Central Nervous System Tumors Research Articles

Oral Mucositis in Children with Cancer in Southeast of Iran: A Single Center Study

Background: Oral mucositis is a significant side effect in patients undergoing chemotherapy or radiotherapy, particularly in pediatric oncology. Objectives: This study aimed to investigate the prevalence of chemotherapy-induced oral mucositis and its associated factors in children with malignancies. Methods: This descriptive, prospective study included 100 children under 16 years of age with lymphohematopoietic malignancies, solid tumors, or central nervous system tumors admitted to the pediatric oncology department due to mucositis. Patients were categorized into three age groups: Zero - 5 years, 6 - 10 years, and 11 - 16 years. Data collected included demographic details such as age, sex, type of malignancy, and mucositis severity. The chi-square statistical test was used for data analysis. Results: The average age of participants was 7.84 ± 3.93 years. Sixty-one percent of the patients were boys, and 39% were girls. The age group 0 - 5 years had the highest prevalence of mucositis, while the 11 - 16 years age group had the lowest. The majority of mucositis cases (64%) were observed in children with acute lymphoblastic leukemia (ALL), followed by acute myeloblastic leukemia (AML) patients (12%), and other malignancies (24%). Grade II mucositis was the most common, affecting 34% of patients, while grade IV mucositis was the least common, affecting 13% of patients. Conclusions: Chemotherapy-induced oral mucositis was most prevalent among children with acute leukemia, constituting three-quarters of the cases. Grade II mucositis was the most frequently observed severity level, while grade IV mucositis was the least frequent. These findings underscore the need for targeted strategies to manage and prevent mucositis, particularly in high-risk groups like pediatric leukemia patients.

Does Adjuvant Radiotherapy Enhance Survival in Intracranial Solitary Fibrous Tumor Patients?

Intracranial solitary fibrous tumor (SFT) is a rare central nervous system (CNS) tumor that lacks a reliable prognostic clinical model. Uncertainty persists regarding the treatment outcomes of surgery and adjuvant radiotherapy (ART). To address this, we investigated the efficacy of ART and applied machine learning (ML) to develop accurate prognostic models. The SEER database was used for this study's analysis. To identify the prognostic variables, we conducted Cox regression analysis and constructed prognostic models using five ML algorithms to predict 5-year survival. A validation method incorporating the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to validate the accuracy and reliability of the models. We investigated the role of ART and surgery using Kaplan Meier survival analysis, competing risk analysis and BRACE method. The study population comprised 747 patients. Among them are 316 patients with "surgery" and 431 patients with "surgery + ART." The therapeutic groups showed significant differences in overall survival (OS). Multivariate Cox regression analysis revealed that older age and surgery alone were poor prognostic factors. The most significant prognostic factors were the local tumor excision, followed by lobectomy and age. Although ART did not lead to a substantial decrease in cancer-specific deaths, it did improve OS. This underscores the broader health benefits of ART, including effective management of comorbid conditions. Caution is advised when interpreting these survival benefits because of potential confounding factors in patient health and treatment management. Our web tool and ML models aid in clinical decision-making.

Postoperative complications after central nervous system tumor resection in pediatric patients admitted to an intensive care unit in Colombia

