Mapping of exogenous choline uptake and metabolism in rat glioblastoma using deuterium metabolic imaging (DMI).

Introduction: There is a lack of robust metabolic imaging techniques that can be routinely applied to characterize lesions in patients with brain tumors. Here we explore in an animal model of glioblastoma the feasibility to detect uptake and metabolism of deuterated choline and describe the tumor-to-brain image contrast. Methods: RG2 cells were incubated with choline and the level of intracellular choline and its metabolites measured in cell extracts using high resolution 1H NMR. In rats with orthotopically implanted RG2 tumors deuterium metabolic imaging (DMI) was applied in vivo during, as well as 1 day after, intravenous infusion of 2H9-choline. In parallel experiments, RG2-bearing rats were infused with [1,1',2,2'-2H4]-choline and tissue metabolite extracts analyzed with high resolution 2H NMR to identify molecule-specific 2H-labeling in choline and its metabolites. Results: In vitro experiments indicated high uptake and fast phosphorylation of exogenous choline in RG2 cells. In vivo DMI studies revealed a high signal from the 2H-labeled pool of choline + metabolites (total choline, 2H-tCho) in the tumor lesion but not in normal brain. Quantitative DMI-based metabolic maps of 2H-tCho showed high tumor-to-brain image contrast in maps acquired both during, and 24 h after deuterated choline infusion. High resolution 2H NMR revealed that DMI data acquired during 2H-choline infusion consists of free choline and phosphocholine, while the data acquired 24 h later represent phosphocholine and glycerophosphocholine. Discussion: Uptake and metabolism of exogenous choline was high in RG2 tumors compared to normal brain, resulting in high tumor-to-brain image contrast on DMI-based metabolic maps. By varying the timing of DMI data acquisition relative to the start of the deuterated choline infusion, the metabolic maps can be weighted toward detection of choline uptake or choline metabolism. These proof-of-principle experiments highlight the potential of using deuterated choline combined with DMI to metabolically characterize brain tumors.

Comparison of long-term outcomes in a 10-year experience of robotic cystectomy vs. open cystectomy.

To compare the outcomes of robotic-assisted (RARC) vs. open radical cystectomy (ORC) at a single academic institution. We retrospectively identified patients undergoing radical cystectomy for urothelial carcinoma of the bladder at our institution from 2007 to 2017. Data collected included age, sex, Body Mass Index (BMI), Charlson Age-Adjusted Comorbidity Index (CCI), final pathologic stage, surgical margins, lymph-node yield, estimated blood loss (EBL), 90-day complication rate, and length of stay (LOS). We evaluated overall survival (OS) and recurrence-free survival (RFS). Multivariable Cox proportional hazard models were used to adjust for covariates. We identified 232 patients (73 RARC, 159 ORC) who underwent radical cystectomy. Patients who underwent RARC were older (71.8 vs. 67.5, p < 0.05) and had higher CCI scores (6.2 vs. 5.3, p < 0.05). In comparing perioperative outcomes, RARC patients had lower EBL (500 vs. 850, p < 0.01), lower blood transfusion rate (p < 0.01), and lower lymph-node yield (12 vs. 20, p < 0.01), and higher ICU admission rate (29% vs. 16% p < 0.01). There was no difference in BMI (p = 0.93), sex (p = 0.28), final pathological stage (p = 0.35), positive surgical margins (p = 0.47), complications (p = 0.58), or LOS (p = 0.34). Kaplan-Meier analysis showed no difference in OS (p = 0.26) or RFS (p = 0.86). There was no difference in restricted mean survival time for OS (53 vs. 56 months, p = 0.81) or for RFS (65 vs. 64 months, p = 0.90). Cox multivariate regression models showed that surgical approach does not have a significant impact on OS (p = 0.46) or RFS (p = 0.35). Our study indicates that in our 10-year experience, patients undergoing there was no difference between RARC and ORC patients with respect to OS and RFS despite being older and having more comorbidities. Our work supports the importance of patient selection to optimize outcomes.

A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth.

BACKGROUND: The dependence of tumor cells, particularly those originating in the brain, on glucose is the target of the ketogenic diet, which creates a plasma nutrient profile similar to fasting: increased levels of ketone bodies and reduced plasma glucose concentrations. The use of ketogenic diets has been of particular interest for therapy in brain tumors, which reportedly lack the ability to oxidize ketone bodies and therefore would be starved during ketosis. Because studies assessing the tumors' ability to oxidize ketone bodies are lacking, we investigated in vivo the extent of ketone body oxidation in 2 rodent glioma models. METHODS: Ketone body oxidation was studied using (13)C MR spectroscopy in combination with infusion of a (13)C-labeled ketone body (beta-hydroxybutyrate) in RG2 and 9L glioma models. The level of ketone body oxidation was compared with nontumorous cortical brain tissue. RESULTS: The level of (13)C-beta-hydroxybutyrate oxidation in 2 rat glioma models was similar to that of contralateral brain. In addition, when glioma-bearing animals were fed a ketogenic diet, the ketone body monocarboxylate transporter was upregulated, facilitating uptake and oxidation of ketone bodies in the gliomas. CONCLUSIONS: These results demonstrate that rat gliomas can oxidize ketone bodies and indicate upregulation of ketone body transport when fed a ketogenic diet. Our findings contradict the hypothesis that brain tumors are metabolically inflexible and show the need for additional research on the use of ketogenic diets as therapy targeting brain tumor metabolism.