No abstract

In glioblastoma, PI3kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor PTEN1. However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. Here we interrogate large databases and find that Shh signaling is activated in PTEN-deficient glioblastoma. We demonstrate that Shh and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and Shh signaling inhibitors not only suppresses activation of both pathways, but also abrogates S6kinase signaling. Accordingly, simultaneously targeting both pathways results in mitotic catastrophe and tumor apoptosis, and dramatically reduces growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear safe in humans; therefore this combination may provide new targeted treatment for glioblastoma.

Background and objectives Trimethylamine N-oxide (TMAO), a compound derived from byproducts of intestinal bacteria, has been shown to accelerate atherosclerosis in rodents. To date, there are conflicting data regarding the association of serum TMAO with cardiovascular outcomes in patients with ESKD, a population exhibiting both high serum TMAO and excessive atherosclerosis.Design, setting, participants, & measurements We measured baseline serum TMAO concentrations in a subset of participants (n=1243) from the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial and conducted post hoc analyses evaluating the association between baseline serum TMAO and cardiovascular outcomes. ResultsWe observed a wide distribution of serum TMAO in our cohort, with approximately 80% of participants exhibiting TMAO concentrations $56 mM and a maximum TMAO concentration of 1103.1 mM. We found no association between TMAO and our primary outcome, a composite of cardiovascular mortality, myocardial infarction, peripheral vascular event, stroke, and hospitalization for unstable angina. Moreover, in unadjusted and adjusted analyses, we observed no relation between TMAO and all-cause mortality, the independent components of our composite outcome, or the original EVOLVE primary outcome. Although we did observe higher TMAO concentrations in white participants, further subgroup analyses did not confirm the previously identified interaction between TMAO and race observed in a prior study in patients receiving dialysis. ConclusionsWe found no evidence linking TMAO to adverse clinical outcomes in patients receiving maintenance hemodialysis with moderate to severe secondary hyperparathyroidism.All data are shown as n (%) unless otherwise indicated. TMAO, trimethylamine N-oxide; IQR, interquartile range; ECG, electrocardiogram; PTH, parathyroid hormone; spKt/V, single-pool Kt/V; FGF23, fibroblast growth factor 23. a One patient missing dialysis vintage, six patients missing FGF23, 96 patients missing hemoglobin, four patients missing BUN. b 3.6% of patients were missing BMI.

Objective The primary aim of this trial was to assess the feasibility of MIE in a multi-institutional setting. Background Esophagectomy is an important, potentially curative treatment for localized esophageal cancer, but is a complex operation. Minimally invasive esophagectomy (MIE) may decrease the morbidity and mortality of resection, and single-institution studies have demonstrated successful outcomes with MIE. Methods We conducted a multi-center, phase II, prospective cooperative group study (coordinated by ECOG) to evaluate the feasibility of MIE. Patients with biopsy-proven high-grade-dysplasia or esophageal cancer were enrolled at 17 credentialed sites. Protocol surgery consisted of either 3-stage MIE or Ivor Lewis MIE. The primary end point was 30-day mortality. Secondary end points included adverse events, duration of hospital-stay, and 3-year outcomes. Results Protocol surgery was completed in 95 of the 104 patients eligible for the primary analysis (91.3%). The 30-day mortality in eligible patients who underwent MIE was 2.1%; perioperative mortality in all registered patients eligible for primary analysis was 2.9%. Median intensive care unit and hospital stay were 2 and 9 days, respectively. Grade 3 or higher adverse events included anastomotic leak (8.6%), acute respiratory distress syndrome (5.7%), pneumonitis (3.8%), and atrial fibrillation (2.9%). At a median follow-up of 35.8 months, the estimated 3-year overall survival was 58.4% (95% confidence interval: 47.7%–67.6%). Locoregional recurrence occurred in only 7 patients (6.7%). Conclusions This prospective multicenter study demonstrated that MIE is feasible and safe with low peri-operative morbidity and mortality and good oncological results. This approach can be adopted by other centers with appropriate expertise in open esophagectomy and minimally invasive surgery.

Background Alternative response criteria have been proposed in patients with metastatic Renal Cell Carcinoma (mRCC) on Vascular Endothelial Growth Factor (VEGF)-targeted therapy, including 10% tumor shrinkage as an indicator of response/outcome. However, intraobserver and interobserver measurement variability have not been defined in this setting. We aim to determine intra- and interobserver agreement of Computed Tomography (CT) size and attenuation measurements, to establish reproducible response indicators. Methods Seventy-one mRCC patients with 179 target lesions were enrolled in Phase II and III trials of VEGF-targeted therapies and retrospectively studied with institutional review board approval. Two radiologists independently measured long axis diameter and mean attenuation of targets on baseline and follow-up CT. Concordance correlation coefficients (CCCs) and Bland-Altman plots were used to assess intra- and interobserver agreement. Results High CCCs (0.8602–0.9984) were observed in all types of measurements. The 95% limits of agreement for percent change of the sum longest diameter was (−7.30%, 7.86%) for intraobserver variability, indicating 10% tumor shrinkage represents true change in tumor size when measured by one observer. The 95% limits of interobserver variability were (−16.3%, 15.4%). In multivariate analysis, liver location significantly contributed to interobserver variability (p=0.048). The 95% limits of intraobserver agreement for percent change in CT attenuation were (−18.34%, 16.7%). Conclusion In mRCC patients treated with VEGF-inhibitors, 10% tumor shrinkage is a reproducible radiologic response indicator when baseline and follow-up studies are measured by a single radiologist. Lesion location contributes significantly to measurement variability and should be considered when selecting target lesions.

