROUND: Childhood tumors in the central nervous system (CNS) have longer diagnostic delays than other pediatric tumors. Vague presenting symptoms pose a challenge in the diagnostic process; it has been indicated that patients and parents may be hesitant to seek help, and health care professionals (HCPs) may lack awareness and knowledge about clinical presentation. To raise awareness among HCPs, the Danish CNS tumor awareness initiative hjernetegn.dk was launched. OBJECTIVE: This study aims to present the learnings from designing and implementing a decision support tool for HCPs to reduce diagnostic delay in childhood CNS tumors. The aims also include decisions regarding strategies for dissemination and use of social media, and an evaluation of the digital impact 6 months after launch. METHODS: The phases of developing and implementing the tool include participatory co-creation workshops, designing the website and digital platforms, and implementing a press and media strategy. The digital impact of hjernetegn.dk was evaluated through website analytics and social media engagement. IMPLEMENTATION (RESULTS): hjernetegn.dk was launched in August 2023. The results after 6 months exceeded key performance indicators. The analysis showed a high number of website visitors and engagement, with a plateau reached 3 months after the initial launch. The LinkedIn campaign and Google Search strategy also generated a high number of impressions and clicks. CONCLUSIONS: The findings suggest that the initiative has been successfully integrated, raising awareness and providing a valuable tool for HCPs in diagnosing childhood CNS tumors. The study highlights the importance of interdisciplinary collaboration, co-creation, and ongoing community management, as well as broad dissemination strategies when introducing a digital support tool.

Non-C19MC-altered embryonal tumor with multilayered rosettes in a young woman with DICER1 syndrome: case report and review of the literature.

Embryonal tumors with multilayered rosettes (ETMR) are highly aggressive and therapy-resistant pediatric central nervous system (CNS) tumors that have three histological patters: embryonal tumor with abundant neuropil and true rosettes, ependymoblastoma, and medulloepithelioma. We present a case of ETMR in an 18-year-old woman with DICER1 syndrome. This report confirms the important role of DNA-methylation analysis in the classification of CNS embryonal tumors and the importance of investigating somatic and germline DICER1 mutations in all CNS embryonal tumors.

Malignant glioma in L-2-Hydroxyglutaric Aciduria: thorough molecular characterization of a case and literature review.

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare neurometabolic disorder characterized by accumulation of L2-hydroxyglutarate (L-2-HG) due to mutations in the L2HGDH gene. L-2-HGA patients have a significantly increased lifetime risk of central nervous system (CNS) tumors. Here, we present a 16-year-old girl with L-2-HGA who developed a tumor in the right cerebral hemisphere, which was discovered after left-sided neurological deficits of the patient. Histologically, the tumor had a high-grade diffuse glioma phenotype. DNA sequencing revealed the inactivating homozygous germline L2HGDH mutation as well as inactivating mutations in TP53, BCOR and NF1. Genome-wide DNA-methylation analysis was unable to classify the tumor with high confidence. More detailed analysis revealed that this tumor clustered amongst IDH-wildtype gliomas by methylation profiling and did not show the glioma CpG island methylator phenotype (G-CIMP) in contrast to IDH-mutant diffuse gliomas with accumulated levels of D-2-HG, the stereoisomer of L-2-HD. These findings were against all our expectations given the inhibitory potential of 2-HG on DNA-demethylation enzymes. Our final integrated histomolecular diagnosis of the tumor was diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. Due to rapid tumor progression the patient died nine months after initial diagnosis. In this manuscript, we provide extensive molecular characterization of the tumor as well as a literature review focusing on oncogenetic considerations of L-2-HGA-associated CNS tumors.

Clinical, pathological, and molecular features of central nervous system tumors with BCOR internal tandem duplication.