IntroductionCentral nervous system (CNS) tumors are the second most prevalent malignant neoplasms in childhood, with surgical resection as the primary therapeutic approach. The immediate postoperative period following CNS tumor resection requires intensive care to mitigate complications associated with high morbidity and mortality. ObjectiveThe primary aim of this study is to comprehensively describe the postoperative complications observed in pediatric patients who underwent primary CNS tumor resection and were subsequently admitted to the pediatric intensive care unit (PICU) at Hospital Universitario Fundación Valle del Lili in Colombia.MethodsWe conducted a cross-sectional observational analysis of pediatric patients who underwent surgery for CNS tumors and were admitted to our PICU from January 2011 to December 2021. Clinical, histopathologic, and postoperative complication data were collected. A descriptive statistical analysis was performed using measures of dispersion and central tendency with a 95% confidence interval.ResultsA total of 114 patients were included, of whom 55.3% were male. The median PICU stay was 4 days (2–7). The most common tumor type was embryonal (25.4%), followed by low-grade glioma (20.1%) and high-grade glioma (14.9%). Mechanical ventilation was required in 24.5% of patients, with a median extubation time of 3 days (2–9). In the immediate postoperative period, 6.14% of patients experienced CNS hemorrhage and 3.5% experienced intracranial hypertension. Common complications included motor deficits, facial paralysis, and sensory deficits. The mortality rate was 3.5%.ConclusionThis study describes the postoperative complications, clinical challenges, and interventions observed in pediatric patients after CNS tumor resection in a resource-limited country. Our findings emphasize the importance of tailored interventions and multidisciplinary collaboration to optimize clinical outcomes. Future data comparison from centers sharing similar characteristics will play a crucial role in identifying best practices and enhancing outcomes globally.

Survival Outcomes Following Chemotherapy for High-Grade Central Nervous System Tumors in Adolescents and Young Adults: An Exploration of Variations According to Ethnicity and Deprivation.

Introduction: Adolescents and young adults (AYA) are a unique subgroup of patients who experience cancer at the interface between pediatric and adult oncology services. Central nervous system (CNS) tumors are the leading cause of cancer-related morbidity and mortality in this group. Socioeconomic status and ethnicity are known to impact CNS tumor survival in patients of all ages. Studies reporting AYA CNS survival outcomes by ethnicity and area-based deprivation, however, are lacking in the United Kingdom (UK). Methods: Using cancer registration data for 351 patients (12-29 years) who received systemic chemotherapy for a high-grade malignant CNS tumor in England between April 2014 and December 2018, we quantified differences in survival at 1, 2, and 3 years post-diagnosis by ethnicity and area-based socioeconomic status. Results: Lower survival estimates were seen for non-White ethnicity and lower socioeconomic groups. Three-year survival was 64.4% (95% CI 58.3-69.9) for White patients but 46.6% (95% CI 29.9-61.7) for non-Whites and 64.0% (95% confidence interval [CI]49.0-75.7) and 62.9% (95% CI 50.7-72.8) in those from the two least deprived fifths compared to 50.2% (95% CI 36.1-62.7) and 56.1% (95% CI 42.4-67.7) in the two most deprived groups. Conclusion: Our study is the first to show the existence of health disparities in AYA treated with chemotherapy for a primary CNS tumor in England, where patients from ethnic minorities and deprived areas had worse survival rates than their White and socioeconomically advantaged counterparts. These findings call for further research into the underlying reasons behind survival differences between sociodemographic groups to improve survivorship outcomes.

Aggressiveness of Care at the End of Life of Children Dying with Cancer in Public Hospitals-A Nationwide Retrospective Cohort Study.

Background: Little is known about the aggressiveness of cancer care at the end of life (ACCEoL) for children with cancer in countries where palliative care (PC) is scarce. Objective: The aim of this study was to determine the frequency and time trends of ACCEoL in the pediatric population in a Western European country. Setting/Subjects: We conducted a retrospective cohort study analyzing children between 0 and 17 years who died of cancer in public hospitals in Portugal, from January 2010 to December 2015. Measurements: Hospital admissions during the last month of life were identified and we analyzed the length of stay and procedures performed. The ACCEoL was measured with a composite indicator. Results: We identified 300 children, with a median age of 9 years. A total of 58.7% were male and 31.3% had central nervous system tumors. We found at least one indicator of ACCEoL in 87.8% of patients. "More than 14 days spent in the hospital" (51.0%) and "more than one hospitalization" (43.3%) were the most frequent individual indicators. Infants and children with hematological malignancies had a numerically higher percentage of ACCEoL. We found no statistically significant differences in the frequencies of the ACCEoL among the subgroups. The prevalence of ACCEoL remained stable over the period. Conclusions: In our cohort about 9 out of 10 children with cancer experienced at least one indicator of ACCEoL, a rate higher than in countries with well-developed PC services. There is a need to improve the care in the last months of life for children with cancer.

