In-bag enzymatic splenic digestion: a novel alternative to manual morcellation?

BACKGROUND: Contained in-bag spleen morcellation is a conventional extraction technique for safe spleen removal during laparoscopic splenectomy. Existing data for the use of in-bag enzymatic splenic digestion as an alternative to morcellation are lacking. This proof-of-concept study sought to evaluate the effectiveness of single and combinatorial enzyme digestion of murine spleens. MATERIALS AND METHODS: Murine spleens were digested with collagenase alone or with combinations of commercially available enzymes (collagenase, elastase, hyaluronidase, neutral protease) to determine their degradation effect. The primary end point was the percentage of mass reduction at 15 and 30 min. RESULTS: For collagenase alone (n = 15), the mean reduction in mass was 14 ± 10% (range: 2%-31%) at 15 min and 30 ± 25% (range: 7%-100%) at 30 min. Using combinatorial dissolution with collagenase, hyaluronidase, and elastase (n = 8), the mean reduction in mass was 27 ± 16% (range: 6%-42%) at 15 min and 48 ± 27% (range: 3%-100%) at 30 min. Injecting the enzyme solution into whole spleens (n = 9) yielded a mean reduction in mass of 22 ± 13% (range: 9%-42%) at 15 min and 55 ± 31% (range: 9%-100%) at 30 min; mean reduction was 9 ± 13% (range: 0%-39%) at 15 min and 23 ± 13% (range: 3%-53%) with no injection (n = 12). CONCLUSIONS: We provide the first demonstration of successful enzymatic murine spleen digestion as an alternative method for in-bag spleen removal during laparoscopic splenectomy. However, the significant cost and quantities of commercial enzyme required for clinical application dampens the enthusiasm for this novel approach.

Gastrostomy Complications in Pediatric Cancer Patients: A Retrospective Single-Institution Review.

BACKGROUND: Complications in pediatric cancer patients after a gastrostomy (GT) placement have not been widely investigated. We aimed to evaluate the complication rate and nature of complications in this specific population. PROCEDURE: Medical records of pediatric cancer patients having a GT placed at our institution from 1998 to 2013 were retrospectively reviewed. Variables analyzed included gender, age, diagnosis, surgical procedure, GT device, duration of GT usage, absolute neutrophil count (ANC) level at surgery, and complications. RESULTS: One hundred seventy-one patients (92 males, 79 females), median age of 6 years (range, 0.2-21), who underwent 181 procedures (110 open, 59 endoscopic, and 12 laparoscopic) were identified. Diagnosis included central nervous system tumor (n = 101), solid tumor (n = 45), and leukemia/lymphoma (n = 25). A GT tube was used in 139 procedures and a GT button in 42. Median ANC level at procedure was 3,300/mm(3) (range, 0-38,988). Median duration of GT usage was 8 months (range, 0.2-142). One hundred seventy-seven complications occurred in 106 patients (61.9%) and were categorized as perioperative (<1 month after surgery, 20.3%) and late (>1 month after surgery, 79.7%). Major complications included 42 (23.7%) GT site infections and four (2.2%) intrabdominal complications. The most common minor complication was granulation tissue (28.8%). Younger age at procedure was associated with complications (P = 0.048) and an open technique was associated with GT site infection (P = 0.003). No statistical significance was observed between complications and gender, diagnosis, GT device, duration of GT usage, and ANC at procedure. CONCLUSIONS: Younger patients were more likely to have complications, and GT site infections were more common after open GT procedures.

Reconstruction of Desmoid Tumors: Case Series and Systematic Review.