Central nervous system tumor with BCOR internal tandem duplication (CNS tumor with BCOR-ITD) constitutes a molecularly distinct entity, characterized by internal tandem duplication within exon 15 of the BCOR transcriptional co-repressor gene (BCOR-ITD). The current study aimed to elucidate the clinical, pathological, and molecular attributes of CNS tumors with BCOR-ITD and explore their putative cellular origin. This study cohort comprised four pediatric cases, aged 23 months to 13 years at initial presentation. Magnetic resonance imaging revealed large, well-circumscribed intra-CNS masses localized heterogeneously throughout the CNS. Microscopically, tumors were composed of spindle to ovoid cells, exhibiting perivascular pseudorosettes and palisading necrosis, but lacking microvascular proliferation. Immunohistochemical staining showed diffuse tumor cell expression of BCOR, CD56, CD99, vimentin, and the stem cell markers PAX6, SOX2, CD133 and Nestin, alongside focal positivity for Olig-2, S100, SOX10, Syn and NeuN. Molecularly, all cases harbored BCOR-ITDs ranging from 87 to 119 base pairs in length, including one case with two distinct ITDs. Notably, the ITDs were interrupted by unique 1-3 bp insertions in all cases. In summary, CNS tumors with BCOR-ITD exhibit characteristic clinical, pathological, and molecular features detectable through BCOR immunohistochemistry and confirmatory molecular analyses. Their expression of stem cell markers raises the possibility of an origin from neuroepithelial stem cells rather than representing true embryonal neoplasms.

BCOR::CREBBP fusion in malignant neuroepithelial tumor of CNS expands the spectrum of methylation class CNS tumor with BCOR/BCOR(L1)-fusion.

Methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" was recently defined based on methylation profiling and tSNE analysis of a series of 21 neuroepithelial tumors with predominant presence of a BCOR fusion and/or characteristic CNV breakpoints at chromosome 22q12.31 and chromosome Xp11.4. Clear diagnostic criteria are still missing for this tumor type, specially that BCOR/BCOR(L1)-fusion is not a consistent finding in these tumors despite being frequent and that none of the Heidelberger classifier versions is able to clearly identify these cases, in particular tumors with alternative fusions other than those involving BCOR, BCORL1, EP300 and CREBBP. In this study, we introduce a BCOR::CREBBP fusion in an adult patient with a right temporomediobasal tumor, for the first time in association with methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" in addition to 35 cases of CNS neuroepithelial tumors with molecular and histopathological characteristics compatible with "CNS tumor with BCOR/BCOR(L1)-fusion" based on a comprehensive literature review and data mining in the repository of 23 published studies on neuroepithelial brain Tumors including 7207 samples of 6761 patients. Based on our index case and the 35 cases found in the literature, we suggest the archetypical histological and molecular features of "CNS tumor with BCOR/BCOR(L1)-fusion". We also present four adult diffuse glioma cases including GBM, IDH-Wildtype and Astrocytoma, IDH-Mutant with CREBBP fusions and describe the necessity of complementary molecular analysis in "CNS tumor with BCOR/BCOR(L1)-alterations for securing a final diagnosis.

In vitro and in vivo modeling systems of supratentorial ependymomas.

Ependymomas are rare brain tumors that can occur in both children and adults. Subdivided by the tumors' initial location, ependymomas develop in the central nervous system in the supratentorial or infratentorial/posterior fossa region, or the spinal cord. Supratentorial ependymomas (ST-EPNs) are predominantly characterized by common driver gene fusions such as ZFTA and YAP1 fusions. Some variants of ST-EPNs carry a high overall survival rate. In poorly responding ST-EPN variants, high levels of inter- and intratumoral heterogeneity, limited therapeutic strategies, and tumor recurrence are among the reasons for poor patient outcomes with other ST-EPN subtypes. Thus, modeling these molecular profiles is key in further studying tumorigenesis. Due to the scarcity of patient samples, the development of preclinical in vitro and in vivo models that recapitulate patient tumors is imperative when testing therapeutic approaches for this rare cancer. In this review, we will survey ST-EPN modeling systems, addressing the strengths and limitations, application for therapeutic targeting, and current literature findings.

