An open-label, dose-escalating phase I study of elsamitrucin (SPI 28090) in treatment of malignant solid tumors in dogs.

BACKGROUND: Elsamitrucin, the most potent topoisomerase II inhibitor available, is unique in that it does not cause neutropenia or cardiotoxicosis. It has antitumor activity in human patients with relapsed or refractory non-Hodgkin's lymphoma. OBJECTIVES: To determine the maximum tolerated dose (MTD), safety, and toxicity of elsamitrucin when administered to tumor-bearing dogs and to evaluate the incidence and severity of adverse events. ANIMALS: Twenty client-owned dogs with spontaneous malignant solid tumors or lymphoma that were refractory to, or for which the owner declined, conventional therapy were enrolled. METHODS: Prospective, open-label, single-agent study. Escalating doses of elsamitrucin were administered once weekly i.v. for up to 16 weeks in a modified 3 + 3 Phase I design. The starting dose was 0.06 mg/kg with escalation to 0.08 and 0.09 mg/kg. Dogs that remained on the study were monitored for evidence of toxicoses for at least 4 weeks and for survival every 2 months. RESULTS: Serious adverse events (SAEs) possibly attributable to elsamitrucin include: 1 dog developed heart failure and another developed hepatotoxicosis manifested by increased alanine aminotransferase, alkaline phosphatase, and total bilirubin (0.06 mg/kg dose); 1 dog developed severe anorexia and diarrhea, another developed severe diarrhea alone, and a 3rd dog went into cardiac arrest (0.09 mg/kg dose). A dose of 0.08 mg/kg was well tolerated with no SAEs. CONCLUSIONS AND CLINICAL IMPORTANCE: The MTD and recommended dose for Phase II trials of elsamitrucin is 0.08 mg/kg i.v. weekly. Elsamitrucin might be considered for combination protocols with myelosuppressive chemotherapy agents.

Neutral vs positive oral contrast in diagnosing acute appendicitis with contrast-enhanced CT: sensitivity, specificity, reader confidence and interpretation time.

OBJECTIVE: The study compared the sensitivity, specificity, confidence and interpretation time of readers of differing experience in diagnosing acute appendicitis with contrast-enhanced CT using neutral vs positive oral contrast agents. METHODS: Contrast-enhanced CT for right lower quadrant or right flank pain was performed in 200 patients with neutral and 200 with positive oral contrast including 199 with proven acute appendicitis and 201 with other diagnoses. Test set disease prevalence was 50%. Two experienced gastrointestinal radiologists, one fellow and two first-year residents blindly assessed all studies for appendicitis (2000 readings) and assigned confidence scores (1=poor to 4=excellent). Receiver operating characteristic (ROC) curves were generated. Total interpretation time was recorded. Each reader's interpretation with the two agents was compared using standard statistical methods. RESULTS: Average reader sensitivity was found to be 96% (range 91-99%) with positive and 95% (89-98%) with neutral oral contrast; specificity was 96% (92-98%) and 94% (90-97%). For each reader, no statistically significant difference was found between the two agents (sensitivities p-values >0.6; specificities p-values>0.08), in the area under the ROC curve (range 0.95-0.99) or in average interpretation times. In cases without appendicitis, positive oral contrast demonstrated improved appendix identification (average 90% vs 78%) and higher confidence scores for three readers. Average interpretation times showed no statistically significant differences between the agents. CONCLUSION: Neutral vs positive oral contrast does not affect the accuracy of contrast-enhanced CT for diagnosing acute appendicitis. Although positive oral contrast might help to identify normal appendices, we continue to use neutral oral contrast given its other potential benefits.