Robotic repair of pediatric hernias: Current techniques and practices.

The use of minimally invasive surgical techniques has gained popularity in pediatric surgery due to decreased length of stay, improved post-operative pain and smaller incisions. Laparoscopic assisted robotic surgical procedures are becoming more common in adults as they carry all of the benefits of traditional MIS but also allow for improved dexterity, visualization and surgeon ergonomics. In adults, hernia repairs are one of the most commonly performed robotic cases but adaption to pediatric repairs has been slower. Case reports and small case series have described a number of various types of pediatric hernia repairs including congenital diaphragmatic hernias, paraesophageal hernias and inguinal hernias. These cases have demonstrated that robotic repair of pediatric hernias is safe and feasible with minimal documented post-operative complications or recurrence. Future directions should focus on larger patient volume in order to assess outcomes between traditional laparoscopic and robotic approaches.

Utilization of robotics in pediatric surgical oncology.

Despite increasing implementation of robotic surgery and minimally invasive techniques within adult surgical oncology and pediatric general surgery, the utilization of robotic-assisted resections for pediatric tumors has been met with controversy. The robotic platform affords numerous advantages over conventional surgical techniques. However, limited data and guidelines regarding patient selection, indications for the robotic approach, and long-term oncologic outcomes have delayed the widespread adoption of robotic-assisted resection of pediatric tumors. This paper reviews the benefits, limitations, and existing guidelines and data regarding the utilization of robotics in pediatric surgical oncology.

Focal adhesion kinase and p53 synergistically decrease neuroblastoma cell survival.

Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of neuroblastoma tumor development and progression. The p53 oncogene, although wild type in most neuroblastomas, lacks significant function as a tumor suppressor in these tumors. Recent reports have found that FAK and p53 interact in some tumor types. We have hypothesized FAK and p53 coordinately control each other's expression and also interact in neuroblastoma. In the present study, we showed that not only do FAK and p53 interact but each one controls the expression of the other. In addition, we also examined the effects of FAK inhibition combined with p53 activation in neuroblastoma and showed that these two, in combination, had a synergistic effect on neuroblastoma cell survival. The findings from this present study help to further our understanding of the regulation of neuroblastoma tumorigenesis and may provide novel therapeutic strategies and targets for neuroblastoma and other pediatric solid tumors.

Preclinical evaluation of engineered oncolytic herpes simplex virus for the treatment of pediatric solid tumors.

Recently, investigators showed that mice with syngeneic murine gliomas that were treated with a neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal cells. Previous studies have shown antitumor effects of other oHSV against a number of adult tumors including hepatocellular carcinoma and renal cell carcinoma. The purpose of the current study was to investigate the oncolytic potential of M002 against difficult to treat pediatric liver and kidney tumors. We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly increased survival and decreased tumor growth. Finally, these studies showed that the primary entry protein for oHSV, CD111 (nectin-1) was present in human hepatoblastoma and malignant rhabdoid kidney tumor specimens. We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors.

FAK inhibition abrogates the malignant phenotype in aggressive pediatric renal tumors.

UNLABELLED: Despite the tremendous advances in the treatment of childhood kidney tumors, there remain subsets of pediatric renal tumors that continue to pose a therapeutic challenge, mainly malignant rhabdoid kidney tumors and nonosseous renal Ewing sarcoma. Children with advanced, metastatic, or relapsed disease have a poor disease-free survival rate. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult renal cellular carcinoma, leading to the hypothesis that FAK contributes to pediatric kidney tumors and would affect cellular survival. In the current study, FAK was present and phosphorylated in pediatric kidney tumor specimens. Moreover, the effects of FAK inhibition upon G401 and SK-NEP-1 cell lines were examined using a number of parallel approaches to block FAK, including RNA interference and small-molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion and migration, and increased apoptosis. Furthermore, small-molecule inhibition of FAK led to decreased SK-NEP-1 xenograft growth in vivo. These data deepen the knowledge of the tumorigenic process in pediatric renal tumors, and provide desperately needed therapeutic strategies and targets for these rare, but difficult to treat, malignancies. IMPLICATIONS: This study provides a fundamental understanding of tumorigenesis in difficult to treat renal tumors and provides an impetus for new avenues of research and potential for novel, targeted therapies.

Preclinical evaluation of engineered oncolytic herpes simplex virus for the treatment of neuroblastoma.

Despite intensive research efforts and therapeutic advances over the last few decades, the pediatric neural crest tumor, neuroblastoma, continues to be responsible for over 15% of pediatric cancer deaths. Novel therapeutic options are needed for this tumor. Recently, investigators have shown that mice with syngeneic murine gliomas treated with an engineered, neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ 1 34.5 gene, enabling replication in tumor cells but precluding infection of normal neural cells. We hypothesized that M002 would also be effective in the neural crest tumor, neuroblastoma. We showed that M002 infected, replicated, and decreased survival in neuroblastoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly decreased tumor growth, and that this effect was augmented with the addition of ionizing radiation. Importantly, survival could be increased by subsequent doses of radiation without re-dosing of the virus. Finally, these studies showed that the primary entry protein for oHSV, CD111 was expressed by numerous neuroblastoma cell lines and was also present in human neuroblastoma specimens. We concluded that M002 effectively targeted neuroblastoma and that this oHSV may have potential for use in children with unresponsive or relapsed neuroblastoma.

FAK Inhibition Decreases Hepatoblastoma Survival Both In Vitro and In Vivo.