Monitoring central nervous system tumour metabolism using cerebrospinal fluid

Central nervous system (CNS) tumours are the most common cancer cause of death in under 40s in the UK, largely because they persist and recur and sometimes metastasise during treatment. Therefore, longitudinal monitoring of patients during and following treatment must be undertaken to understand the course of the disease and alter treatment plans reactively. This monitoring must be specific, sensitive, rapid, low cost, simple, and accepted by the patient. Cerebrospinal fluid (CSF) examination obtained following lumbar puncture, already a routine part of treatment in paediatric cases, could be better utilised with improved biomarkers. In this review, we discuss the potential for metabolites in the CSF to be used as biomarkers of CNS tumour remission, progression, response to drugs, recurrence and metastasis. We confer the clinical benefits and risks of this approach and conclude that there are many potential advantages over other tests and the required instrumentation is already present in UK hospitals. On the other hand, the approach needs more research investment to find more metabolite biomarkers, better understand their relation to the tumour, and validate those biomarkers in a standardised assay in order for the assay to become a clinical reality.

Pediatric neuro-oncology: Highlights of the last quarter-century

The last quarter century has heralded dramatic changes in the field of pediatric neuro-oncology, with the era defined by profound developments in the understanding of the biological underpinnings of childhood central nervous system (CNS) tumors and translational therapeutics. Although there have been momentous strides forward in biologic, diagnostic, therapeutic, and experimental domains, considerable challenges remain and CNS tumors remain the leading cause of pediatric cancer-related mortality. Here, we review the significant advances in the field of pediatric neuro-oncology over the last 25 years and highlight ongoing hurdles facing future progress.

Clinical characteristics and outcome of central nervous system tumors harboring NTRK gene fusions.

TRK fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. We conducted an international retrospective cohort study of patients with TRK fusion-driven CNS tumors. 119 patients were identified. The median age at time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG) (57.1%) followed by low-grade glioma (LGG) (27.7%). Pediatric patients had a better prognosis with a median overall survival of 185.5 months compared to 24.8 months in adults (p<.0001). Patients with LGG also had a better outcome when compared to HGG (p=0.0012). The objective response was 68.8% with larotrectinib compared to 38.1% for non-targeted treatment. Children with LGG glioma had a favorable outcome compared to adult and HGG. TRK inhibitors appear to improve tumor control.

Liquid Biopsy for Evaluating Mutations and Chromosomal Aberrations in Cerebrospinal Fluid from Patients with Primary or Metastatic Central Tumors

BackgroundCytopathology analysis of cerebrospinal fluid (CSF) is limited in detecting tumors in patients with suspected primary or metastatic central nervous system (CNS) malignancy. We investigated the use of CSF liquid biopsy (LBx) to detect neoplastic processes in the CNS. Methods: Cell-free DNA (cfDNA) from the CSF of patients with suspected metastatic (N=106) or primary CNS (N=23) tumors was deep sequenced using a 302-gene panel. ResultsFour samples (3%) (3 metastatic and 1 primary) failed sequencing quality control criteria. Metastatic tumor was confirmed in 84 (82%) of the 103 patients suspected of metastatic tumor. Primary CNS tumor was confirmed in 11 of 22 (50%) patients suspected of CNS tumor. Chromosomal abnormalities were detected in 55 samples (54%). Germline mutations were detected in 23 (22%) patients with metastatic tumors and in 1 (5%) with a primary CNS tumor. Of the 29 patients with metastatic breast cancers, 2 (7%) had mutations in ESR1 and 9 (31%) had mutations in PIK3CA. Of the 21 patients with metastatic lung cancer, 9 (43%) had EGFR mutations and 5 (24%) had KRAS mutations. Upon comparing CSF LBx with peripheral blood LBx in 14 patients, 13 (93%) showed only CHIP and one patient showed CNS primary tumor mutation. Serial samples from 14 patients demonstrate that CSF LBx can be used for monitoring therapy efficacy. ConclusionsLBx using CSF is clinically reliable and provides informative results in a substantial proportion of patients with metastatic CNS tumors and to a lesser degree in patients with primary CNS tumors.

