A hemolysis study of an intravascular blood cooling system for localized organ tissue cooling

Therapeutic hypothermia can reduce both ischemic and reperfusion injury arising after strokes and heart attacks. New localized organ cooling systems offer a way to reduce tissue damage more effectively with fewer side effects. To assess initial blood safety of our new organ cooling system, the CoolGuide Cooling System (CCS), we investigated safe operating conditions and configurations from a hemolysis perspective. The CCS consists of a peristaltic pump, a custom-built external heat exchanger, a chiller, biocompatible polyvinyl cellulose (PVC) tubing, and a control console. The CCS cools and circulates autologous blood externally and re-delivers cooled blood to the patient through a conventional catheter inserted directly into the organ at risk. Catheter configurations used included: a 7F guide catheter only, a 7F guide with a 0.038” wire inserted through the center and advanced 2 cm distal to the catheter distal tip, a 6F guide catheter only and a 6F guide with a 0.014” guidewire similarly inserted through the center. Using porcine blood, an in vitro test rig was used to measure the degree of hemolysis generation, defined as the percentage change in free hemoglobin, adjusted for total hemoglobin and hematocrit, between exiting and entering blood. The highest degree of hemolysis generation was 0.11±0.04%, based on the average behavior with a 6F catheter and a 0.014” guidewire configuration at a blood flow rate of approximately 130 mL/min. In terms of average percentage free hemoglobin exiting the system, based on total hemoglobin, the highest value measured was 0.17%±0.03%, using this 6F and 0.014” guidewire configuration. This result is significantly below the most stringent European guideline of 0.8% used for blood storage and transfusion. This study provides initial evidence showing hemolysis generation arising from the CoolGuide Cooling System is likely to be clinically insignificant. </jats:p

0524 Web-Delivered CBT for Insomnia Intervention Improves Sleep Among Adults with Insomnia and Depressive Symptoms

Abstract Introduction Cognitive behavioral therapy for insomnia (CBT-I) is the first line recommended treatment for adults with chronic insomnia. In a prior randomized controlled trial (RCT), data showed web-delivered CBT-I (SHUTi) reduced insomnia severity as well as symptoms of depression, among adults with insomnia and elevated depressive symptoms. The present study aimed to further evaluate the effectiveness of web CBT-I to improve sleep outcomes as measured by prospectively entered sleep diaries in this same sample. Methods A large-scale RCT (N=1149) of Australian adults with insomnia and depressive symptoms compared a 9-week, web CBT-I therapeutic with an attention-matched web program at baseline, posttest and 6-, 12-, and 18-month follow-ups. Although depression outcomes have been presented previously, the online sleep-diary derived variables have not yet been presented, including sleep-onset latency (SOL), wake after sleep onset (WASO), sleep efficiency (SE), number of awakenings, sleep quality, and total sleep time (TST). Sleep diaries were entered online for 10 days at each assessment period. Results Data showed web CBT-I participants demonstrated greater reductions from baseline to posttest compared with control for the following sleep variables: SOL (LS mean difference [95% CI]=-22.3 min [-29.2, -15.3]; p&amp;lt;.0001), WASO (-17.8 min [-23.4, -12.3]; p&amp;lt;.0001), and number of awakenings (-0.38 [-0.68, -0.09]; p=.0113). Web CBT-I also showed greater improvements in SE (9.18% [7.25%, 11.10%]; p&amp;lt;.0001) and sleep quality (0.41 [0.30, 0.53]; p&amp;lt;.0001) from baseline to posttest compared with control. TST was not significantly different between groups at posttest or 6-month follow-up, although it improved over baseline at 12 (18.73 min [7.39, 30.07]; p=.0013) and 18 months (23.76 min [9.15, 38.36]; p=.0015) relative to control. All other significant sleep treatment effects were maintained in the treatment arm at 6, 12, and 18-month follow-up. Conclusion Data showed web CBT-I produced lasting improvements in sleep outcomes among adults with insomnia and elevated depressive symptoms. Support Clinical trial ACTRN12611000121965 was funded by the Australian National Health and Medical Research Council. The statistical analysis described here was funded by Pear Therapeutics, Inc and conducted by Provonix. </jats:sec

An open-label study of the safety and tolerability of pazopanib in combination with FOLFOX6 or CapeOx in patients with colorectal cancer

Background Although combining targeted agents with conventional, first-line cytotoxic therapy has improved survival outcomes in patients with advanced colorectal cancer, further improvements in outcomes and tolerability are needed. Methods This phase I study evaluated the feasibility of combining oral pazopanib, an agent that targets multiple proangiogenic factors, with FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) or CapeOx (oxaliplatin and capecitabine). This phase I study evaluated the optimally tolerated regimen of daily pazopanib (dose-escalated) plus standard FOLFOX6 or CapeOx in patients with advanced colorectal cancer. At the optimally tolerated regimen, each cohort was expanded to further evaluate safety and clinical response. Results The optimally tolerated regimens were pazopanib 800 mg plus FOLFOX6 and pazopanib 800 mg plus reduced CapeOx (capecitabine 850 mg/m2). The most commonly reported adverse events in the FOLFOX6 cohorts included decreased appetite, neutropenia, diarrhea, peripheral neuropathy, and vomiting. Similarly, the most commonly reported adverse events in the CapeOx cohorts included fatigue, vomiting, and decreased appetite. The overall response rate was 40 % (8/20 patients) in the pazopanib plus FOLFOX6 cohorts and 38 % (8/21 patients) in the pazopanib plus CapeOx cohorts. Conclusion Pazopanib combined with FOLFOX6 or reduced CapeOx was adequately tolerated in this patient population. © 2013 Springer Science+Business Media New York

A phase I study of pazopanib in combination with FOLFOX 6 or capeOx in subjects with colorectal cancer

4133 Background: Pazopanib (paz) is a tyrosine kinase inhibitor of VEGFR-1, -2, -3, PDGF-α, -β, and c-kit. Inhibition of angiogenic pathways in combination with chemotherapy has been shown to benefit patients (pts) with colorectal cancer (CRC). Methods: Pts with previously untreated advanced or metastatic CRC and adequate organ function were assigned to paz with FOLFOX6 (FO) or capeOx (CO) by their physician. Doses of paz were escalated with full strength chemotherapy, starting at 400mg daily. The optimally tolerated regimen (OTR) was the combination dose at which &lt;1/6 pts experienced dose-limiting toxicity (DLT). Results: Fifty pts were enrolled in FO (paz 400 mg, n=6; 800, 15), CO (400, 12; 800, 9) and reduced capecitabine (rc) CO (800, 8) cohorts: median age = 55.5, M/F = 37/13. Pts have remained on therapy for a median of 3 (range 0–17) months. Three pts remain on study. Safety data is available on 41. The most common AEs are summarized in the table below. The OTR was exceeded with CO in combination with 800 mg and 400 mg of pazopanib, but was not exceeded with 800 mg pazopanib when capecitabine was reduced to 850 mg/m2 twice daily or with FO with 800 mg pazopanib. Efficacy and pharmacokinetic analyses are ongoing. Conclusions: The OTRs were achieved at 800 mg paz with full-dose FO, and at 800mg paz with rcCO. [Table: see text] [Table: see text] </jats:p