Erythromycin is a substrate of cytochrome P4503A4 (CYP3A4) and multiple drug transporters. Although clinical evidence suggests that uptake transport is likely to play a dominant role in erythromycin's disposition, the relative contributions of individual pathways are unclear. Phenotypic evaluation of multiple pathways generally requires a probe drug cocktail. This approach can result in ambiguous conclusions due to imprecision stemming from overlapping specificity of multiple drugs. We hypothesized that an individualized physiologically based pharmacokinetic modeling approach incorporating 14 CO 2 production rates (iPBPK-R) of the erythromycin breath test (ERMBT) would enable us to differentiate the contribution of metabolic and transporter pathways to erythromycin disposition. A sevencompartmental physiologically based pharmacokinetic (PBPK) model was built for 14 C-erythromycin administered intravenously. Transporter clearance and CYP3A4 clearance were embedded in hepatic compartments. 14 CO 2 production rates were simulated taking the first derivative of by-product 14 CO 2 concentrations. Parameters related to nonrenal elimination pathways were estimated by model fitting the ERMBT data of 12 healthy subjects individually. Optimized iPBPK-R models fit the individual rate data well. Using one probe, nine PBPK parameters were simultaneously estimated per individual. Maximum velocity of uptake transport, CYP3A4 clearance, total passive diffusion, and others were found to collectively control 14 CO 2 production rates. The median CYP3A4 clearance was 12.2% of the input clearance. Male subjects had lower CYP3A4 activity than female subjects by 11.3%. We applied iPBPK-R to ERMBT data to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways in healthy subjects. The iPBPK-R framework is a novel tool for delineating rate-limiting and nonrate-limiting elimination pathways using a single probe. SIGNIFICANCE STATEMENT Our developed individualized physiologically based pharmacokinetic modeling approach incorporating rate data (iPBPK-R) enabled us to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways of erythromycin in healthy subjects. A new interpretation of erythromycin breath test (ERMBT) data was also obtained via iPBPK-R. We found that rate data have rich information allowing estimation of per-person PBPK parameters. This study serves as proof of principle that the iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe. iPBPK-R can be applied to other rate-derived data beyond ERMBT. Potential areas of application include drug-drug interaction, pathophysiological effects on drug disposition, and the role of biomarkers on hemodialysis efficiency utilizing estimated adjustment factors with correlation analysis.

Background. Vascular endothelial growth factor (VEGF)‐targeted agents are standard therapies for metastatic renal cell carcinoma (mRCC), associated with variable tumor shrinkage. Response Evaluation Criteria in Solid Tumors (RECIST) is of limited utility in this setting, and other imaging changes are sought to reliably predict outcome early. We aim to validate 10% tumor shrinkage as the best early indicator of outcome. Methods. In this institutional review board‐approved, Health Insurance Portability and Accountability Act‐compliant study, 66 mRCC patients with 165 lesions on clinical trials of VEGF‐targeted agents underwent thoracic and abdominal computed tomography at baseline and at first follow‐up after therapy. Measurements were performed according to RECIST and tumor shrinkage of ≥10% decrease in sum of the longest diameter (−10%SLD). Correlation with time‐to‐treatment failure (TTF) and overall survival (OS) were compared and stratified by response to the radiologic criteria. Receiver‐operating characteristics (ROC) analysis yielded the optimal threshold change in SLD, defining patients with prolonged survival. Results. More than −10%SLD significantly differentiated responders from nonresponders (median TTF 8.4 vs. 4.1 months, p = .001), whereas partial response by RECIST did not (median TTF 6.9 vs. 5.5 months in responders vs. nonresponders, p = .34). −10%SLD was also significantly predictive of OS (median OS 35.1 vs. 15.0 months in responders vs. nonresponders, p = .003). ROC curve analysis yielded −9.3% in SLD as the optimal threshold for response/no response. Conclusion. Ten percent tumor shrinkage is validated as a reliable early predictor of outcome in mRCC patients receiving VEGF‐targeted therapies and may provide a practical measure to guide therapeutic decisions.

BackgroundIt is unknown whether childhood physical development in Asian populations differs from western populations, since no longitudinal analysis has been performed in Asian countries yet. Utilizing the 21st Century Longitudinal Survey in Newborns, we studied the timing of adiposity rebound (AR) among Japanese children and determined whether AR occurs earlier in obese children compared to nonobese children. Furthermore, we identified important demographic, social, and lifestyle factors that affect their physical development.MethodsWe used data from the annual surveillance of Japanese children born in 2001, with 45,392 eligible subjects. We applied survival analysis to evaluate the AR and a trajectory method for the BMI transition across 5 ½ years. Time-dependent and time-independent factors affecting BMI changes were investigated using longitudinal analysis. Accounting for the known difference in prevalence between Japanese and Western children, we adopted a 95th percentile of BMI as criterion for obesity.ResultsMean BMI at birth and at ages 1 ½, 2 ½, 3 ½, 4 ½, and 5 ½ years for all subjects were 12.6, 16.3, 16.1, 15.8, 15.5, and 15.4, respectively, showing a progressive reduction after 1 ½ years. However, among obese children at 5 ½ years, 39.6% had experienced AR as early as at age 4 ½ years. Controlling for sex, Cox’s proportional hazards model showed that obese children had a 48.5% higher hazard to experience AR than nonobese children. The difference in BMI transition between obese and non-obese children was also captured by a trajectory method. In longitudinal analysis, BMI was lower for children who had a longer gestational period whereas children who received parental care from non-family members gained higher BMI values.ConclusionsWith the 95th percentile cutoff for children obesity, obese Japanese children developed AR earlier than nonobese Japanese children, similar to those in Western countries reported in the literature. Primary caretakers and length of gestational period were the most important socio-demographic factors affecting physical development.