BACKGROUND: Desmoid tumors (DT) represent a group of rare, distinct lesions. There are few published studies examining outcomes and safety of complex reconstruction after DT resection. METHODS: A retrospective review identified 39 patients who underwent surgical treatment of DT at St. Jude Children's Research Hospital over a 12-year period. A systematic review of the literature identified 17 further studies for inclusion. Treatment characteristics were analyzed. RESULT: Thirty-nine patients were treated during the study period, with a total number of 67 resections. Median age was 12.2 years; 49% of patients were male, and 51% were female. Median tumor size was 9.8 cm. DT most commonly arose in the extremities (40%), thorax (23%), head and neck (21%), and trunk (16%). One- and 5-year recurrence-free survival were 97.1% and 73.1%, respectively. The majority of defects were closed primarily, with the exception of head and neck defects. Long-term outcomes were good for chest, abdomen, and upper extremity defects, but were problematic for head and neck, breast, and lower extremity defects. There were no recurrences at the site of flap harvest in either the study population or in reviewed studies. CONCLUSION: For patients with DT, surgical extirpation should not come at the expense of functional preservation, as overall survival is excellent. However, specific defects, including those of the lower extremity, breast, and head and neck, will benefit from improved techniques for resection and reconstruction.

Aggressive Cunninghamella pneumonia in an adolescent.

Children with hematologic malignancies may be challenged with life-threatening, invasive fungal infections by organisms that would otherwise have a low potential for virulence in healthy hosts. Presented is a case of a 15-year-old adolescent with B-cell acute lymphoblastic leukemia who was receiving steroids and chemotherapy. He developed cough associated with left chest pain with suspicion for fungal pneumonia. He began systemic antifungal therapy, underwent computed tomography of the chest demonstrating a large cavitary lesion (reversed halo sign) in the left lung. Over a 48-hour period the patient clinically deteriorated with worsening pneumonia and required left thoracotomy with nonanatomic pulmonary resection. This case illustrates the aggressive nature of Cunninghamella pneumonia in patients with hematologic malignancies, and the multidisciplinary approach required to have the greatest possible outcome.

Surgical treatment of pediatric desmoid tumors. A 12-year, single-center experience.

BACKGROUND: Pediatric desmoid tumors (PDTs) represent a group of rare, distinct lesions. While sparse, available literature suggests that PDT are particularly aggressive and difficult to control when compared with their adult counterpart. METHODS: A retrospective review identified 39 patients who underwent treatment of PDT at St. Jude Children's Research Hospital over a 12-year period. Clinicopathologic and treatment characteristics were analyzed to identify predictors of outcome. RESULT: A total of 39 patients were treated during the study period, with a total number of 67 resections. Median age was 12.2 years; 49 % of patients were male, and 51 % were female. Median tumor size was 9.8 cm. PDT most commonly arose in the extremities (40 %), thorax (23 %), head and neck (21 %), and trunk (16 %). Also, 18 % of resections had negative margins (R0), 48 % were microscopic positive (R1), and 30 % were macroscopic positive (R2). The 1- and 5-year recurrence-free survival (RFS) was 97.1 and 73.1 %, respectively. Factors associated with worse RFS were patient age >12 years (HR = 5.08, p = 0.038) and tumor size >5 cm (HR = 1.22, p = 0.0597). Margin status did not affect RFS. Selective use of radiation therapy appeared to improve RFS. CONCLUSIONS: Our study suggests that margin status alone at the time of extirpation is not a predictor of ultimate cure or likelihood of recurrence. Many patients received adjuvant therapy, with benefits suggested after analysis. For patients with PDT, surgical extirpation should not come at the expense of functional preservation, as overall survival is excellent.

Late onset diaphragmatic hernia complicated by intestinal strangulation.

We present a case of a 7-week-old infant who presented with nonspecific respiratory symptoms that quickly progressed to sudden cardiac arrest as a consequence of late-onset diaphragmatic hernia and intestinal strangulation. Unless discovered as an incidental finding, late-onset diaphragmatic hernia should be considered a surgical emergency.

Clinical significance of serum biomarkers in pediatric solid mediastinal and abdominal tumors.

Childhood cancer is the leading cause of death by disease among U.S. children between infancy and age 15. Despite successes in treating solid tumors such as Wilms tumor, disappointments in the outcomes of high-risk solid tumors like neuroblastoma have precipitated efforts towards the early and accurate detection of these malignancies. This review summarizes available solid tumor serum biomarkers with a special focus on mediastinal and abdominal cancers in children.

Management of button battery-induced hemorrhage in children.

