Molecular Sequence of Events and Signaling Pathways in Cerebral Metastases

Brain metastases are the leading cause of morbidity and mortality among cancer patients, and are reported to occur in about 40% of cancer patients with metastatic disease in the United States of America. Primary tumor cells appear to detach from the parent tumor site, migrate, survive and pass through the blood brain barrier in order to establish cerebral metastases. This complex process involves distinct molecular and genetic mechanisms that mediate metastasis from these primary organs to the brain. Furthermore, an interaction between the invading cells and cerebral milieu is shown to promote this process as well. Here, we review the mechanisms by which primary cancer cells metastasize to the brain via a mechanism called epithelial-to-mesenchymal transition, as well as the involvement of certain microRNA and genetic aberrations implicated in cerebral metastases from the lung, breast, skin, kidney and colon. While the mechanisms governing the development of brain metastases remain a major hindrance in treatment, understanding and identification of the aforementioned molecular pathways may allow for improved management and discovery of novel therapeutic targets

Molecular Stratification of Medulloblastoma: Clinical Outcomes and Therapeutic Interventions

Medulloblastoma (MB) is the most common malignant pediatric posterior fossa tumor. Recent genetic, epigenetic, and transcriptomic analyses have classified MB into three subgroups, Wingless Type (WNT), Sonic Hedgehog (SHH), and non-WNT/non-SHH (originally termed Group 3 and Group 4), with discrete patient profiles and prognoses. WNT is the least common subgroup with the best prognosis, characterized by nuclear β-catenin expression, mutations in Catenin beta-1 (CTNNB1), and chromosome 6 monosomy. SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway. Originally, the presence of TP53 gene alterations and/or MYC amplifications was considered the most reliable prognostic factor. However, recent molecular analyses have subdivided SHH MB into several subtypes with distinct characteristics such as age, TP53 mutation, MYC amplification, presence of metastases, TERT promoter alterations, PTEN loss, and other chromosomal alterations as well as SHH pathway-related gene mutations. The third non-WNT/non-SHH MB (Group3/4) subgroup is genetically highly heterogeneous and displays several molecular patterns, including MYC and OTX2 amplification, GFI1B activation, KBTBD4 mutation, GFI1 rearrangement, PRDM6 enhancer hijacking, KDM6A mutation, LCA histology, chromosome 10 loss, isochromosome 17q, SNCAIP duplication, and CDK6 amplification. However, based on molecular profiling and methylation patterns, additional non-WNT/non-SHH MB subtypes have been described. Recent WHO (2021) guidelines stratified MB into four molecular subgroups with four and eight further subgroups for SHH and non-WNT/non-SHH MB, respectively. In this review, we discuss advancements in genetics, epigenetics, and transcriptomics for better characterization, prognostication, and treatment of MB using precision medicine

Resting-state functional MRI connectivity impact on epilepsy surgery plan and surgical candidacy: prospective clinical work

OBJECTIVE: The authors\u27 goal was to prospectively quantify the impact of resting-state functional MRI (rs-fMRI) on pediatric epilepsy surgery planning. METHODS: Fifty-one consecutive patients (3 months to 20 years old) with intractable epilepsy underwent rs-fMRI for presurgical evaluation. The team reviewed the following available diagnostic data: video-electroencephalography (n = 51), structural MRI (n = 51), FDG-PET (n = 42), magnetoencephalography (n = 5), and neuropsychological testing (n = 51) results to formulate an initial surgery plan blinded to the rs-fMRI findings. Subsequent to this discussion, the connectivity results were revealed and final recommendations were established. Changes between pre- and post-rs-fMRI treatment plans were determined, and changes in surgery recommendation were compared using McNemar\u27s test. RESULTS: Resting-state fMRI was successfully performed in 50 (98%) of 51 cases and changed the seizure onset zone localization in 44 (88%) of 50 patients. The connectivity results prompted 6 additional studies, eliminated the ordering of 11 further diagnostic studies, and changed the intracranial monitoring plan in 10 cases. The connectivity results significantly altered surgery planning with the addition of 13 surgeries, but it did not eliminate planned surgeries (p = 0.003). Among the 38 epilepsy surgeries performed, the final surgical approach changed due to rs-fMRI findings in 22 cases (58%), including 8 (28%) of 29 in which extraoperative direct electrical stimulation mapping was averted. CONCLUSIONS: This study demonstrates the impact of rs-fMRI connectivity results on the decision-making for pediatric epilepsy surgery by providing new information about the location of eloquent cortex and the seizure onset zone. Additionally, connectivity results may increase the proportion of patients considered eligible for surgery while optimizing the need for further testing