The impact of methylome analysis on the diagnosis and treatment of CNS tumours in children and adolescents: a population-based study in Greece.

BackgroundThe recently published WHO classification of central nervous system (CNS) tumours recognizes DNA methylation profiling as a desirable and, for some diagnoses, essential diagnostic tool adjunctive to conventional histopathology. DNA methylation profiling is not routinely available in many countries, including Greece. MethodsIn this collaborative study, we report the DNA methylation results in a series of children and adolescents with CNS tumours in Greece (2018-2023). In total, 130 tumour samples were analyzed using the latest applicable version of the Heidelberg brain tumour classifier. ResultsUpon initial analysis, 80% (104/130) achieved calibrated scores (Cs) ≥0.9 and matched an established methylation class family/subclass. Among them, methylation results confirmed (90/104, 86.5%), refined (50/104, 48%) or changed (10/104, 9.6%) the histological diagnosis. Only four results were regarded as non-contributing (4/104, 3.9%). Twenty-six tumour samples received Cs <0.9. Despite low scores, methylation results supported the initial diagnosis with lower confidence in 38.5% (10/26) and established the diagnosis in two tumours with non-conclusive histopathology. Additional t-distributed stochastic neighbour embedding (t-SNE) analysis allowed the possible classification of twelve tumours. Nine more samples reached high Cs using the newer brain tumour classifiers, since available. Samples co-tested in Greece demonstrated excellent test reproducibility, supporting the analysis' local implementation. Methylome profiling impacted the clinical management of 40% of patients, modifying stratification, prognosis, or treatment approach. ConclusionsThis study supports the need to integrate methylome analysis into routine diagnostics in our country and highlights the importance of collaboration between European pediatric oncology centres.

Exploration of the biological mechanisms of CENPA as an oncogene in glioma: Screening based on cancer functional status

AbstractGlioma is the most common primary tumour in central nervous system, characterized by high invasiveness, a high recurrence rate and extremely poor prognosis. Machine learning based on cancer functional state helps to combine multi‐omics methods to screen for key gene, such as CENPA, that influences the phenotype of glioma and patients' prognosis. Based on 14 CFS, glioma was divided into three subtypes. Bioinformatics and machine learning methods were utilized to develop an enhanced prognostic prediction signature based on three subtypes. We selected CENPA as a hub biomarker and conducted in vitro experiments such as IHC, western blot, Coip, transwell, cck8, flow cytometry, scratch assay, qPCR, AlphaFold, MOE and in vivo experiments. We identified three subtypes of glioma based on the 14 CFS. The C subtype exhibits poor clinical outcomes, increased carbohydrate and nucleotide metabolism, high infiltration of immune cells, high CNV and tumour mutation burden (p &lt; 0.05). The differential expression of gene between three subtypes were used to construct a novel signature with improved performance in prognostic prediction via machine learning. CENPA was selected as the hub gene, in vitro experiments such as ihc, western blot and qPCR showed that CENPA had high expression in tissues and cell lines (p &lt; 0.05). The scratch assay, edu, cck8, flow cytometry and transwell after CENPA knockdown or overexpression had significant effects on the functions of glioma. Meanwhile, CENPA was regulated by EZH2 and influenced downstream wnt pathway, affecting phosphorylation of two sites, Ser675 and Ser552, on β‐catenin. The effect of CENPA knockdown was reversed by drug CHIR‐99021. Animal experiments indicated that the tumour volume of control and overexpression group increased faster, especially the overexpression group, which was significantly faster (p &lt; 0.001). Machine learning based on CFS is beneficial for the selection of key genes and disease assessment. In glioma, CENPA is positively correlated with WHO grading at both the gene and protein levels, and high CENPA affects patients' poor prognosis. Regulating CENPA can affect functions of glioma, and these phenomena may act through the EZH2/CENPA/β‐catenin signalling axis. CENPA knockdown can be reversed by the drug CHIR‐99021. CENPA may become one of the therapeutic targets in glioma.