OBJECTIVES: Button battery ingestions are potentially life threatening for children. Catastrophic and fatal injuries can occur when the battery becomes lodged in the esophagus, where battery-induced injury can extend beyond the esophagus to the trachea or aorta. Increased production of larger, more powerful button batteries has coincided with more frequent reporting of fatal hemorrhage secondary to esophageal battery impaction, but no recommendations exist for the management of button battery-induced hemorrhage in children. MATERIALS AND METHODS: We reviewed all of the reported pediatric fatalities due to button battery-associated hemorrhage. Our institution engaged subspecialists from a wide range of disciplines to develop an institutional plan for the management of complicated button battery ingestions. RESULTS: Ten fatal cases of button battery-associated hemorrhage were identified. Seven of the 10 cases have occurred since 2004. Seventy percent of cases presented with a sentinel bleeding event. Fatal hemorrhage can occur up to 18 days after endoscopic removal of the battery. Guidelines for the management of button battery-associated hemorrhage were developed. CONCLUSIONS: Pediatric care facilities must be prepared to act quickly and concertedly in the case of button battery-associated esophageal hemorrhage, which is most likely to present as a "sentinel bleed" in a toddler.

Proteomic approaches in neuroblastoma: a complementary clinical platform for the future.

Neuroblastoma (NB) is one of the most common solid tumors of childhood and displays a remarkable diversity in both biologic characteristics and clinical outcomes. Availability of high-throughput 'omics technologies and their subsequent application towards oncology has provided insight into the complex pathways of tumor formation and progression. Investigation of NB 'omics profiles may better define tumor behavior and provide targeted therapy with the goal of improving outcomes in patients with high-risk disease. Utilization of these technologies in NB has already led to advances in classification and risk stratification. The gradual emergence of NB-directed proteomics adds a layer of intricacy to the analysis of biologic organization but may ultimately provide a better comprehension of this complex disease. In this review, we cite specific examples of how NB-directed proteomics has provided information regarding novel biomarkers and possible therapeutic targets. We finish by examining the impact of high-throughput 'omics in the field of NB and speculate on how these emerging technologies may further be incorporated into the discipline.

Proteomic analysis of neuroblastoma microenvironment: effect of the host-tumor interaction on disease progression.

BACKGROUND: Children with advanced-stage neuroblastoma (NB) traditionally experience poor outcomes. Because early detection of advanced-stage disease may impact survival, finding new targets for early diagnosis is crucial. Evidence suggests the tumor microenvironment may have profound effects on cancer progression. METHODS: As little is known concerning the NB-host microenvironment, this study applied proteomic techniques, two-dimensional polyacrylamide gel electrophoresis (2D PAGE) combined with matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry to determine protein differences between cell cultured NB and tumors grown in mice for 2, 4, and 5 wk. RESULTS: We found an increase in proteins in cultured NB compared with implanted mouse tumors during tumor progression. Additionally, analyzing in vivo tumors to cultured NB, we observed less expressed proteins. However, 16 out of 19 proteins were of mouse origin, thus inferring host-derived factors contributing to tumor growth. CONCLUSION: We show that the dynamic relationship between NB and host microenvironment is important for tumor growth and better understanding of this milieu maybe relevant towards finding unique approaches for identifying advanced-stage disease.

Bin1 is linked to metastatic potential and chemosensitivity in neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children. At the time of diagnosis, the tumor has metastasized in as many as 7 of 10 cases, and survival in high-risk patients remains poor. Accurate classification of high-risk patients is very important since this determines treatment plan, and although a consensus risk classification system has been established for NB, it contains few specific molecular markers that account for aggressive nature and metastatic potential of the tumor. Bin1 expression is reduced in breast, NB, and other cancer types and the reduction correlates with high-risk clinical features. Here we hypothesize that Bin1 has an inhibitory role in metastasis, and therefore decrease in its expression may be a marker of high-risk NB. PROCEDURE: Initially, breast cancer and NB cell lines derived from metastasis were examined for Bin1 expression. Then, a stable Bin1-overexpressing NB cell line was created and evaluated for in vitro metastatic behaviors using anoikis, invasion, and migration assays, and chemoresponsiveness using MTT assay. RESULTS: Reduced Bin1 was detected in all cancer cell lines examined, and forced Bin1 overexpression increased NB cell anoikis and enhanced the cell killing by doxorubicin. However, Bin1 overexpression did not significantly affect cell invasion, motility, or proliferation. CONCLUSIONS: Bin1 appears to function as a metastasis suppressor and chemosensitizer in NB, and resistance to anoikis may be an important metastatic mechanism. Thus, Bin1 expression status could serve as a marker for metastatic potential and chemosensitivity thereby allowing for more accurate classifications of high-risk NB patients.