Palliative care for children with central nervous system tumors: results of a Spanish multicenter study

Background Brain tumors represent the most common cause of cancer-related death in children. Few studies concerning the palliative phase in children with brain tumors are available. Objectives (i) To describe the palliative phase in children with brain tumors; (ii) to determine whether the use of palliative sedation (PS) depends on the place of death, the age of the patient, or if they received specific palliative care (PC). Methods Retrospective multicenter study between 2010 and 2021, including children from one month to 18 years, who had died of a brain tumor. Results 228 patients (59.2% male) from 10 Spanish institutions were included. Median age at diagnosis was 5 years (IQR 2–9) and median age at death was 7 years (IQR 4–11). The most frequent tumors were medulloblastoma (25.4%) and diffuse intrinsic pontine glioma (DIPG) (24.1%). Median number of antineoplastic regimens were 2 (range 0–5 regimens). During palliative phase, 52.2% of the patients were attended by PC teams, while 47.8% were cared exclusively by pediatric oncology teams. Most common concerns included motor deficit (93.4%) and asthenia (87.5%) and communication disorders (89.8%). Most frequently prescribed supportive drugs were antiemetics (83.6%), opioids (81.6%), and dexamethasone (78.5%). PS was administered to 48.7% patients. Most of them died in the hospital (85.6%), while patients who died at home required PS less frequently (14.4%) (p = .01). Conclusion Children dying from CNS tumors have specific needs during palliative phase. The optimal indication of PS depended on the center experience although, in our series, it was also influenced by the place of death (AU)

Unclassifiable CNS tumors in DNA methylation-based classification: clinical challenges and prognostic impact.

DNA methylation analysis has become a powerful tool in neuropathology. Although DNA methylation-based classification usually shows high accuracy, certain samples cannot be classified and remain clinically challenging. We aimed to gain insight into these cases from a clinical perspective. To address, central nervous system (CNS) tumors were subjected to DNA methylation profiling and classified according to their calibrated score using the DKFZ brain tumor classifier (V11.4) as "≥ 0.84" (score ≥ 0.84), "0.3-0.84" (score 0.3-0.84), or "< 0.3" (score < 0.3). Histopathology, patient characteristics, DNA input amount, and tumor purity were correlated. Clinical outcome parameters were time to treatment decision, progression-free, and overall survival. In 1481 patients, the classifier identified 69 (4.6%) tumors with an unreliable score as "< 0.3". Younger age (P < 0.01) and lower tumor purity (P < 0.01) compromised accurate classification. A clinical impact was demonstrated as unclassifiable cases ("< 0.3") had a longer time to treatment decision (P < 0.0001). In a subset of glioblastomas, these cases experienced an increased time to adjuvant treatment start (P < 0.001) and unfavorable survival (P < 0.025). Although DNA methylation profiling adds an important contribution to CNS tumor diagnostics, clinicians should be aware of a potentially longer time to treatment initiation, especially in malignant brain tumors.

CNS tumor with CREBBP::BCORL1 Fusion and pathogenic mutations in BCOR and CREBBP: expanding the spectrum of BCOR-altered tumors.

