The tumor microenvironment plays a critical regulatory role in cancer progression, especially in central nervous system metastases. Cancer cells within the cerebrospinal fluid (CSF)–filled leptomeninges face substantial microenvironmental challenges, including inflammation and sparse micronutrients. To investigate the mechanism by which cancer cells in these leptomeningeal metastases (LM) overcome these constraints, we subjected CSF from five patients with LM to single-cell RNA sequencing. We found that cancer cells, but not macrophages, within the CSF express the iron-binding protein lipocalin-2 (LCN2) and its receptor SCL22A17. These macrophages generate inflammatory cytokines that induce cancer cell LCN2 expression but do not generate LCN2 themselves. In mouse models of LM, cancer cell growth is supported by the LCN2/SLC22A17 system and is inhibited by iron chelation therapy. Thus, cancer cells appear to survive in the CSF by outcompeting macrophages for iron.

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein and a member of the tyrosine kinase superfamily receptor. Gliomas are tumors originating from glial cells, which show a range of aggressiveness depending on grade and stage. Many EGFR gene alterations have been identified in gliomas, especially glioblastomas, including amplifications, deletions and single nucleotide polymorphisms (SNPs). Glioblastomas are discussed as a separate entity due to their high correlation with EGFR mutants and the reported association of the latter with survival and response to treatment in this glioma subgroup. This review is a comprehensive report of EGFR gene alterations and their relations with several clinical factors in glioblastomas and other gliomas. It covers all EGFR gene alterations including point mutations, SNPs, methylations, copy number variations and amplifications, assessed with regard to different clinical variables, including response to therapy and survival. This review also discusses the current prognostic status of EGFR in glioblastomas and other gliomas, and highlights gaps in previous studies. This serves as an update for the medical community about the role of EGFR gene alterations in gliomas and specifically glioblastomas, as a means for targeted treatment and prognosis.

This case-control study explores the association between pregnancy/birth complications and other factors with Autism Spectrum Disorder (ASD) in Lebanese subjects aged 2-18 years. Researchers interviewed 136 ASD cases from the American University of Beirut Medical Center Special Kids Clinic, and 178 controls selected by systematic digit dialing in the Greater-Beirut area. Male gender (Adjusted Odds Ratio [95% CI]: 3.9 [2.2-7.0]); postpartum feeding difficulties (2.5 [1.2-5.4]); maternal infections/complications during pregnancy (2.9 [1.5-5.5], 2.1 [1.1-3.9]); consanguinity (2.5 [1.0-6.0]); family history of psychiatric disorders (2.2 [1.1-4.4]) were risk factors for ASD. Being born first/second (0.52 [0.28-0.95]) and maternal psychological support during pregnancy (0.49 [0.27-0.89]) were negatively associated with ASD. Identifying ASD correlates is crucial for instigating timely screening and subsequent early intervention.

ObjectiveNeuronal Ceroid Lipofuscinoses (NCL) are fatal inherited neurodegenerative diseases with established neuronal cell death and increased ceramide levels in brain, hence, a need for disease‐modifying drug candidates, with potential to enhance growth, reduce apoptosis and lower ceramide in neuronal precursor PC12 cells and human NCL cell lines using enhanced flupirtine aromatic carbamate derivatives in vitro.MethodsAromatic carbamate derivatives were tested by establishing growth curves under pro‐apoptotic conditions and activity evaluated by trypan blue and JC‐1 staining, as well as a drop in pro‐apoptotic ceramide in neuronal precursor PC12 cells following siRNA knockdown of the CLN3 gene, and CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts. Ceramide levels were determined in CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts before and after treatment. Expression of BCL‐2, ceramide synthesis enzymes (CERS2/CERS6/SMPD1/DEGS2) and Caspases 3/8/9 levels were compared in treated versus untreated CLN3‐deficient PC12 cells by qRT‐PCR.ResultsRetigabine, the benzyl‐derivatized carbamate and an allyl carbamate derivative were neuroprotective in CLN3‐defective PC12 cells and rescued CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts from diminished growth and accelerated apoptosis. All drugs decreased ceramide in CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts. Increased BCL‐2 and decreased ceramide synthesis enzyme expression were established in CLN3‐derived PC12 cells treated with the benzyl and allyl carbamate derivatives. They down‐regulated Caspase 3/Caspase 8 expression. Caspase 9 expression was reduced by the benzyl‐derivatized carbamate.InterpretationThese findings establish that compounds analogous to flupirtine demonstrate anti‐apoptotic activity with potential for treatment of NCL disease and use of ceramide as a marker for these diseases.

Background: Leptomeningeal metastasis (LM), or spread of cancer cells into the cerebrospinal fluid (CSF), is characterized by a rapid onset of debilitating neurological symptoms and markedly bleak prognosis. The lack of reproducible in vitro and in vivo models has prevented the development of novel, LM-specific therapies. Although LM allows for longitudinal sampling of floating cancer cells with a spinal tap, attempts to culture patient-derived leptomeningeal cancer cells have not been successful.Aim: We, therefore, employ leptomeningeal derivatives of human breast and lung cancer cell lines that reproduce both floating and adherent phenotypes of human LM in vivo and in vitro. Methods and Results:We introduce a trypsin/EDTA-based fractionation method to reliably separate the two cell subsets and demonstrate that in vitro cultured floating cells have decreased proliferation rate, lower ATP content, and are enriched in distinct metabolic signatures. Long-term fractionation and transcriptomic analysis suggest high degree plasticity between the two phenotypes in vitro. Floating cells colonize mouse leptomeninges more rapidly and associate with shortened survival. In addition, patients harboring LM diagnosed with CSF disease alone succumbed to the disease earlier than patients with adherent (MRI positive) disease. Conclusion:Together, these data support mechanistic evidence of a metabolic adaptation that allows cancer cells to thrive in their natural environment but leads to death in vitro.

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Treating adult low-grade gliomas (LGGs) is particularly challenging due to the highly infiltrative nature of this type of brain cancer. Although surgery, radiotherapy, and chemotherapy are the mainstay treatment modalities for LGGs, the optimal combination management plan for a particular patient based on individual symptoms and the risk of treatment-induced toxicity remains unclear. This review highlights the competency and limitations of standard treatment options while providing an essential therapeutic update regarding current clinical trials aimed at implementing targeted therapies with morbidity rates lower than those for current LGG treatments and also augmenting the killing of cancerous cells while maintaining an improved quality of life.

This study reveals 5 risk factors for postoperative seizures after resection of supratentorial tumors. These factors should be considered in postoperative management of these patients.