Minimally Invasive Surgery in Pediatric Surgical Oncology: Practice Evolution at a Contemporary Single-Center Institution and a Guideline Proposal for a Randomized Controlled Study.

Background: Despite the lack of randomized or controlled trials for minimally invasive surgery (MIS) in pediatric surgical oncology, the integration of MIS into the surgical practice of pediatric oncology has become increasingly popular. The aim of this study was to evaluate the implementation of MIS in a pediatric tertiary cancer center and compare present use of MIS to that in a previous analysis at our center. Methods: We retrospectively reviewed the medical records of patients with pediatric cancer treated with MIS at a single institution between 2000 and 2014. Results: A total of 252 MIS procedures were performed: 73 laparoscopic (29%) and 179 thoracoscopic (71%). MIS was used for diagnostic purposes in 59% (146 thoracoscopic and 34 laparoscopic) and the therapeutic resection in 24% (39 laparoscopic cases and 33 thoracoscopic cases). Conversion to an open procedure occurred in 18 tumor resections (6%) and in 22 diagnostic biopsies (7%), mostly due to technical challenges in identifying or mobilizing tumors. Complications occurred in seven tumor resections (2%) and included three pneumothoraces, two bleeding complications, one bowel injury, and one wound infection. Complications occurred in 10 diagnostic biopsies (3%), mostly pneumothoraces. No tumor upstaging or trocar site recurrences occurred (follow-up time, 1-15 years). Conclusions: Over the last decade, we demonstrate the evolution of MIS in the management of solid tumors in children. We encourage surgeons and oncologists to join the call to arms to establish prospective trials evaluating MIS in pediatric surgical oncology.

Operative and Immediate Postoperative Differences Between Traditional Multiport and Reduced Port Laparoscopic Total Splenectomy in Pediatric Patients.

BACKGROUND: Laparoscopy offers many benefits to splenectomy, such as reduced incisional pain and shortened hospital duration. The purpose of this study is to evaluate procedural and outcome differences between multiport (MP) and reduced port (RP) splenectomy when utilized to treat children. PATIENTS AND METHODS: An institutional review board approved retrospective analysis of all consecutive laparoscopic total splenectomies performed at a single institution between January 2010 and October 2015 was conducted. We evaluated demographics, surgical technique, instance of conversion, operative duration, estimated blood loss, need for intraoperative blood transfusion, postoperative length of stay, time to full feeds, complications, and follow-up duration. RESULTS: Over a 5-year period, 66 patients less than 20 years of age underwent laparoscopic total splenectomy. RP splenectomy was attempted in 14 patients. The remaining 52 were MP operations. Populations were comparable with regard to demographics. Preoperative splenic volumes (mL) were greater in the RP population (median [IQR]: 1377 [747-1508] versus 452 [242-710], P = .039). RP splenectomy demonstrated no difference compared to MP splenectomy in operative time (153 versus 138 minutes, P = .360), estimated blood loss (120 versus 154 mL, P = .634), or percent of cases requiring intraoperative blood transfusion (14 versus 23, P = .716). By the first postoperative day, 57% of RP and 17% of MP patients could be discharged (P = .005). Thirty-day readmission rates were similar, at 7% for RP and 8% for MP operations. Fever was the indication for all readmissions. Mean duration of follow-up is 28 months for MP and 13 months for RP cases. CONCLUSION: A reduced number of ports can be safely utilized for total splenectomy in pediatric patients without increasing procedural duration or need for intraoperative blood transfusion. In addition, rate of discharge on the first postoperative day was significantly higher in the RP splenectomy group.

