Specific glycogen synthase kinase-3 inhibition reduces neuroendocrine markers and suppresses neuroblastoma cell growth.

OBJECTIVE: Neuroblastoma is a common neuroendocrine (NE) tumor that presents in early childhood, with a high incidence of malignancy and recurrence. The glycogen synthase kinase-3 (GSK-3) pathway is a potential therapeutic target, as this pathway has been shown to be crucial in the management of other NE tumors. However, it is not known which isoform is necessary for growth inhibition. In this study, we investigated the effect of the GSK-3 inhibitor AR-A014418 on the different GSK-3 isoforms in neuroblastoma. METHODS: NGP and SH-5Y-SY cells were treated with 0-20 µM of AR-A014418 and cell viability was measured by MTT assay. Expression levels of NE markers CgA and ASCL1, GSK-3 isoforms, and apoptotic markers were analyzed by western blot. RESULTS: Neuroblastoma cells treated with AR-A014418 had a significant reduction in growth at all doses and time points (P<0.001). A reduction in growth was noted in cell lines on day 6, with 10 µM (NGP-53% vs. 0% and SH-5Y-SY-38% vs. 0%, P<0.001) treatment compared to control, corresponding with a noticeable reduction in tumor marker ASCL1 and CgA expression. CONCLUSION: Treatment of neuroblastoma cell lines with AR-A014418 reduced the level of GSK-3α phosphorylation at Tyr279 compared to GSK-3ß phosphorylation at Tyr216, and attenuated growth via the maintenance of apoptosis. This study supports further investigation to elucidate the mechanism(s) by which GSK-3α inhibition downregulates the expression of NE tumor markers and growth of neuroblastoma.

Safety and feasibility of laparoscopic resection for large (≥ 6 CM) pheochromocytomas without suspected malignancy.

OBJECTIVE: To determine whether laparoscopic adrenalectomy in patients without radiologic evidence of cancer compromises the perioperative and long-term outcomes in patients with large (≥ 6 cm) pheochromocytomas. METHODS: We analyzed a prospective adrenal database of consecutive patients who underwent adrenalectomy at our institution between September 2000 and September 2010. Patients with diagnosed pheochromocytoma who underwent laparoscopic adrenalectomy were included. Patients with tumors smaller than 6 cm were compared with those presenting with tumors 6 cm or larger. RESULTS: One hundred fifty-seven patients underwent adrenalectomy, and there were 32 catecholamine-secreting tumors. Of the 33, 7 were excluded from the study because of open surgery. Thus, 25 patients presented with 26 pheochromocytomas and underwent laparoscopic adrenalectomy. Thirteen of the 25 patients (52%) were women. Mean age (± standard error of the mean) was 53 ± 3 years. Mean tumor size was 5.2 ± 0.5 cm, and 11 pheochromocytomas (42%) were 6 cm or larger. Tumor size was significantly different between the large pheochromocytoma and the small pheochromocytoma groups (7.6 ± 0.4 vs 3.6 ± 0.4 cm, P<.001), but there was no significant difference in intraoperative complications, estimated blood loss, cancer diagnosis, or recurrence. The length of stay was comparable between the 2 cohorts, and there were no incidents of capsular invasion or adverse cardiovascular events. CONCLUSION: Laparoscopic adrenalectomy of pheochromocytomas larger than 6 cm is feasible and safe with comparable results to those achieved with laparoscopic adrenalectomy in patients with smaller pheochromocytomas.

Pathogenesis, management, and consequences of primary graft dysfunction.

Primary graft dysfunction continues to be a major contributing factor to morbidity and mortality after lung transplantation. This condition is presumed to be the result of ischemia-reperfusion injury, which is associated with the release of endogenous substances that can activate the innate immune system. Primary graft dysfunction has been shown to be an independent risk factor for the development of bronchiolitis obliterans syndrome indicating that it can shape alloimmune responses. In this review, we focus on the classification, pathogenesis, possible prevention strategies, management and consequences of primary graft dysfunction.