Phenotypic and epigenetic heterogeneity in FGFR2-fused glial and glioneuronal tumours.

FGFR-fused central nervous system (CNS) tumours are rare and are usually within the glioneuronal and neuronal tumours or the paediatric-type diffuse low-grade glioma spectrum. Among this spectrum, FGFR2 fusion has been documented in tumours classified by DNA-methylation profiling as polymorphous low-grade neuroepithelial tumours of the young (PLNTY), a recently described tumour type. However, FGFR2 fusions have also been reported in glioneuronal tumours, highlighting the overlapping diagnostic criteria and challenges. We investigated the FGFR2 fusion landscape in a French national series of tumours sent to the RENOCLIP-LOC network. We comprehensively analysed histology, radiology and molecular data including DNA-methylation profiling for 16 FGFR2-fused glioneuronal tumours. Most tumours were located in the temporal or parietal lobe with a median age at diagnosis of 7years [1-44]. Epilepsy was the most frequent symptom. Five patients had tumour progression or recurrence with a median progression-free survival of 22.6months. Histological phenotypes corresponding to PLNTY, GG, MVNT or unclassified tumours were recorded. Epigenetic profiling could not properly distinguish epigenetic clusters related to the GG and PLNTY methylation classes among FGFR2-fused glioneuronal tumours. However, a neuroradiological review identified strikingly distinct neuroradiological patterns. While delineating tumour types among the FGFR2-fused glioneuronal tumour spectrum, by histopathology or DNA-methylation profiling, remains challenging, neuroimaging data revealed two distinct patterns that could correlate to PLNTY and ganglioglioma. However, more series including extensive histo-radio-molecular data are needed to confirm this hypothesis.

Pathological diagnosis of central nervous system tumours in adults: what’s new?

Pathological diagnosis of central nervous system tumours in adults: what’s new?

CAR-T Cells for the Treatment of Central Nervous System Tumours: Known and Emerging Neurotoxicities

The advent of chimeric antigen receptor (CAR)-T cells has recently changed the prognosis of relapsing/refractory diffuse large B-cell lymphomas, showing response rates as high as 60 to 80%. Common toxicities reported in the pivotal clinical trials include the cytokine release syndrome (CRS) and the Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), a stereotyped encephalopathy related to myeloid cell activation and blood–brain barrier dysfunction, presenting with a distinctive cascade of dysgraphia, aphasia, disorientation, attention deficits, vigilance impairment, motor symptoms, seizures, and diffuse brain oedema. The tremendous oncological efficacy of CAR-T cells observed in systemic B-cell malignancies is leading to their growing use in patients with primary or secondary central nervous system (CNS) lymphomas and in patients with solid tumours, including several CNS cancers. Early studies conducted in adult and paediatric patients with solid CNS tumours reported a distinct profile of neurotoxicity referred to as Tumour inflammation-associated neurotoxicity (TIAN), corresponding to local inflammation at the tumour site manifesting with focal neurological deficits or mechanical complications (e.g., obstructive hydrocephalus). The present review summarises available data on the efficacy and safety of CAR-T cells for solid and haematological CNS malignancies, emphasising known and emerging phenotypes, ongoing challenges, and future perspectives.

