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Background: Laparoscopic herniorrhaphy in pediatrics is rarely performed. We evaluated our 2-year experience of minimally invasive inguinal herniorrhaphy in children., Methods: All procedures were performed under general anesthesia using <2-mm instruments and scopes and a surgical awl to accomplish high ligation of the hernia sac under direct vision., Results: A total of 90 consecutive children (76 males and 14 females) older than the age of 6 months underwent a minimally invasive herniorrhaphy (60 unilateral and 30 bilateral; total of 120 hernias repaired). Seventeen children underwent herniorrhaphy in conjunction with another procedure. All children who underwent herniorrhaphy alone were discharged immediately and allowed unrestricted activity. Only four patients requested a narcotic analgesic. There was one recurrence early in the series (0.83%), prompting a change in technique., Conclusions: Minimally invasive inguinal herniorrhaphy in children is a safe alternative for the experienced pediatric laparoscopist. There is a similar recurrence rate as that of the traditional open approach with a superior cosmetic result.

Background: The specific use of minimally invasive surgery (MIS) in pediatric cancer patients is limited. We evaluated the 5-year experience at a single institution with MIS in children with malignancies., Methods: A retrospective review was undertaken of all MIS performed between November 1995 and October 2000., Results: A total of 101 pediatric oncology patients underwent 113 MIS procedures-64 laparoscopic (57%) and 49 thoracoscopic (43%)-during this period. Laparoscopy was performed for diagnostic purposes in 27 cases (42%) and was successful in 25 (93%) cases. Laparoscopic tumor resection was performed in seven cases (11%). Thirty additional laparoscopic procedures (47%) were attempted for complications of the malignancy or its treatment. Four of these cases were converted to open laparotomies. Indications for thoracoscopy included the evaluation of a mediastinal mass (n = 7) or biopsy or resection of pulmonary lesions (metastatic, n = 31; infectious, n = 9). Fourteen cases (29%) had to be converted to open thoracotomy procedures, generally because of the inability to localize a lesion. The other 35 procedures were successful. The overall complication rate was 5%. No trocar site recurrences or infections were observed., Conclusions: We conclude that MIS in pediatric cancer patients is a safe and effective diagnostic modality. The role of MIS for primary tumor resection remains to be defined.

Destruction and remodeling of the extracellular matrix occurs during the formation of new blood vessels that are required for tumor growth. We sought to determine whether gene-therapy mediated in vivo delivery of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), using retroviral vector-producer cells, could suppress angiogenesis and subsequent tumor growth in a murine neuroblastoma model. Tumor volume 28 days after coinjection of tumor cells with producer cells generating TIMP-3-encoding retroviral vectors was 21% that of controls, as was the mean tumor vascular index, a measure of blood vessel maturity. When tumors were allowed to reach a mean volume of 0.05 cm(3) before treatment, their size 2 weeks later was 47% relative to controls; larger tumors were not significantly affected. When producer cells were injected at surgical sites following excision of subcutaneous tumors, local recurrence 14 days later was only 22% in TIMP-3 producer cell treated mice as compared to 71% in controls. Unsuccessful transduction of melanoma cells in situ, another tumor of neural crest origin, resulted in unimpaired tumor growth, despite the fact that these tumors are susceptible to TIMP-3 overexpression, demonstrating the importance of tumor cell transduction in this approach. Thus, retroviral vector-producer cell-mediated in vivo gene transfer of TIMP-3 to tumor cells can significantly restrict tumor-induced angiogenesis and tumor growth. This approach may be an effective adjuvant in the treatment of neuroblastoma and other solid tumors refractory to traditional therapy, although it appears to be most effective in smaller tumors or in the setting of minimal residual disease, and the tumor cells must be susceptible to retroviral vector-mediated transduction.

Homeostasis of the extracellular matrix is a delicate balance between degradation and remodeling, the balance being maintained by the interaction of activated matrix metalloproteinases (MMPs) and specific tissue inhibitors of matrix metalloproteinases (TIMPs). Up-regulation of MMP activity, favoring proteolytic degradation of the basement membrane and extracellular matrix, has been linked to tumor growth and metastasis, as well as tumor-associated angiogenesis, whereas inhibition of MMP activity appears to restrict these processes. We have used retroviral-mediated gene delivery to effect sustained autocrine expression of TIMP-3 in murine neuroblastoma and melanoma tumor cells in order to further examine the ability of TIMPs to inhibit angiogenesis in vivo. Growth of both histologic types of gene-modified tumor cells in severe combined immunodeficiency (SCID) mice was significantly restricted when compared with controls. Grossly, these tumors were small and had few feeding vessels. Histologic evaluation revealed that although tumors overexpressing TIMP-3 had an increased number of CD31(+) endothelial cells, these endothelial cells had not formed functional tubules, as evidenced by decreased vessel continuity and minimal pericyte recruitment. This effect appears to be mediated, in part, by decreased expression of vascular endothelial (VE)-cadherin by endothelial cells in the presence of TIMP-3 as seen both in an in vitro assay and in TIMP-3-overexpressing tumors. Taken together, these results demonstrate that overexpression of TIMP-3 can inhibit angiogenesis and associated tumor growth, and that the antiangiogenic effects of TIMP-3 appear to be mediated through the inhibition of functional capillary morphogenesis.

