Dataset Information

A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E ?-tocotrienol in Patients with Pancreatic Ductal Neoplasia.

ABSTRACT: Vitamin E ?-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability, pharmacokinetics, and apoptotic activity.Patients received oral VEDT at escalating doses (from 200 to 3200 mg) daily for 13 days before surgery and one dose on the day of surgery. Dose escalation followed a three-plus-three trial design. Our primary endpoints were safety, VEDT pharmacokinetics, and monitoring of VEDT-induced neoplastic cell apoptosis (ClinicalTrials.gov number NCT00985777).In 25 treated patients, no dose-limiting toxicity was encountered; thus no maximum-tolerated dose was reached. One patient had a drug-related adverse event (diarrhea) at a 3200-mg daily dose level. The effective half-life of VEDT was ~ 4 h. VEDT concentrations in plasma and exposure profiles were quite variable but reached levels that are bioactive in preclinical models. Biological activity, defined as significant induction of apoptosis in neoplastic cells as measured by increased cleaved caspase-3 levels, was seen in the majority of patients at the 400-mg to 1600-mg daily dose levels.VEDT from 200 to 1600 mg daily taken orally for 2 weeks before pancreatic surgery was well tolerated, reached bioactive levels in blood, and significantly induced apoptosis in the neoplastic cells of patients with pancreatic ductal neoplasia. These promising results warrant further clinical investigation of VEDT for chemoprevention and/or therapy of pancreatic cancer.

SUBMITTER: Springett GM

PROVIDER: S-EPMC4703733 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Publications

A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia.

Springett Gregory M GM Husain Kazim K Neuger Anthony A Centeno Barbara B Chen Dung-Tsa DT Hutchinson Tai Z TZ Lush Richard M RM Sebti Saïd S Malafa Mokenge P MP

EBioMedicine 20151114 12

<h4>Background</h4>Vitamin E δ-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability, pharmacokinetics, and apoptotic activity.<h4>Methods</h4>Patients received oral VEDT at escalating doses (from 200 to 3200 mg) daily for 13 days before su ...[more]

PMID: 26844278

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Project description:ObjectivesTo develop a radiomics signature for predicting surgical portal vein-superior mesenteric vein (PV-SMV) in patients with pancreatic ductal adenocarcinoma (PDAC) and measure the effect of providing the predictions of radiomics signature to radiologists with different diagnostic experiences during imaging interpretation.MethodsBetween February 2008 and June 2020, 146 patients with PDAC in pancreatic head or uncinate process from two institutions were retrospectively included and randomly split into a training (n = 88) and a validation (n =58) cohort. Intraoperative vascular exploration findings were used to identify surgical PV-SMV invasion. Radiomics features were extracted from the portal venous phase CT images. Radiomics signature was built with a linear elastic-net regression model. Area under receiver operating characteristic curve (AUC) of the radiomics signature was calculated. A senior and a junior radiologist independently review CT scans and made the diagnosis for PV-SMV invasion both with and without radiomics score (Radscore) assistance. A 2-sided Pearson's chi-squared test was conducted to evaluate whether there was a difference in sensitivity, specificity, and accuracy between the radiomics signature and the unassisted radiologists. To assess the incremental value of providing Radscore predictions to the radiologists, we compared the performance between unassisted evaluation and Radscore-assisted evaluation by using the McNemar test.ResultsNumbers of patients identified as presence of surgical PV-SMV invasion were 33 (37.5%) and 19 (32.8%) in the training and validation cohort, respectively. The radiomics signature achieved an AUC of 0.848 (95% confidence interval, 0.724-0.971) in the validation cohort and had a comparable sensitivity, specificity, and accuracy as the senior radiologist in predicting PV-SMV invasion (all p-values > 0.05). Providing predictions of radiomics signature increased both radiologists' sensitivity in identifying PV-SMV invasion, while only the increase of the junior radiologist was significant (63.2 vs 89.5%, p-value = 0.025) instead of the senior radiologist (73.7 vs 89.5%, p-value = 0.08). Both radiologists' accuracy had no significant increase when provided radiomics signature assistance (both p-values > 0.05).ConclusionsThe radiomics signature can predict surgical PV-SMV invasion in patients with PDAC and may have incremental value to the diagnostic performance of radiologists during imaging interpretation.

Dataset Information

A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E ?-tocotrienol in Patients with Pancreatic Ductal Neoplasia.

Publications

A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia.

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