Exosomes in Central Nervous System Diseases: A Comprehensive Review of Emerging Research and Clinical Frontiers

Exosomes, nano-sized lipid bilayer vesicles, have garnered significant attention as mediators of cell communication, particularly within the central nervous system (CNS). Their unique properties, including high stability, low immunogenicity, and the ability to traverse the blood-brain barrier (BBB), position them as promising tools for understanding and addressing CNS diseases. This comprehensive review delves into the biogenesis, properties, composition, functions, and isolation of exosomes, with a particular focus on their roles in cerebrovascular diseases, neurodegenerative disorders, and CNS tumors. Exosomes are involved in key pathophysiological processes in the CNS, including angiogenesis, inflammation, apoptosis, and cellular microenvironment modification. They demonstrate promise in mitigating ischemic injury, regulating inflammatory responses, and providing neuroprotection across various CNS conditions. Furthermore, exosomes carry distinct biomolecules, offering a novel method for the early diagnosis and monitoring of CNS diseases. Despite their potential, challenges such as complex extraction processes, the heterogeneity of exosomal contents, and targeted delivery limitations hinder their clinical application. Nevertheless, exosomes hold significant promise for advancing our understanding of CNS diseases and developing novel therapeutic strategies. This manuscript significantly contributes to the field by highlighting exosomes’ potential in advancing our understanding of CNS diseases, underscoring their unique value in developing novel therapeutic strategies and mediating cellular communication.

Implications of sociodemographic and clinical factors on symptom burden: age-specific survivorship care in the primary central nervous system tumor population

Abstract Background This analysis aims to provide insight into differences in symptom burden and general health status between young adults (YA; 18-39 years old) and older adults (OA; ≥40 years old) with primary central nervous system tumors (PCNST). Methods Data were retrospectively analyzed from the National Cancer Institute Neuro-Oncology Branch’s Natural History Study (NCT02851706 PI: T.S. Armstrong) to determine differences in patient-reported outcomes (general health status [EQ-5D-3L], symptom burden [MDASI-BT and MDASI-SP], anxiety/depression [PROMIS], and perceived cognition [Neuro-QOL]) and demographic and clinical data using chi-square, one-way ANOVA, and Student’s t-tests. Linear regression with backward elimination determined which characteristics impacted perceived symptom burden and general health status. Results The sample included 271 YA (82% with a primary brain tumor (PBT); median age 31 [range, 18-39]) and 516 OA (88% with a PBT; median age 54 [range, 40-85]). YA were more likely to be single (P&amp;lt;0.001), employed (P&amp;lt;0.001), and make &amp;lt; $50,000 per year (P=0.014). More YA reported pain (P=0.008), nausea (P&amp;lt;0.001), drowsiness (P=0.043), and vomiting (P=0.001) than OA. Among demographic and clinical characteristics, when controlling for age, Karnofsky Performance Scale score (P&amp;lt;0.001) and employment status (P&amp;lt;0.001) were predictors of symptom interference, activity- and mood-related interference in patients with PBTs. Compared to OA with spinal tumors, YA reported more moderate-severe anxiety (P=0.050) and moderate-severe perceived cognitive deficits (P=0.023). Conclusions Significant differences in characteristics and symptom burden exist between YA and OA. Developmentally tailored survivorship programs providing additional psychosocial support and resources to address symptom presentation in YA are needed.

A four-hit mechanism is sufficient for meningioma development.

