Ian C. Mitchell

Single-incision laparoscopic surgery: feasibility for pediatric appendectomies

INTRODUCTION Single-incision laparoscopic surgery (SILS) is a novel area of minimally invasive surgery using a single incision. The end result is a lone incision at the umbilicus for a perceived scarless abdomen. We report our early experience using the SILS technique for appendectomies in the pediatric population. METHODS A retrospective chart review was performed on our first patients to undergo SILS appendectomy (SILS-A) or laparoscopic appendectomy (LAP-A) during the same period at a freestanding childrens hospital. RESULTS Thirty-nine patients were reviewed. Nineteen patients underwent SILS-A (8.7 +/- 0.76 [SEM] years old), and 20 patients underwent LAP-A (10.5 +/- 0.87 years old, 2-17). Ages were 19 months to 14 years in the SILS-A group, with 21% (4 patients) not older than 6 years. Median weight for SILS-A was 32 kg (14.5-80.3). Twelve patients had acute nonperforated appendicitis (62%). Mean duration of operation was 58 +/- 5.6 (30-135) minutes vs 43 +/- 3.6 (30-85) minutes for standard LAP-A. Two patients were converted to a transumbilical appendectomy, one for inability to maintain a pneumoperitoneum and one for extensive adhesions. Postoperative complications consisted of one wound seroma. No wound infections, hernias, readmissions, or difference in length of stay were noted. CONCLUSION The SILS approach for acute appendicitis is feasible in the pediatric population even in patients as young as 19 months. Operating room times are somewhat longer than with LAP-A, but should decrease with improved instrumentation and experience. Larger studies and further technical refinements are needed before its widespread implementation.

Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer.

Anaplastic thyroid carcinoma is an aggressive form of cancer with no treatment. Angiogenesis inhibitors, such as TNP-470, a synthetic derivative of fumagillin, have been shown to reduce tumor size and increase survival in heterotopic animal models of thyroid cancer. Our goals were to determine the effect of TNP-470 on anaplastic thyroid cancer using an orthotopic murine model, to identify the molecular pathways of TNP-470 actions on endothelial cells, and to determine the non-endothelial tumor effects of TNP-470. We injected human anaplastic thyroid carcinoma cells (DRO′90) into the thyroid glands of nude mice. Mice received TNP-470 (30 mg/kg) s.c. for 6 weeks. TNP-470 prolonged survival and reduced liver metastases. TNP-470 had direct cytotoxic effects on anaplastic thyroid carcinoma cells in vitro and in vivo. Paradoxically, TNP-470 increased vascular endothelial growth factor secretion from tumor cells in vitro and in vivo. However, there was no associated increase in tumor microvessel density. In endothelial cells, TNP-470 prevented vascular endothelial growth factor–induced endothelial permeability, intercellular gap formation, and ruffle formation by preventing Rac1 activation. [Mol Cancer Ther 2007;6(4):1329–37]

Effect of Vascular Cadherin Knockdown on Zebrafish Vasculature during Development

Background Vascular endothelial cadherin (VE-cad) is essential for endothelial barrier integrity and vascular sprouting. However, the role of this important protein in cardiovascular development is only recently becoming apparent. Methodology/Principal Findings To characterize the role of VE-cadherin in cardiovascular development, we analyzed cardiovascular development in a zebrafish VE-cad knockdown model. Embryos deficient in VE-cad show profoundly impaired cardiac development despite having apparently normal peripheral vasculature. Initial formation of the heart proceeds normally in knockdown embryos, but subsequent looping morphogenesis is impaired. Consistent with these results, VE-cad knockdown embryos demonstrate impaired cardiac function and early circulatory arrest. Histologic examination of knockdown embryos shows persistent, abnormal separation of the endocardial and myocardial layers. Using transmission electron microscopy, we demonstrate that endocardial junctions form poorly in VE-cad knockdown embryos, with resulting leak across the endothelial layer and reduction in the density of the cardiac jelly. Conclusions Our results demonstrate a significant role for VE-cadherin in cardiac development independent of its effects on the formation of the peripheral vasculature.

Inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin in an orthotopic model of anaplastic thyroid carcinoma.