Risk-reduction surgery in pediatric surgical oncology: A perspective.

OBJECTIVE: A small percentage of pediatric solid cancers arise as a result of clearly identified inherited predisposition syndromes and nongenetic lesions. Evidence supports preemptive surgery for children with genetic [multiple endocrine neoplasia type 2 (MEN2), familial adenomatous polyposis syndrome (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), and hereditary diffuse gastric cancer (HDGC) and nongenetic [thyroglossal duct cysts (TGDC), congenital pulmonary airway malformations (CPAM), alimentary tract duplication cysts (ATDC), and congenital choledochal cysts (CCC)] developmental anomalies. Our aim was to explore the utility of risk reduction surgery to treat and prevent cancer in children. METHODS: A systematic review of the available peer-reviewed literature on PubMed was performed using a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) search strategy, where possible. Search items included "risk reduction surgery", "hereditary cancer predisposition syndrome", "multiple endocrine neoplasia type 2", "familial adenomatous polyposis", "hereditary nonpolyposis colorectal cancer", "hereditary diffuse gastric cancer", "thyroglossal duct cysts", congenital pulmonary airway malformations", "alimentary tract duplication cysts", "malignant transformation", and "guidelines". RESULTS: We identified 67 articles that met the inclusion criteria describing the indications for prophylactic surgery in surgical oncology. For the genetic predisposition syndromes, 7 studies were related to professional endorsed guidelines, 7 were related to surgery for MEN2, 11 were related to colectomy for FAP, 6 were related to colectomy for HNPCC, and 12 related to gastrectomy for HDGC. Articles for the nongenetic lesions included 5 for techniques related to TGDC resection, 9 for surgery for CPAMs, and 10 for resection of ATDCs. Guidelines and strategies varied significantly especially related to the extent and timing of surgical intervention; the exception was for the timing of thyroidectomy in children with MEN2. CONCLUSION: Current evidence supporting prophylactic surgery in the management of pediatric cancer predisposition syndromes and nongenetic lesions is best delineated for thyroidectomy to prevent medullary thyroid cancer in children with MEN2 (Strength of Recommendation Grade B/C). Despite the lack of pediatric specific evidence-based recommendations regarding the appropriate extent and timing for risk-reduction surgery for FAP, HNPCC, HDGC and nongenetic anomalies, our review represents an opportunity towards understanding the postgenomic development of these lesions and provides current indications and techniques for preemptive cancer prevention surgery in children.

Neonatal Germ Cell Tumors.

Excluding hemangiomas, germ cell tumors (GCTs) are the most common neoplasm in neonates, comprising a wide range of benign and malignant tumors with unique histological diversity. Although these tumors are relatively rare, antenatal ultrasonography has increased their detection before birth. Extragonadal GCTs (EGCTs) are the most common GCTs in neonates, with sacrococcygeal teratomas (SCTs) being the most prevalent EGCTs. SCTs are characterized as protruding masses arising from the sacrococcygeal region with or without variable extension into the presacral space. Patients with SCTs typically have an excellent prognosis, though this is dependent on the ease of surgical resection, the timing of diagnosis, and the malignant potential of the tumor. Whereas some GCTs can be diagnosed and treated prenatally, this review focuses on postnatal management of GCTs. We explore the embryological development, histopathology, biomarkers, clinical presentation, diagnostic features, and treatment of neonatal GCTs. Because the overall prognosis is excellent for the majority of patients with GCTs, we also discuss the potential long-term effects of antineoplastic agents used to treat patients with malignant disease.

Hepatic metastatic disease in pediatric and adolescent solid tumors.