It is now well established that tumor growth is angiogenesis dependent. Inhibition of angiogenesis, therefore, is likely to be an effective anticancer approach. A gene therapy-mediated approach to the delivery of antiangiogenic agents using adeno-associated virus (AAV) vectors has a number of advantages, including the potential for sustained expression. We have constructed a rAAV vector in which the expression of a soluble, truncated form of the vascular endothelial growth factor receptor-2 (Flk-1), a known inhibitor of endothelial cell activation, is driven by a composite beta-actin-based promoter. After intraportal injection of this vector, high-level, stable transgene expression was generated in mice. This established a systemic state of angiogenesis inhibition; sera from these mice inhibited endothelial cell activation in vitro and Matrigel plug neovascularization in vivo. Significant antitumor efficacy was observed in two murine models of pediatric kidney tumors. Tumor development was prevented in 10 of 15 (67%) mice, with significant growth restriction of tumors in the remaining mice. For the first time, long-term, in vivo expression of a functional angiogenesis inhibitor has been established using rAAV, with resultant anticancer efficacy in a relevant, orthotopic tumor model. These findings establish the feasibility of using rAAV vectors in antiangiogenic gene therapy.

Inhibition of tumor-induced neovascularization appears to be an effective anticancer approach, although long-term angiogenesis inhibition may be required. An alternative to chronic drug administration is a gene therapy-mediated approach in which long-term in vivo protein expression is established. We have tested this approach by modifying murine bone marrow-derived cells with a gene encoding an angiogenesis inhibitor: a soluble, truncated form of the vascular endothelial growth factor receptor-2, fetal liver kinase-1 (Flk-1). Murine bone marrow cells were transduced with a retroviral vector encoding either truncated, soluble Flk-1 (tsFlk-1) together with green fluorescent protein (GFP) or GFP alone. Tumor growth in mice challenged 3 months after transplantation with tsFlk-1-expressing bone marrow cells was significantly inhibited when compared with tumor growth in control-transplanted mice. Immunohistochemical analysis of tumors in each group demonstrated colocalization of GFP expression in cells staining with endothelial cell markers, suggesting that the endothelial cells of the tumor-induced neovasculature were derived, at least in part, from bone marrow precursors. These results suggest that long-term expression of a functional angiogenesis inhibitor can be generated through gene-modified, bone marrow-derived stem cells, and that this approach can have significant anticancer efficacy. Modifying these cells seems to have the added potential benefit of targeting transgene expression to the tumor neovasculature, because bone marrow-derived endothelial cell precursors seem to be recruited in the process of tumor-induced angiogenesis.

Modalities that act through different mechanisms can often provide synergistic antitumor activity for the treatment of refractory tumors when used in combination. Here we report a gene therapy approach in which the genes for the angiogenesis inhibitor, endostatin, and the marker protein and potent immunogen, green fluorescent protein (GFP), were delivered to murine neuroblastoma cells prior to inoculation of the tumor cells into syngeneic immunocompetent mice. Although the effect of either angiogenesis inhibition or immunomodulation alone resulted in only a modest delay in tumor growth, when these approaches were used in combination, prevention of the formation of appreciable tumors was effected in 15 of 24 (63%) mice. The combination of endostatin and GFP expression elicited a strong immune response that was T cell-mediated and was reactive against both GFP and tumor cell line-specific antigens. This afforded treated mice protection against subsequent tumor challenge with unmodified tumor cells. These results suggest that antiangiogenic and immunotherapy strategies, when used in a gene therapy-mediated approach, can act synergistically in an effective multimodality anticancer approach.

Background/purpose: Because the management of pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) is determined by extrapolation from adult studies, the effect of margin of tumor resection and postoperative radiation therapy (RT) on local tumor recurrence in children has not been assessed., Methods: Records of NRSTS patients from a single institution were reviewed with regard to demographic data, TNM staging, grade, histological type and site of primary tumor, RT, and local tumor recurrence. The margin of resection was determined by pathological review and did not necessarily reflect operative margins., Results: Eighty-eight clinical group I patients were treated over a 30-year period. The most common histological tumor subtypes were synovial cell sarcoma (n = 26), malignant fibrous histiocytoma (n = 17), and fibrosarcoma (n = 7). The mean age was 9.4 years (range, 0 to 29 years). Thirty-four patients had high-grade tumors. Two of ten patients with low-grade tumors and margins less than 1 cm, including one of five who had received RT, had a local recurrence. Patients with low-grade tumors and margins greater than 1 cm (n = 44) had a lower recurrence rate (2 of 44, 4.5%). None of these patients had received RT. Fourteen patients with high-grade tumors had margins less than 1 cm. Seven of these had RT and had no recurrence. Three of the seven patients who received no RT had a recurrence (42.9%). None of the 20 patients with high-grade tumors and margins greater than 1 cm received RT; four of these patients had recurrences (20%). Seven of the 12 irradiated patients (58.3%) had serious radiation-associated complications (wound dehiscence, fracture, growth retardation, and joint dysfunction)., Conclusions: Grade alone does not determine the rate of local recurrence. In both low- and high-grade tumors, a pathological margin of resection greater than 1 cm reduced local recurrence. Radiotherapy provided no advantage in low grade tumors but did decrease local recurrence rates in high-grade tumors with less than 1 cm pathological margins.

Laparoscopic appendectomy is a common surgery in most pediatric surgical centers. Many studies, mostly retrospective reviews in adults, show the advantages of the laparoscopic approach to be less wound infections, shortened postoperative recovery, and faster return to normal activities. In addition, less analgesic medication is required postoperatively. Potential disadvantages of laparoscopic appendectomy include an increased operative time, elevated costs when disposable instruments are used, and possibly more infectious complications when performed for complicated appendicitis. There are no prospective, randomized trials comparing laparoscopic versus open appendectomy in children. Until these studies are completed, questions will persist regarding the benefits of laparoscopic appendectomy in children., (Copyright 1998 W.B. Saunders Company.)