Patients with anaplastic thyroid carcinoma (ATC) typically succumb to their disease months after diagnosis despite aggressive therapy. A large percentage of ATCs have been shown to harbor the V600E B-Raf point mutation, leading to the constitutive activation of the mitogen-activated protein kinase pathway. ATC invasion, metastasis, and angiogenesis are in part dependent on the gelatinase class of matrix metalloproteinases (MMP). The explicit targeting of these two tumor markers may provide a novel therapeutic strategy for the treatment of ATC. The MMP-activated anthrax lethal toxin (LeTx), a novel recombinant protein toxin combination, shows potent mitogen-activated protein kinase pathway inhibition in gelatinase-expressing V600E B-Raf tumor cells in vitro. However, preliminary in vivo studies showed that the MMP-activated LeTx also exhibited dramatic antitumor activity against xenografts that did not show significant antiproliferative responses to the LeTx in vitro. Here, we show that the MMP-activated LeTx inhibits orthotopic ATC xenograft progression in both toxin-sensitive and toxin-resistant ATC cells via reduced endothelial cell recruitment and subsequent tumor vascularization. This in turn translates to an improved long-term survival that is comparable with that produced by the multikinase inhibitor sorafenib. Our results also indicate that therapy with the MMP-activated LeTx is extremely effective against advanced tumors with well-established vascular networks. Taken together, these results suggest that the MMP-activated LeTx-mediated endothelial cell targeting is the primary in vivo antitumor mechanism of this novel toxin. Therefore, the MMP-activated LeTx could be used not only in the clinical management of V600E B-Raf ATC but potentially in any solid tumor. Mol Cancer Ther; 9(1); 190–201

Experience performing 64 consecutive stapled intestinal anastomoses in small children and infants

BACKGROUND/PURPOSE Intestinal anastomosis in children has traditionally been performed using hand-sewn techniques. Little data exist evaluating the efficacy of stapled intestinal anastomoses in the infant and pediatric populations. METHODS A review of a 5-year experience using a mechanical stapler to treat 64 consecutive children requiring intestinal anastomoses was performed. An intestinal stapler was used to complete a side-to-side functional end-to-end anastomosis. Postoperative outcomes and modifications made to the technique were identified. RESULTS Since 2004, 64 children (median age, 3 months; range, newborn to 24 months) underwent procedures requiring intestinal anastomosis. Twenty-six children (41%) were 1 week or less in age. Twenty-seven children (42%) underwent a stoma closure using a stapler. Thirty-seven children (58%) underwent bowel resection and stapled anastomosis in treating a variety of surgical disorders. Complications included wound infection (n = 2) and anastomotic stricture (n = 1). No issues suggesting anastomotic dilatation and subsequent stasis/overgrowth were identified. CONCLUSIONS These results suggest that stapled bowel anastomosis is an effective approach applicable to a variety of surgical diseases in newborns and infants.

Reducing scheduled phlebotomy in stable pediatric patients with blunt liver or spleen injury.

BACKGROUND/PURPOSE Although consensus-based guidelines exist for managing pediatric liver/spleen injuries, optimal phlebotomy frequency is unknown. We hypothesize surgeons order more phlebotomy than necessary and propose a pathway with one blood draw, early ambulation and discharge, fewer ICU admissions, and physiology-driven interventions. METHODS Records of 120 children with solid organ injury from two hospital registries (2008-2012) were analyzed. We compared resource utilization between our current management and management if the proposed pathway were in place. Paired t-test was used for statistical analysis. RESULTS Sixty-one patients were included (35 spleen, 22 liver, 4 combined). Average age was 11.6 (±4.2) years, injury severity score 9 (±5), and median injury grade 3. 51% of children were admitted to the ICU. Average phlebotomy per patient was 5 (±2) and length-of-stay 4.3 (±1.5) days. Three patients became unstable and required transfusion. No patients required operation or angioembolization. Our pathway would decrease ICU admissions by 65% (p<0.001), blood draws by 70% (p<0.001), and length-of-stay by 37% (p<0.001), while identifying all patients requiring transfusion based on hemodynamic status. CONCLUSION Our data suggest that clinical parameters could identify patients requiring intervention and decrease resource utilization. This suggests that serial phlebotomy may be unnecessary, and the proposed pathway is worthy of prospective validation.