The fifth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors introduced the new tumor type CNS tumor with BCOR internal tandem duplication (ITD), characterized by a distinct DNA methylation profile and peculiar histopathological features, including a circumscribed growth pattern, ependymoma-like perivascular pseudorosettes, microcystic pattern, absent or focal GFAP immunostaining, OLIG2 positivity, and BCOR immunoreactivity. We describe a rare case of a CNS tumor in a 45-year-old man with histopathological and immunohistochemical features overlapping the CNS tumor with BCOR internal tandem duplication (ITD) but lacking BCOR immunostaining and BCOR ITD. Instead, the tumor showed CREBBP::BCORL1 fusion and pathogenic mutations in BCOR and CREBBP, along with a DNA methylation profile matching the "CNS tumor with EP300:BCOR(L1) fusion" methylation class. Two CNS tumors with fusions between CREBBP, or its paralog EP300, and BCORL1, and approximately twenty CNS tumors with CREBBP/EP300::BCOR fusions have been reported to date. They exhibited similar ependymoma-like features or a microcystic pattern, along with focal or absent GFAP immunostaining, and shared the same DNA methylation profile. Given their morphological and epigenetic similarities, circumscribed CNS tumors with EP300/CREBBP::BCOR(L1) fusions and CNS tumors with BCOR ITD may represent variants of the same tumor type. The ependymoma-like aspect coupled with the lack of diffuse GFAP immunostaining and the presence of OLIG2 positivity are useful clues for recognizing these tumors in histopathological practice. The diagnosis should be confirmed after testing for BCOR(L1) gene fusions and BCOR ITD.

Bevacizumab and gamma knife radiosurgery for first-recurrence glioblastoma.

INTRODUCTION: Glioblastoma (GBM) is the most common central nervous system malignancy in adults. Despite decades of developments in surgical management, radiation treatment, chemotherapy, and tumor treating field therapy, GBM remains an ultimately fatal disease. There is currently no definitive standard of care for patients with recurrent glioblastoma (rGBM) following failure of initial management. OBJECTIVE: In this retrospective cohort study, we set out to examine the relative effects of bevacizumab and Gamma Knife radiosurgery on progression-free survival (PFS) and overall survival (OS) in patients with GBM at first-recurrence. METHODS: We conducted a retrospective review of all patients with rGBM who underwent treatment with bevacizumab and/or Gamma Knife radiosurgery at Roswell Park Comprehensive Cancer Center between 2012 and 2022. Mean PFS and OS were determined for each of our three treatment groups: Bevacizumab Only, Bevacizumab Plus Gamma Knife, and Gamma Knife Only. RESULTS: Patients in the combined treatment group demonstrated longer post-recurrence median PFS (7.7 months) and median OS (11.5 months) compared to glioblastoma patients previously reported in the literature, and showed improvements in total PFS (p=0.015), total OS (p=0.0050), post-recurrence PFS (p=0.018), and post-recurrence OS (p=0.0082) compared to patients who received either bevacizumab or Gamma Knife as monotherapy. CONCLUSION: This study demonstrates that the combined use of bevacizumab with concurrent stereotactic radiosurgery can have improve survival in patients with rGBM.

Palliative care for children with central nervous system tumors: results of a Spanish multicenter study.

BACKGROUND: Brain tumors represent the most common cause of cancer-related death in children. Few studies concerning the palliative phase in children with brain tumors are available. OBJECTIVES: (i) To describe the palliative phase in children with brain tumors; (ii) to determine whether the use of palliative sedation (PS) depends on the place of death, the age of the patient, or if they received specific palliative care (PC). METHODS: Retrospective multicenter study between 2010 and 2021, including children from one month to 18 years, who had died of a brain tumor. RESULTS: 228 patients (59.2% male) from 10 Spanish institutions were included. Median age at diagnosis was 5 years (IQR 2-9) and median age at death was 7 years (IQR 4-11). The most frequent tumors were medulloblastoma (25.4%) and diffuse intrinsic pontine glioma (DIPG) (24.1%). Median number of antineoplastic regimens were 2 (range 0-5 regimens). During palliative phase, 52.2% of the patients were attended by PC teams, while 47.8% were cared exclusively by pediatric oncology teams. Most common concerns included motor deficit (93.4%) and asthenia (87.5%) and communication disorders (89.8%). Most frequently prescribed supportive drugs were antiemetics (83.6%), opioids (81.6%), and dexamethasone (78.5%). PS was administered to 48.7% patients. Most of them died in the hospital (85.6%), while patients who died at home required PS less frequently (14.4%) (p = .01). CONCLUSION: Children dying from CNS tumors have specific needs during palliative phase. The optimal indication of PS depended on the center experience although, in our series, it was also influenced by the place of death.