Hepatoblastoma is the most frequently diagnosed liver tumor of childhood, and children with advanced, metastatic or relapsed disease have a disease-free survival rate under 50%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult hepatocellular carcinoma, leading us to hypothesize that FAK would be present in hepatoblastoma and would impact its cellular survival. In the current study, we showed that FAK was present and phosphorylated in human hepatoblastoma tumor specimens. We also examined the effects of FAK inhibition upon hepatoblastoma cells using a number of parallel approaches to block FAK including RNAi and small molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion, and migration and increased apoptosis. Further, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse xenograft model of hepatoblastoma. The findings from this study will help to further our understanding of the regulation of hepatoblastoma tumorigenesis and may provide desperately needed novel therapeutic strategies and targets for aggressive, recurrent, or metastatic hepatoblastomas.

Cell survival signaling in neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Neuroblastoma tumorigenesis and malignant transformation is driven by overexpression and dominance of cell survival pathways and a lack of normal cellular senescence or apoptosis. Therefore, manipulation of cell survival pathways may decrease the malignant potential of these tumors and provide avenues for the development of novel therapeutics. This review focuses on several facets of cell survival pathways including protein kinases (PI3K, AKT, ALK, and FAK), transcription factors (NF-κB, MYCN and p53), and growth factors (IGF, EGF, PDGF, and VEGF). Modulation of each of these factors decreases the growth or otherwise hinders the malignant potential of neuroblastoma, and many therapeutics targeting these pathways are already in the clinical trial phase of development. Continued research and discovery of effective modulators of these pathways will revolutionize the treatment of neuroblastoma.

FAK inhibition decreases cell invasion, migration and metastasis in MYCN amplified neuroblastoma.

Neuroblastoma, the most common extracranial solid tumor of childhood, is responsible for over 15 % of pediatric cancer deaths. We have shown that neuroblastoma cell lines overexpress focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase that controls a number of tumorigenic pathways. In this study, we hypothesized that inhibition of FAK would result in decreased cellular migration and invasion in neuroblastoma cell lines, and decrease metastasis in a murine model. We utilized non-isogenic and isogenic MYCN human neuroblastoma cell lines and parallel methods of FAK inhibition. Cell viability, migration, and invasion assays were employed to assess the effects of FAK inhibition in vitro. A nude mouse model was utilized to determine the effects of FAK inhibition on in vivo liver metastasis. FAK knockdown with siRNA resulted in decreased invasion and migration in neuroblastoma cell lines, and the effects of siRNA-induced FAK inhibition were more pronounced in MYCN amplified cell lines. In addition, abrogation of FAK with a small molecule inhibitors resulted in decreased cell survival, migration and invasion in neuroblastoma cell lines, again most pronounced in cell lines with MYCN amplification. Finally, small molecule FAK inhibition in a nude mouse model resulted in a significant decrease in metastatic tumor burden in SK-N-BE(2) injected animals. We believe that FAK plays an important role in maintaining and propagating the metastatic phenotype of neuroblastoma cells, and this driver role is exaggerated in cell lines that overexpress MYCN. FAK inhibition warrants further investigation as a potential therapeutic target in the treatment of aggressive neuroblastoma.

Laparoscopic surgery in children with congenital heart disease.

PURPOSE: The study aim was to determine outcomes of children with congenital heart disease who underwent laparoscopic procedures. METHODS: A single-institution, institutional review board-approved, retrospective review was conducted including children younger than 5 years with congenital heart disease who underwent laparoscopic or open abdominal procedures. Patient demographics, operative details, complications, and 30-day mortality were examined. RESULTS: Over 10 years, 111 children with congenital heart disease underwent 121 laparoscopic procedures. Median age was 2.5 months, with 87% being infants. Laparoscopic gastrostomy was the most common procedure (101). There was no intraoperative hemodynamic instability, median operative time was 70 minutes, postoperative complications were low (5%), and all children were alive at 30 days. Only 8 patients required conversion from laparoscopic to open, all secondary to technical issues, not hemodynamic instability. There were 42 children with cardiac disease who underwent 45 open procedures during the study period. There were no significant differences between patient demographics, type of procedure, operative time, complications, or 30-day mortality comparing the open and laparoscopic groups. CONCLUSION: In this review, there were no major contraindications to performing laparoscopic procedures in children with congenital heart disease, and we conclude that it is reasonably safe to perform laparoscopic surgery on these children.

Targeting gastrin-releasing peptide as a new approach to treat aggressive refractory neuroblastomas.

BACKGROUND: The overall survival for neuroblastoma remains dismal, in part due to the emergence of resistance to chemotherapeutic drugs. We have demonstrated that gastrin-releasing peptide (GRP), a gut peptide secreted by neuroblastoma, acts as an autocrine growth factor. We hypothesized that knockdown of GRP will induce apoptosis in neuroblastoma cells and potentiate the cytotoxic effects of chemotherapeutic agents. METHODS: The human neuroblastoma cell lines (JF, SK-N-SH) were transfected with small interfering (si) RNA targeted at GRP. Apoptosis was assessed by DNA fragmentation assay. Immunoblotting was used to confirm molecular markers of apoptosis, and flow cytometry was performed to determine cell cycle arrest after GRP knockdown. RESULTS: siGRP resulted in an increase in apoptosis in the absence of chemotherapeutic interventions. A combination of GRP silencing and chemotherapeutic drugs resulted in enhanced apoptosis when compared to either of the treatments alone. GRP silencing led to increased expression of proapoptotic proteins, p53 and p21. CONCLUSION: Silencing of GRP induces apoptosis in neuroblastoma cells; it acts synergistically with chemotherapeutic effects of etoposide and vincristine. GRP knockdown-mediated apoptosis appears to be associated with upregulation of p53 in neuroblastoma cells. Targeting GRP may be postulated as a potential novel agent for combinational treatment to treat aggressive neuroblastomas.