Cullen, Joseph J

Abstract Purpose: Pharmacologic ascorbate (P-AscH−) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH− with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH− in humans. Patients and Methods: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan–Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. Results: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7–26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. Conclusions: P-AscH− combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255

TPS791 Background: FOLFIRINOX or gemcitabine/nab-paclitaxel are both frontline chemotherapy options for patients with metastatic pancreas cancer. For most who cannot tolerate the triplet, the latter doublet is the preferred option. Through previous work by our group, pharmacologic ascorbate is known to synergize with gemcitabine; preliminary in vitro data from our group suggests a similar synergistic response with paclitaxel. Though ascorbate has been utilized in cancer therapy, few robust trials have investigated intravenous delivery of ascorbate to deliver plasma concentrations that are cytotoxic to tumor cells. Our prior studies have demonstrated ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells; this cytotoxicity appears to be greater in tumor vs. normal cells. We hypothesize that production of hydrogen peroxide mediates the increased susceptibility of pancreatic cancer cells to ascorbate-induced metabolic oxidative stress, resulting in improved treatment outcomes, which has led to the development of the clinical trial (NCT02905578). Methods: All participants receive gemcitabine (1000 mg/m2 weekly) and nab-paclitaxel (125 mg/m2) on cycle days 1, 8, and 15 of a 28-day cycle. Participants are randomized to ± pharmacologic ascorbate (75-gram infusion 3x weekly) in addition to chemotherapy. Study therapy continues until tumor progression. The primary objective is to determine overall survival in patients when treated with combination gemcitabine, nab-Paclitaxel and high-dose ascorbic acid compared to gemcitabine and nab-paclitaxel in patients with non-resectable pancreatic cancer. Secondary objectives include determining objective response rate as well as progression free survival using RECIST 1.1 criteria employing a blinded reviewer for RECIST measurements. The study opened to accrual in 2018 with a goal of enrolling 65 participants. Oversight.Study is conducted under IND 105715 (J. Cullen, sponsor). The University of Iowa Biomedical IRB (IRB-01) serves as the IRB of record. Clinical trial information: NCT02905578.

Our hypothesis was that the proximal colon relaxes to accommodate flow from the ileum. Therefore, we recorded tonic responses of the canine proximal colon to flow through the ileum and colon stimulated by 1) an 840-kcal meal, 2) nutrients perfused into the ileum and colon, or 3) rapid infusion of saline into the ileum with overflow into the colon. Saline infusion was considered to be a model of diarrhea, and the effects of an antidiarrheal (morphine sulfate) were therefore assessed. Proximal colonic tone was measured with a barostat. Tone increased before and after the arrival of chyme in the ileocolonic region. Perfusion of nutrients into the ileum and colon also significantly increased (P < 0.05) colonic tone compared with equal volumes of saline. Rapid perfusion of the ileocolonic segment with saline increased colonic tone; this increase was significantly greater (P < 0.01) when preceded by morphine. In contrast to our hypothesis, tone of the canine proximal colon increased in response to ileal flow. The increase in colonic tone during the late response to food was at least partly attributable to stimulation by intraluminal contents.

The hypothesis was that orally moving pacesetter potentials distal to a site of jejunal transection and anastomosis would slow transit through jejunum containing them and that reoperation with excision of bowel containing these pacesetter potentials would restore transit to the control. In six conscious dogs with jejunal serosal electrodes for recording myoelectric activity and a jejunal perfusion/aspiration catheter for measuring transit, jejunal pacesetter potential frequency decreased distal to a midjejunal transection and anastomosis from 18.7 +/- 0.3 (SE) cycles/min (cpm) proximal to the site to 14.4 +/- 0.6 cpm distal to the site (P < 0.05). In addition, orally propagating pacesetter potentials occurred > 25% of the time in a 37 +/- 7 cm length of bowel distal to the site during fasting and after feeding. Transit through the segment with the orally moving pacesetter potentials was slowed during feeding (half time before and after transection, 7.7 +/- 1.1 and 13 +/- 2.0 min, respectively, P < 0.05). Resection of the segment with the abnormal pacesetter potentials shortened the length of bowel containing them to 24 +/- 2 cm (P > 0.05) and restored transit to the control. In conclusion, orally moving pacesetter potentials distal to a canine jejunal transection and anastomosis slowed transit through the segment of bowel containing them. Resection of the segment restored transit to the control.