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BACKGROUND Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We sought to assess the feasibility of combined radiation, KD and metformin in adults with high grade gliomas. METHODS A prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin combined with dietary intervention and 3) high-dose metformin combined with dietary intervention. Clinicaltrials.gov NCT02149459. RESULTS A total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4 / 5 adverse events, and only one grade 3 event (nausea). The median level of ketones during the intervention was 0.5 mM. Ketone levels were associated with dietary factors (high fat, low carbohydrates, MCT intake), use of metformin and low insulin levels. Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease. CONCLUSIONS The intervention was fairly well tolerated, however only moderate ketones levels were obtained. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a low-carbohydrate diet combined with 850mg metformin twice daily.

Background Studies have shown that exclusive enteral nutrition (EEN) treatment is as effective to corticosteroids (CS) for induction of remission in pediatric Crohn's disease (CD) with fewer side effects, but long-term outcome data are scarce. In this nationwide study we aimed to compare the risk of complicated disease course (CDC) after 2 years of follow-up in children with CD receiving EEN or CS as induction therapy. Methods Data of children diagnosed with CD in the epi-IIRN cohort between 2005-2020 were retrieved from the 4 Israeli Health-Maintenance-Organizations covering 98% of the population. The primary outcome was CDC defined as CD-related surgery, steroid-dependency, or need for more than one biologic class during 2 years post-diagnosis. Secondary outcomes included hospitalizations, and the use of biologics (any). Additionally, anthropometrics, labs reflecting nutrition (i.e., Alb and HGB), and growth were assessed at repeated visits until 2 years thereafter. To account for confounding by indication bias, we compared children with similar baseline characteristics based on Propensity Score (PS) individual matching. Time to CDC outcome was evaluated using Kaplan-Meier survival curves and compared by the log-rank test. A Cox proportional hazard model was sought to assess the relationship between the type of induction and time to CDC outcome. Results A total of 785 children with CD were induced after diagnosis with either EEN (n=410) or CS (n=375); mean age 13.3±3.5 years, 59% males. PS successfully matched 116 pairs of whom 85 (36%) had CDC. The survival probability of CDC at 6, 12,18, and 24 months was higher in the CS group compared to the EEN group at all time points (5%vs4%, 12% vs 10%, 22% vs 3%, and 27% vs.16%, respectively p=0.045; fig. 1). In a Cox multivariable model adjusted by year of diagnosis, CS induction treatment was similarly associated with higher hazard of CDC by 2 years (HR 1.8 [95%CI 1.01-3.25]). The survival probability of hospitalization was also higher in the CS group at 6,12,8, and 24 months (16% vs 9%, 20% vs 12%, 25% vs 14%, and 27% vs. 15%, respectively, p=0.024; fig.2). There was no difference in time to biologics (p=0.96, n=59 (51%) in EEN, n=57 (49%) in CS) and anthropometric data (Table 1). Significant improvements were observed in HGB and Alb levels for the EEN group during the first 3 months from diagnosis compared with the CS (p=0.046 and p=0.035 respectively) (table 1). Conclusion EEN as induction therapy in pediatric CD is associated with a lower long-term risk of complicated disease course and larger improvement in HGB and Alb but not in growth parameters compared with CS, even when adjusting to baseline disease severity and patients characteristics.