Meningiomas are central nervous system tumors whose incidence increases with age. Benign meningioma pathogenesis involves germline or somatic mutation of target genes, such as NF2, leading to clonal expansion. We used an established cancer epidemiology model to investigate the number of rate-limiting steps sufficient for benign meningioma development. Incidence data was obtained from the Surveillance, Epidemiology and End Results Program (SEER) for nonmalignant meningioma from 2004 to 2020. Age-adjusted incidence rates per 100,000 person-years were divided into 5-year bands. This was repeated for vestibular schwannomas as a negative control. The Armitage-Doll methodology was applied. Mathematical solutions correcting for volatile tumor microenvironments were applied to fit higher-order models using polynomial regression when appropriate. A 75:25 training:test split was utilized for validation. 222,509 cases of benign meningiomas were identified. We noted strong linear relationships between log-transformed incidence and age across the cohort and multiple subpopulations: male, white, black, Hispanic, Asian/Pacific Islander, and American Indian subpopulations all demonstrated R2 = 0.99. Slopes were between 3.1 and 3.4, suggesting a four-step process for benign meningioma development. Female patients exhibited nonlinear deviations, but the corrected model demonstrated R2 = 0.99 with a four-hit pathway. This model performed robustly on test data with R2 = 0.99. Vestibular schwannomas demonstrated a slope of 2.1 with R2 = 0.99, suggesting a separate three-step process. Four mutations are uniquely required for the development of benign meningiomas. Correcting for volatile tumor microenvironments reliably accounted for nonlinear deviations in behavior. Further studies are warranted to elucidate genomic findings suggestive of key mutations in this pathway.

Desmoplastic myxoid tumor of the pineal region, SMARCB1 mutant: illustrative case.

Desmoplastic myxoid tumor (DMT) of the pineal region, SMARCB1 mutant is a newly proposed tumor in the 2021 World Health Organization classification of central nervous system tumors. Based on a comprehensive literature review, only 10 cases have been reported so far. Here, the authors describe a 50-year-old female who presented with sudden headache and dizziness combined with paralysis of upward gaze. Imaging studies showed a pineal region mass with obstructive hydrocephalus. The patient underwent a pineal region tumor resection, and the pathological result confirmed the diagnosis of DMT, SMARCB1 mutant. This case showed a patient with DMT, SMARCB1 mutant with a relatively low Ki-67 proliferation index (less than 1%), clinically combined with typical Parinaud's syndrome. At the same time, the follow-up of this case may provide a better understanding of the prognosis of this specific kind of tumor. https://thejns.org/doi/10.3171/CASE24419.

Mechanistic Modeling of Spatial Heterogeneity of Drug Penetration and Exposure in the Human Central Nervous System and Brain Tumors.

Direct measurement of spatial-temporal drug penetration and exposure in the human central nervous system (CNS) and brain tumors is difficult or infeasible. This study aimed to develop an innovative mechanistic modeling platform for quantitative prediction of spatial pharmacokinetics of systemically administered drugs in the human CNS and brain tumors. A nine-compartment CNS (9-CNS) physiologically-based pharmacokinetic model was developed to account for general anatomical structure and pathophysiological heterogeneity of the human CNS and brain tumors. Drug distribution into and within the CNS and tumors is driven by plasma concentration-time profiles and governed by drug properties and CNS pathophysiology. The model was validated by comparisons of model predictions and clinically observed data of six drugs (abemaciclib, ribociclib, pamiparib, olaparib, temuterkib, and ceritinib) in glioblastoma patients. As rigorously validated, the 9-CNS model allows reliable prediction of spatial pharmacokinetics in different regions of the brain parenchyma (i.e., parenchyma adjacent to CSF and deep parenchyma), tumors (i.e., tumor rim, bulk tumor, and tumor core), and CSF (i.e., ventricular CSF, cranial and spinal subarachnoid CSF). By considering inter-individual plasma pharmacokinetic variability and CNS/tumor heterogeneity, the model well predicts the inter-individual variability and spatial heterogeneity of drug exposure in the CNS and tumors as observed for all six drugs in glioblastoma patients. The 9-CNS model is a first-of-its kind, mechanism-based computational modeling platform that enables early reliable prediction of spatial CNS and tumor pharmacokinetics based on plasma concentration-time profiles. It provides a valuable tool to assist rational drug development and treatment for brain cancer.

Research progress on the use of the optical coherence tomography system for the diagnosis and treatment of central nervous system tumors

Research progress on the use of the optical coherence tomography system for the diagnosis and treatment of central nervous system tumors