Background: Recently, the ketogenic diet has been proposed as an adjunct treatment for a range of medical conditions including weight loss, diabetes, cancer, and neurodegenerative diseases. Because malignant CNS tumors are highly dependent on glucose, the use of a ketogenic diet as an adjunct therapy is currently being explored. This case series summarizes our experience implementing a ketogenic diet for patients with CNS malignancies.Methods: Patients diagnosed with CNS malignancies following a ketogenic diet were identified between 2015 and 2017. Malignancies included confirmed diagnoses of glioblastoma (GBM), astrocytoma, or oligodendroglioma. With guidance from a registered dietitian, ketone levels, glucose levels, and weight were regularly collected for several patients along with patient-reported symptoms and adverse effects. Interested patients were asked to follow a 3:1 ketogenic diet for 120 days. The ketogenic diet is a high-fat, moderate protein, and very low carbohydrate diet, where patients limited carbohydrate intake to ≤20 g per day. Brain imaging was reviewed. A series of descriptive analyses were conducted.Results: The ketogenic diet was initiated in 12 patients of which 8 patients contributed data on their blood glucose and ketone levels. The majority of patients were male (n = 10) with a median age of 45 (range 32-62). Diagnoses included GBM (n = 6), grade 2/3 astrocytomas (n = 5) and one patient with a grade 2 spinal cord astrocytoma. Ten of the 12 patients were receiving concurrent treatment; two received supportive care only. The majority of patients with evaluable data (n = 8) maintained ketone levels above 0.5 mM for the duration of 120-day period. Ketone levels generally increased from baseline while glucose levels and BMI decreased. Overall, patients reported improved symptoms over the course of the diet. Imaging also suggested improved disease control and reduction in vasogenic edema. Conclusion:Taking advantage of a tumor's metabolic inflexibility can have a positive impact on patients, particularly those with CNS malignancies. More structured and statistically planned clinical trials are needed to determine the margin of impact of a ketogenic diet.

Rationale Gaps in our understanding of glutamatergic signaling may be key obstacles in accurately modeling complex CNS diseases. System xc− is an example of a poorly understood component of glutamate homeostasis that has the potential to contribute to CNS diseases. Objectives To determine whether system xc− contributes to behaviors used to model features of CNS disease states. Methods In situ hybridization was used to map mRNA expression of xCT throughout the brain. Microdialysis in the prefrontal cortex was used to sample extracellular glutamate levels; HPLC was used to measure extracellular glutamate and tissue glutathione concentrations. Acute administration of sulfasalazine (8–16 mg/kg, IP) was used to decrease system xc− activity. Behavior was measured using attentional set shifting, elevated plus maze, open-field maze, Porsolt swim test, and social interaction paradigm. Results The expression of xCT mRNA was detected throughout the brain, with high expression in several structures including the basolateral amygdala and prefrontal cortex. Doses of sulfasalazine that produced a reduction in extracellular glutamate levels were identified and subsequently used in the behavioral experiments. Sulfasalazine impaired performance in attentional set shifting, reduced the amount of time spent in an open arm of an elevated plus maze and the center of an open-field maze without altering behavior in a Porsolt swim test, total distance moved in an open-field maze, or social interaction. Conclusions The widespread distribution of system xc− and involvement in a growing list of behaviors suggests that this form of nonvesicular glutamate release is a key component of excitatory signaling.

A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F-S-CH 3 (2), an α2/α3/α5 (Bz)GABA (A)ergic receptor subtype selective ligand, which reverses PCP-induced prepulse inhibition (PPI) of acoustic startle, were synthesized. These chiral (S)-CH 3 ligands are targeted for the treatment of schizophrenia and depression. These new ligands were designed by modifying the labile ester functionality in 2 to improve the metabolic stability, cytotoxicity, and activity as compared to 2. Based on the data to date, the most promising ligands are the N-cyclopropyl amide GL-I-55 (8c) and the methyl bioisostere GL-I-65 (9a). The in vitro metabolic stability, cytotoxicity and in vivo locomotor effects are described in this report. Based on these results, 8c and 9a are the most promising for further in vivo pharmacology.

BACKGROUND Many patients with CNS tumors express interest in initiating a ketogenic diet (KD). Following a discussion with the physician regarding the limited clinical evidence of KD for CNS tumors, interested patients were referred for evaluation by an oncology-certified dietitian. METHODS We performed a single institution retrospective chart review of patients with CNS tumors on a KD. Demographics, clinical characteristics, and diet information were extracted from patient charts. Descriptive statistics were conducted to summarize patterns of adherence to KD across patient characteristics. RESULTS From May 2016 to May 2018, 40 patients expressed interest in KD; 24 initiated it. M:F = 18:6, median age 46 (range 27–62). Diagnoses: 18 glioblastoma, 1 anaplastic astrocytoma, 2 grade 2 astrocytoma, 1 grade 2 oligodendroglioma, 1 spinal grade 2 astrocytoma, 1 chordoma. 18 tumors with methylated MGMT, 8 with mutant IDH1. At diet initiation, median KPS 80 (range 70–100); median BMI 25.6 (20.8–39). Median days on diet = 190 days; interquartile range 126–673 days; range 24–1479 days. Diet composition: 15 patients on 3:1 diet (grams fat: grams protein + carbs), 7 patients on 2:1, 2 patients on 1:1. 14 patients monitored blood ketone levels. 11 patients stopped KD: 5 for restrictiveness of diet (median 158 days, range 60–239); 1 for decreased KPS (673 days); 1 for excessive weight loss (108 days); 2 for disease progression (24 and 217 days); 2 lost to follow-up (109 and 125 days). In this small sample, no statistically significant associations between time on diet and age / gender / BMI / KPS / diet composition. However, trend toward longer adherence to diet in females, age < 50, 2:1 diet. CONCLUSION It is feasible for patients with CNS tumors to adopt KD. Results from prospective studies are needed to assess effects on QOL, neurocognition, performance status, and survival.