Glioma Tumor Grading Using Radiomics on Conventional MRI: A Comparative Study of WHO 2021 and WHO 2016 Classification of Central Nervous Tumors.

BACKGROUND: Glioma grading transformed in World Health Organization (WHO) 2021 CNS tumor classification, integrating molecular markers. However, the impact of this change on radiomics-based machine learning (ML) classifiers remains unexplored. PURPOSE: To assess the performance of ML in classifying glioma tumor grades based on various WHO criteria. STUDY TYPE: Retrospective. SUBJECTS: A neuropathologist regraded gliomas of 237 patients into WHO 2016 and 2021 from 2007 criteria. FIELD STRENGTH/SEQUENCE: Multicentric 0.5 to 3 Tesla; pre- and post-contrast T1-weighted, T2-weighted, and fluid-attenuated inversion recovery. ASSESSMENT: Radiomic features were selected using random forest-recursive feature elimination. The synthetic minority over-sampling technique (SMOTE) was implemented for data augmentation. Stratified 10-fold cross-validation with and without SMOTE was used to evaluate 11 classifiers for 3-grade (2, 3, and 4; WHO 2016 and 2021) and 2-grade (low and high grade; WHO 2007 and 2021) classification. Additionally, we developed the models on data randomly divided into training and test sets (mixed-data analysis), or data divided based on the centers (independent-data analysis). STATISTICAL TESTS: We assessed ML classifiers using sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC). Top performances were compared with a t-test and categorical data with the chi-square test using a significance level of P < 0.05. RESULTS: In the mixed-data analysis, Stacking Classifier without SMOTE achieved the highest accuracy (0.86) and AUC (0.92) in 3-grade WHO 2021 grouping. The results of WHO 2021 were significantly better than WHO 2016 (P-value<0.0001). In the 2-grade analysis, ML achieved 1.00 in all metrics. In the independent-data analysis, ML classifiers showed strong discrimination between grade 2 and 4, despite lower performance metrics than the mixed analysis. DATA CONCLUSION: ML algorithms performed better in glioma tumor grading based on WHO 2021 criteria. Nonetheless, the clinical use of ML classifiers needs further investigation. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Diagnostic Insights into Pediatric Pleomorphic Xanthoastrocytoma through DNA Methylation Class and Pathological Diagnosis Analysis.

This study adopts an innovative approach to utilize the DNA methylation class (MC) by prioritizing the understanding of discrepancies over traditional direct comparisons with the pathological diagnosis (PD). The aim is to clarify the morphological criteria for pleomorphic xanthoastrocytoma (PXA). Using the Children's Brain Tumor Network online database, PXA-diagnosed cases were sourced. MCs and CDKN2A/B statuses were ascertained using the Heidelberg methylation brain tumor classifier v12.5 (v12.8 for selected cases). Three distinct groups emerged: Group 1 confirmed PXA through both PD and MC (7 cases); Group 2 identified PXA via PD alone (7 cases); and Group 3 diagnosed PXA using MC (5 cases). Key insights from the study include the frequent local infiltration of PXA into gray matter structures, mirroring infiltrative astrocytoma. The MC for PXA stands out for its sensitivity. Cases with a PXA morphological diagnosis diverging from the DNA class warrant attention to newer differential diagnoses such as high-grade astrocytoma with piloid features, pilocytic astrocytoma NF1-associated, and NET-PATZ1. Tumors with a MC indicative of PXA but lacking its typical features may, if high-grade, behave as grade 4 gliomas. In contrast, their low-grade counterparts could belong to the PXA morphological continuum. Further research is pivotal for cementing these findings.

Pediatric neurosurgical-oncology scope and management paradigms in Sub-Saharan Africa: a collaboration among 7 referral hospitals on the subcontinent.

