A phase 2 trial of verubulin for recurrent glioblastoma: a prospective study by the Brain Tumor Investigational Consortium (BTIC).

Treatment options are limited for recurrent glioblastoma (GBM). Verubulin is a microtubule destabilizer and vascular disrupting agent that achieve high brain concentration relative to plasma in animals. Adults with recurrent GBM who failed prior standard therapy were eligible. The primary endpoint was 1-month progression-free survival (PFS-1) for bevacizumab refractory (Group 2) and 6-month progression-free survival (PFS-6) for bevacizumab naïve patients (Group 1). Verubulin was administered at 3.3 mg/m(2) as a 2-h intravenous infusion once weekly for 3 consecutive weeks in a 4-week cycle. The planned sample size was 34 subjects per cohort. 56 patients (37 men, 19 women) were enrolled, 31 in Group 1 and 25 in Group 2. The PFS-6 for Group 1 was 14% and the PFS-1 for Group 2 was 20%. Median survival from onset of treatment was 9.5 months in Group 1 and 3.4 months in Group 2. Best overall response was partial response (n = 3; 10% in Group 1; n = 1; 4.2% in Group 2) and stable disease (n = 7; 23% in Group 1; n = 5; 21% in Group 2). In Group 1, 38.7% of patients experienced a serious adverse event; however only 3.2% were potentially attributable to study drug. In Group 2, 44% of patients experienced a serious adverse event although none were attributable to study drug. Accrual was terminated early for futility. Single agent verubulin, in this dose and schedule, is well tolerated, associated with moderate but tolerable toxicity but has limited activity in either bevacizumab naïve or refractory recurrent GBM.

Preserving the mucosal barrier during small bowel storage.

BACKGROUND: A major obstacle to successful small bowel transplantation is that of bacterial infection. The aim of this study was to preserve the small bowel mucosal barrier by using oxygenated luminal perfusion with a proven amino acid (AA)-based solution. METHODS: Rat small bowel (n=4) was flushed vascularly with modified University of Wisconsin solution and flushed luminally as follows: group 1, none (control); group 2, AA solution; group 3, 1-hr perfusion then storage with AA; group 4, continuous perfusion with AA. Energetics, malondialdehyde (MDA), glutathione (reduced), and histology were assessed over 24 hr at 4 degrees C. RESULTS: Within 4 hr, adenosine triphosphate (ATP) dropped by 25% to 65% in all groups except for group 4, which remained unchanged from fresh tissue values throughout 12 hr. After 12 hr, ATP in groups 1 through 3 had dropped to 0.5 to 0.9 micromol/g, compared with 1.5 micromol/g for group 4. Even after 24 hr, group 4 levels were more than twofold greater than groups 1 through 3. MDA increased transiently in tissues subjected to simple flush (no perfusion), whereas levels in perfused tissues remained elevated throughout the 24-hr period. Glutathione in group 1 dropped by greater than 50% from fresh tissue values but increased over 24 hr in groups 2 and 3 by 50% to 55%. Overall, histologic injury was markedly less in groups 2 through 4; however, after 24 hr, the lowest injury was observed in group 3 (median, grade 2) compared with groups 1 and 4 (grades 7 and 4). CONCLUSIONS: Our data indicate that perfusion clearly improves tissue energetics. However, mucosal integrity is markedly superior, with only a brief 1-hr period of perfusion; oxidative and mechanical stress are the factors likely responsible for injury resulting from continuous perfusion.

A novel technique of hypothermic luminal perfusion for small bowel preservation.

BACKGROUND: This study improved small bowel preservation using University of Wisconsin (UW) solution in conjunction with hypothermic luminal perfusion. METHODS: Small bowels from Sprague-Dawley rats (n=4) were flushed vascularly with modified UW solution and flushed luminally: group 1, none (clinical control); group 2, UW solution; group 3, 1-hr oxygenated perfusion then static storage with UW; and group 4, 24-hr continuous oxygenated perfusion with UW. Energetics, lipid peroxidation, and histology were assessed during 24 hr at 4 degrees C. RESULTS: After 12 hr, adenosine triphosphate ranged from 0.5 to 0.8 micromol/g in groups 1 to 3 compared with 1.5 micromol/g in group 4. Even after 24 hr, levels in group 4 were more than twofold greater than levels in groups 1 to 3. Energy charge values ([adenosine triphosphate+adenosine diphosphate/2]/total adenylates) decreased from fresh tissue values of 0.69 in all groups except group 4 throughout 24-hr perfusion. Malondialdehyde (MDA; a product of lipid peroxidation) doubled within 4 hr in group 1 and remained high throughout storage. In groups 3 and 4, MDA levels increased as the time of perfusion increased; group 2 showed no elevated MDA levels at any time. After 12 hr, histologic integrity was superior in groups 3 and 4; however after 24 hr, the best Park's grade was observed in group 3 (median grade 4) compared with groups 1 (grade 7) and 4 (grade 6). CONCLUSIONS: Our data indicate that perfusion clearly improves tissue energetics; however, mucosal integrity is superior with only a brief 1-hr period of luminal perfusion, despite limited improvements in energetics.

A metabolic mechanism for the detrimental effect of exogenous glucose during cardiac storage.

The purpose of this study was to clarify the metabolic events that explain why supplemental glucose is detrimental during cardiac storage. Four solutions were used to flush and store porcine hearts: St. Thomas Hospital Solution (STHS), University of Wisconsin (UW) solution, and UW + 90 mM histidine, and UW + 90 mM histidine + 11 mM glucose. Despite equivalent increases in lactate in the two histidine-buffered groups throughout 10 h of storage, glycogen utilization was evident in the group without supplemental glucose. The presence of glucose resulted in a reduction in energy production, presumably mediated by direct inhibition of glycogenolysis. Furthermore, UW + histidine was the only group to show consistent improvements in ATP and total adenylates. It was concluded that inclusion of the buffering agent, histidine, to UW solution promotes anaerobic energy production as a result, in part, of preserved high levels of the regulatory control enzyme, phosphofructokinase.