Retrospective examination of pseudoprogression in IDH mutant gliomas.

Background: Tumor surveillance of isocitrate dehydrogenase (IDH) mutant gliomas is accomplished via serial contrast MRI. When new contrast enhancement (CEnew) is detected during postsurgical surveillance, clinicians must assess whether CEnew indicates pseudoprogression (PsP) or tumor progression (TP). PsP has been better studied in IDH wild-type glioblastoma but has not been well characterized in IDH mutant gliomas. We conducted a retrospective study evaluating the incidence, predictors, natural history, and survival of PsP patients in a large cohort of IDH mutant glioma patients treated at a single institution. Methods: We identified 587 IDH mutant glioma patients treated at UCLA. We directly inspected MRI images and radiology reports to identify CEnew and categorized CEnew into TP or PsP using MRI or histopathology. Results: Fifty-six percent of patients developed CEnew (326/587); of these, 92/326 patients (28% of CEnew; 16% of all) developed PsP and 179/326 (55%) developed TP. All PsP patients had prior radiation, chemotherapy, or chemoradiotherapy. PsP was associated with longer overall survival (OS) versus TP patients and similar OS versus no CEnew. PsP differs from TP based on earlier time of onset (median 5.8 vs 17.4 months from treatment, P < .0001) and MRI features that include punctate enhancement and enhancement location. Conclusion: PsP patients represented 28% of CEnew patients and 16% of all patients; PsP patients demonstrated superior outcomes to TP patients, and equivalent survival to patients without CEnew. PsP persists for <1 year, occurs after treatment, and differs from TP based on time of onset and radiographic features. Poor outcomes after CEnew are driven by TP.

A single-institution retrospective analysis of pathologically determined malignant transformation in IDH mutant glioma patients.

Background: Lower-grade IDH mutant glioma patients frequently undergo malignant transformation (MT), with apparent worse prognosis. Many studies examine MT in mixed IDH status cohorts and define MT using imaging, not histopathology. Our study examines the timing, predictors, and prognostic implications of pathologically determined MT in a large, exclusively IDH mutant cohort. Methods: We identified 193 IDH mutant lower-grade glioma patients at UCLA who received multiple surgeries. We examined the outcomes of pathologically determined MT patients. Results: Time to MT is longer in grade 2 oligodendroglioma (G2 Oligo) than in grade 2 astrocytoma (G2 Astro) (HR = 0.46, P = .0007). The grade 3 astrocytoma (G3 Astro) to grade 4 astrocytoma (G4 Astro) interval is shorter in stepwise MT (G2 to G3 to G4 Astro) patients than in initial G3 Astro patients (P = .03). Novel contrast enhancement had 65% positive predictivity, 67% negative predictivity, 75% sensitivity, and 55% specificity in indicating pathologically defined MT. In G2 Astro, initial gross total resection delayed MT (HR = 0.50, P = .02) and predicted better overall survival (OS) (HR = 0.34, P = .009). In G2 Oligo, spontaneous MT occurred earlier than treated MT (HR = 11.43, P = .0002), but treatment did not predict improved OS (P = .8). MT patients (n = 126) exhibited worse OS than non-MT patients (n = 67) in All (HR = 2.54, P = .0009) and G2 Astro (HR = 4.26, P = .02). Conclusion: Our study expands the understanding of MT to improve IDH mutant lower-grade glioma management.

In vivo safety evaluation of polyarginine coated magnetic nanovectors.