Background: Understanding of the epidemiology and biology of pediatric CNS tumors has advanced dramatically over the last decade; however there remains a discrepancy in the understanding of epidemiologic data and clinical capacity between high- and lower-income countries. Objective: We collected and analyzed hospital-level burden and capacity-oriented data from pediatric neurosurgical oncology units at 7 referral hospitals in Sub-Saharan Africa (SSA). Methods: A cross sectional epidemiological survey was conducted using REDCap at the 7 SSA sites, capturing 3-month aggregate data for patients managed over a total of 9 months. Descriptive statistical analyses for the aggregate data were performed. Results: Across the neurosurgical spectrum, 15% of neurosurgery outpatient and 16% of neurosurgery operative volume was represented by pediatric neuro-oncology across the 7 study sites. Eighty-six percent and 87% of patients who received surgery underwent preoperative CT scan and/or MRI respectively. Among 312 patients evaluated with a CNS tumor, 211 (68%) underwent surgery. Mean surgery wait time was 26.6 ± 36.3 days after initial presentation at the clinic. The most common tumor location was posterior fossa (n=94, 30%), followed by sellar/suprasellar region (n=56, 18%). Histopathologic analysis was performed for 189 patients (89%). The most common pathologic diagnosis was low grade glioma (n=43, 23%), followed by medulloblastoma (n=37, 20%), and craniopharyngioma (n=31, 17%). Among patients for whom adjuvant therapy was indicated, only 26% received chemotherapy and 15% received radiotherapy. Conclusion: The histopathologic variety of pediatric brain and spinal tumors managed across 7 SSA referral hospitals was similar to published accounts from other parts of the world. About two-thirds of patients received a tumor-directed surgery with significant inter-institutional variability. Less than a third of patients received adjuvant therapy when indicated. Multi-dimensional capacity building efforts in neuro-oncology are necessary to approach parity in the management of children with brain and spinal tumors in SSA.

A Review of the Clinical Features and Management of Systemic Congenital Mastocytosis through the Presentation of An Unusual Prenatal-Onset Case.

Mastocytosis is a heterogeneous group of rare hematological disorders that can occur in infancy. We report a 16-year-old girl who presented with an aggressive form of systemic congenital mastocytosis, associated with a significant global developmental delay, deafness, and multiple anomalies. At 4 years of age, she developed a germinoma presenting as an invasive spinal mass. Extensive cytogenetic, metabolic, and molecular genetic studies that included whole-exome sequencing studies revealed a KIT alteration (NM_000222.3(KIT):c2447A > 7 pAsp816Val) and likely pathogenic variant in the DNA from peripheral blood and skin lesions. C-kit was also found to be overexpressed in the spinal tumor cells. We compared the features of this child to those of six previously reported pediatric patients with cutaneous mastocytosis, microcephaly, microtia, and/or hearing loss reported in OMIM as mastocytosis, conductive hearing loss, and microtia (MIM 248910), for which the etiology has not yet been determined. This report extends the currently recognized spectrum of KIT-related disorders and provides clues as to the potential etiology of a syndromic form of congenital mastocytosis. International efforts to understand the benefits of long-term targeted therapy with tyrosine kinase inhibitors for this KIT-altered rare disease should continue to be evaluated in clinical trials.

An image-based modeling framework for predicting spatiotemporal brain cancer biology within individual patients.

Imaging is central to the clinical surveillance of brain tumors yet it provides limited insight into a tumor's underlying biology. Machine learning and other mathematical modeling approaches can leverage paired magnetic resonance images and image-localized tissue samples to predict almost any characteristic of a tumor. Image-based modeling takes advantage of the spatial resolution of routine clinical scans and can be applied to measure biological differences within a tumor, changes over time, as well as the variance between patients. This approach is non-invasive and circumvents the intrinsic challenges of inter- and intratumoral heterogeneity that have historically hindered the complete assessment of tumor biology and treatment responsiveness. It can also reveal tumor characteristics that may guide both surgical and medical decision-making in real-time. Here we describe a general framework for the acquisition of image-localized biopsies and the construction of spatiotemporal radiomics models, as well as case examples of how this approach may be used to address clinically relevant questions.