The management of hepatic metastatic disease from solid tumors in adults has been extensively described and resection of metastatic liver lesions from colorectal adenocarcinoma, renal adenocarcinoma, breast cancer, testicular cancer, and neuroendocrine tumors (NET) have demonstrated therapeutic benefits in select patients. However, there are few reports in the literature on the management of hepatic metastatic disease in the pediatric and adolescent populations and the effectiveness of hepatic metastasectomy. This may be due to the much lower incidence of pediatric malignancies and the higher chemosensitivity of childhood tumors which make hepatic metastasectomy less likely to be required. We review liver involvement with metastatic disease from the main pediatric solid tumors, including neuroblastoma and Wilms tumor focusing on the management and treatment options. We also review other solid malignant tumors which may have liver metastases including germ cell tumors, gastrointestinal stromal tumors, osteosarcoma, desmoplastic small round cell tumors and NET. However, these histological subtypes are so rare in the pediatric and adolescent populations that the exact incidence and best management of hepatic metastatic disease are unknown and can only be extrapolated from adult series.

An approach to renal masses in pediatrics.

Renal masses in children may be discovered during routine clinical examination or incidentally during the course of diagnostic or therapeutic procedures for other causes. Renal cancers are rare in the pediatric population and include a spectrum of pathologies that may challenge the clinician in choosing the optimal treatment. Correct identification of the lesion may be difficult, and the appropriate surgical procedure is paramount for lesions suspected to be malignant. The purpose of this article is to provide a comprehensive overview regarding the spectrum of renal tumors in the pediatric population, both benign and malignant, and their surgical management.

The Mechanism by Which MYCN Amplification Confers an Enhanced Sensitivity to a PCNA-Derived Cell Permeable Peptide in Neuroblastoma Cells.

Dysregulated expression of MYC family genes is a hallmark of many malignancies. Unfortunately, these proteins are not amenable to blockade by small molecules or protein-based therapeutic agents. Therefore, we must find alternative approaches to target MYC-driven cancers. Amplification of MYCN, a MYC family member, predicts high-risk neuroblastoma (NB) disease. We have shown that R9-caPep blocks the interaction of PCNA with its binding partners and selectively kills human NB cells, especially those with MYCN amplification, and we now show the mechanism. We found elevated levels of DNA replication stress in MYCN-amplified NB cells. R9-caPep exacerbated DNA replication stress in MYCN-amplified NB cells and NB cells with an augmented level of MYC by interfering with DNA replication fork extension, leading to Chk1 dependence and susceptibility to Chk1 inhibition. We describe how these effects may be exploited for treating NB.

Detection of PI3K inhibition in human neuroblastoma using multiplex luminex bead immunoassay: a targeted approach for pathway analysis.

Neuroblastoma (NB) is a common solid tumor in children. Outcomes for advanced stage NB have not improved, at least in part because of multimodality therapy resistance. Better comprehension of novel molecular targets will likely lead to improved therapies with specific cytotoxic agents. For instance, the role of deregulated IGF-1R/AKT/PI3K/mTOR (PI3K) pathway activity has attracted much attention across several tumors, including NB. Thus, modulating this pathway via anti-PI3K drugs has taken center stage in many cancer clinical trials. However, varied clinical effects have hampered the precise application of these agents. Tumor PI3K pathway profiling may reveal a method to enhance the efficacy of these inhibitors. To this end, solid-phase antibody-based array platforms have emerged as a direct, rapid means of profiling intracellular signaling pathways. We tested the efficacy of four PI3K inhibitors against a panel of human NB cell lines using Luminex xMAP bead array technology to establish PI3K phosphoprotein profiles. We demonstrate the utility of the xMAP approach in following intracellular signaling signatures specific for PI3K targeted therapy. Further validation is required before xMAP is used routinely for clinical PI3K pathway evaluation, but this method may eventually be personalized by taking into account each child's basal NB pathway status.

Minimally invasive surgery in the management of abdominal tumors in children.

The application of minimally invasive surgical techniques to pediatric abdominal tumors is a controversial application towards the surgical management of childhood cancer. Although general pediatric surgeons practice minimally invasive surgery techniques in a vast array of abdominal cases, its role in pediatric oncology is still developing, with no consensus in North America about its use for pediatric solid abdominal tumors. The purposes of this article are to review the current literature about the use of minimally invasive surgery in pediatric abdominal oncology and to examine established indications, procedures and technologic advances.