Safety and efficacy are of critical importance to any nanomaterial-based diagnostic and therapy. The innocuity and functionality of a nanomaterial in vivo is largely dependent on the physicochemical properties of the material, particularly its surface coating. Here, we evaluated the influence of polycationic coating on the efficacy, clearance organ uptake, and safety of magnetic nanovectors designed for siRNA delivery. Polyethylene glycol (PEG) coated superparamagnetic iron oxide nanoparticles (NPs) of 12 nm in core diameter were modified with a polycationic coating of either poly-l-arginine (pArg) or polyethylenimine (PEI) and further covalently functionalized with siRNA oligonucleotides. The produced NP-pArg-siRNA and NP-PEI-siRNA nanovectors were similar in hydrodynamic size (21 and 22 nm, respectively) but significantly differed in zeta potentials (+2.1 mV and +29.8 mV, respectively). Fluorescence quantification assays revealed that the NP-pArg-siRNA nanovector was 3-fold more potent than NP-PEI-siRNA in delivering siRNA and 1.8-fold more effective in gene silencing when tested in rat C6 glioblastoma cells. In vivo, both nanovector formulations were similarly taken up by the spleen and liver as determined by histopathological and hemopathological assays. However, PEI coated nanovectors elicited severe hemoincompatibility and damage to the liver and spleen, while pArg coated nanovectors were found to be safe and tolerable. Combined, our findings suggest that polycationic coatings of pArg were more effective and safer than commonly used PEI coatings for preparation of nanovectors. The NP-pArg-siRNA nanovector formulation developed here shows great potential for in vivo based biomedical applications.

Effect of alcoholic beverages on postprandial glycemia and insulinemia in lean, young, healthy adults.

BACKGROUND: Ethanol's ability to inhibit gluconeogenesis might reduce postprandial glycemia in realistic meal settings. OBJECTIVE: The objective was to explore the effect of 3 types of alcoholic beverages consumed alone, with a meal, or 1 h before a meal on postprandial glycemia in healthy subjects. DESIGN: In study 1, isoenergetic (1000 kJ) servings of beer, white wine, and gin were compared with a 1000-kJ portion of white bread. In study 2, the same servings were compared with water as an accompaniment to a bread meal. In study 3, 20-g alcohol portions were served as a premeal drink. Fingertip capillary blood samples were taken at regular intervals over 2-3 h. RESULTS: In study 1, the mean (+/-SE) glucose scores for beer (58 +/- 11), wine (7 +/- 3), and gin (10 +/- 5) were significantly lower (P < 0.001) than those for bread (= 100). In study 2, meals consumed with beer (84 +/- 11; P = 0.03), wine (63 +/- 6; P < 0.001), and gin (80 +/- 12; P = 0.007) produced less glycemia than did the meal consumed with water (= 100). In study 3, all 3 beverages reduced the postprandial glycemic response to the subsequent meal (67 +/- 5, 75 +/- 6, and 78 +/- 4 with the beer, wine, and gin trials, respectively; P < 0.003). CONCLUSION: In realistic settings, alcoholic beverage consumption lowers postprandial glycemia by 16-37%, which represents an unrecognized mechanism by which alcohol may reduce the risk of chronic disease.

The glycemic index of foods influences postprandial insulin-like growth factor-binding protein responses in lean young subjects.

BACKGROUND: Growth in normal and malignant tissues has been linked to hyperinsulinemia and insulin-like growth factors (IGFs). We hypothesized that IGF and IGF-binding protein (IGFBP) responses may be acutely affected by differences in the glycemic index (GI) of foods. OBJECTIVE: We compared the postprandial responses of IGFs and IGFBP to 2 foods of similar macronutrient composition but with greatly different GIs-pearled barley (GI: 25) and instant mashed potato (GI: 85). DESIGN: Ten young lean subjects consumed 50-g carbohydrate portions of the 2 foods or water (extended fast) in random order after an overnight fast. Capillary blood was collected at regular intervals over 4 h for measurement of blood glucose, insulin, and components of the IGF system. RESULTS: Serum IGFBP-1 declined markedly after both meals, but the mean (+/-SEM) change at 4 h was significantly (P < 0.01) more prolonged after the low-GI meal (-55 +/- 20 ng/mL) than after the high-GI meal (-13 +/- 15 ng/mL). Conversely, the change in serum IGFBP-3 concentration at 4 h was significantly (P < 0.05) higher after the low-GI meal (251 +/- 102 ng/mL) than after the high-GI meal (-110 +/- 96 ng/mL); the same pattern was observed at 2 h. Changes in IGFBP-2, free IGF-1, and total IGF-1 responses were minimal and did not differ significantly from those during the 4-h fast. CONCLUSION: Acute changes in IGFBP-3 after low-GI and high-GI foods may provide a biologic mechanism linking cell multiplication with greater consumption of high-GI carbohydrates.