Global, Regional, and National Incidence and Mortality Trends in Pediatric Central Nervous System Tumors over the Past 2 Decades.

BACKGROUND: Pediatric tumors of the brain and central nervous system (CNS) are a worldwide issue with variances in epidemiology. How exactly incidence and mortality rates have changed over time has not been summarized. Correspondingly, the aim of this study was to quantitively define the global, regional, and national epidemiological trends of these tumors. METHODS: A retrospective review of data from the Global Burden of Disease Study 2019 Database was performed incorporating data from 1999 to 2019. Global, regional, and national outcomes for pediatric CNS tumors were collected for incidence and mortality at a worldwide level, as well as across 7 continental regions, and then 204 countries and territories. RESULTS: Globally, the latest incidence of pediatric CNS tumors was 47,600 (uncertainty interval, 36,500-55,200) at a rate of 1.8 (1.4-2.2) per 100,000, with 23,500 (18,000-27,500) deaths due to these tumors at a rate of 0.9 (0.7-1.1) per 100,000 population. Both rates per 100,000 have decreased over the past 2 decades. With respect to regions, East Asia and Pacific had the highest incidence and mortality cases overall, but in terms of rate per 100,000, North America and Latin America and Caribbean had the highest values, respectively. There were 3/7 (43%) and 6/7 (86%) regions with decreasing incidence and mortality rates per 100,000 over the past 2 decades. China, India, and Pakistan were the 3 countries with both the highest incidence and mortality cases overall; however, San Marino, Denmark, and Norway had the highest incidence rates per 100,000, and Albania, Armenia, and Haiti had the highest mortality rates per 100,000. In the past 2 decades, 79/204 (39%) and 120/204 (59%) countries observed decreasing incidence and mortality rates per 100,000, respectively. CONCLUSIONS: Pediatric CNS tumors remains a worldwide issue, with there being multiple regions and countries worldwide that continue to experience uptrending incidence and mortality rates per 100,000. For both incidence and mortality, there is a clear discordance between regions and countries that report the highest number of cases versus the highest rate of cases per 100,000. Future research efforts are needed to identify positive intervention measures that respect the epidemiology of these tumors at global, regional, and national levels.

Leptomeningeal Metastasis: A Review of the Pathophysiology, Diagnostic Methodology, and Therapeutic Landscape.

The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer types. For our purposes, the focused metastatic malignancies include breast cancer, lung cancer, melanoma, primary central nervous system tumors, and hematologic cancers (lymphoma, leukemia, and multiple myeloma). Of note, our discussion was limited to cancer-specific leptomeningeal metastases secondary to the aforementioned primary cancers. LMD mechanisms secondary to non-cancerous pathologies, such as infection or inflammation of the leptomeningeal layer, were excluded from our scope of review. Furthermore, we intended to characterize general leptomeningeal disease, including the specific anatomical infiltration process/area, CSF dissemination, manifesting clinical symptoms in patients afflicted with the disease, detection mechanisms, imaging modalities, and treatment therapies (both preclinical and clinical). Of these parameters, leptomeningeal disease across different primary cancers shares several features. Pathophysiology regarding the development of CNS involvement within the mentioned cancer subtypes is similar in nature and progression of disease. Consequently, detection of leptomeningeal disease, regardless of cancer type, employs several of the same techniques. Cerebrospinal fluid analysis in combination with varied imaging (CT, MRI, and PET-CT) has been noted in the current literature as the gold standard in the diagnosis of leptomeningeal metastasis. Treatment options for the disease are both varied and currently in development, given the rarity of these cases. Our review details the differences in leptomeningeal disease as they pertain through the lens of several different cancer subtypes in an effort to highlight the current state of targeted therapy, the potential shortcomings in treatment, and the direction of preclinical and clinical treatments in the future. As there is a lack of comprehensive reviews that seek to characterize leptomeningeal metastasis from various solid and hematologic cancers altogether, the authors intended to highlight not only the overlapping mechanisms but also the distinct patterning of disease detection and progression as a means to uniquely treat each metastasis type. The scarcity of LMD cases poses a barrier to more robust evaluations of this pathology. However, as treatments for primary cancers have improved over time, so has the incidence of LMD. The increase in diagnosed cases only represents a small fraction of LMD-afflicted patients. More often than not, LMD is determined upon autopsy. The motivation behind this review stems from the increased capacity to study LMD in spite of scarcity or poor patient prognosis. In vitro analysis of leptomeningeal cancer cells has allowed researchers to approach this disease at the level of cancer subtypes and markers. We ultimately hope to facilitate the clinical translation of LMD research through our discourse.

Cerebrospinal fluid protein levels are elevated 100 times in a Leptomeningeal metastasis patient: a case report and literature review.

Leptomeningeal metastasis (LM) has a high degree of malignancy and high mortality. We describe a patient admitted to hospital with acute lower extremity weakness, dysuria, and high intracranial pressure. Enhanced magnetic resonance imaging (MRI) showed extensive enhancement of the leptomeningeal and spinal meninges with multiple nodular changes and extensive fusion. His cerebrospinal fluid (CSF) was yellow and cloudy, the Pandy test was strongly positive (++++), the protein was 46 g/L (normal range 0.15-0.45 g/L), which attracted our attention. Initially, miliary TB with associated tuberculous meningitis (TBM) was diagnosed, and neurosarcoidosis cannot be ruled out. After poor therapeutic effect of standard antituberculosis (anti-TB) therapy, further inspection found that malignant cells were detected by cerebrospinal fluid (CSF) cytology. PET/CT suggested the diagnosis of LM. The purpose of this paper is to describe the characteristics of atypical diffuse LM. In conclusion, when patient with unexplained high levels of CSF protein, it is necessary to be alert to the diagnosis of LM. Multiple examinations of fresh CSF are helpful to increase the positive detection rate of tumor cells. Early diagnosis and active treatment are conducive to improving survival rate.

A phase 1 study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.

BACKGROUND: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of simvastatin with topotecan and cyclophosphamide in children with relapsed/refractory solid and central nervous system (CNS) tumors. METHODS: Simvastatin was administered orally twice daily on days 1-21, with topotecan and cyclophosphamide intravenously on days 1-5 of a 21-day cycle. Four simvastatin dose levels (DLs) were planned, 140 (DL1), 180 (DL2), 225 (DL3), 290 (DL4) mg/m2 /dose, with a de-escalation DL of 100 mg/m2 /dose (DL0) if needed. Pharmacokinetic and pharmacodynamic analyses were performed during cycle 1. RESULTS: The median age of 14 eligible patients was 11.5 years (range: 1-23). The most common diagnoses were neuroblastoma (N = 4) and Ewing sarcoma (N = 3). Eleven dose-limiting toxicity (DLT)-evaluable patients received a median of four cycles (range: 1-6). There were three cycle 1 DLTs: one each grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) elevations at DL1, and one grade 4 CPK elevation at DL0. All patients experienced at least one grade 3/4 hematologic toxicity. Best overall response was partial response in one patient with Ewing sarcoma (DL0) and stable disease for four or more cycles in four patients. Simvastatin exposure increased with higher doses and may have correlated with toxicity. Plasma interleukin 6 (IL-6) concentrations (N = 6) showed sustained IL-6 reductions with decrease to normal values by day 21 in all patients, indicating potential on-target effects. CONCLUSIONS: The MTD of simvastatin with topotecan and cyclophosphamide was determined to be 100 mg/m2 /dose.