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Background Testicular germ cell tumors are uncommon tumors that are encountered by pediatric surgeons and urologists and require a knowledge of appropriate contemporary evaluation and surgical and medical management. Method A review of the recommended diagnostic evaluation and current surgical and medical management of children and adolescents with testicular germ cell tumors based upon recently completed clinical trials was performed and summarized in this article. Results In this summary of childhood and adolescent testicular germ cell tumors, we review the initial clinical evaluation, surgical and medical management, risk stratification, results from recent prospective cooperative group studies, and clinical outcomes. A summary of recently completed clinical trials by pediatric oncology cooperative groups is provided, and best surgical practices are discussed. Conclusions Testicular germ cell tumors in children are rare tumors. International collaborations, data-sharing, and enrollment of patients at all stages and risk classifications into active clinical trials will enhance our knowledge of these rare tumors and most importantly improve outcomes of patients with testicular germ cell tumors. Level of evidence This is a review article of previously published and referenced level 1 and 2 studies, but also includes expert opinion level 5, represented by the American Pediatric Surgical Association Cancer Committee.

BACKGROUND The currently utilized International Neuroblastoma Risk Group (INRG) staging system developed in 2009 uses image-defined risk factors as a measure of surgical risk, separating resectable neuroblastoma from those best preceded by chemotherapy. The previous International Neuroblastoma Staging System was based primarily on surgical findings. We hypothesized there would be a change to the role of the surgeon in neuroblastoma treatment in the more recent decade. METHODS This is a single center 20-year retrospective analysis of 104 patients with International Classification of Diseases-9 and -10 codes for neuroblastoma. Patient demographics, tumor site, cancer treatment modality, survival, biopsy technique, surgical intervention, and pathology staging were collected. Data was analyzed by analysis of variance (ANOVA) and Student's t test. RESULTS There was a decrease in open surgeries for extra-adrenal neuroblastomas in the later decade (77%, 31%, P = 0.01). There was a narrowing of the time interval to surgery in the later cohort, likely as a result of uniformity in surgical timing on treatment protocols relying on INRG staging. CONCLUSIONS Our findings mirror changes in practice patterns globally. We found an increase in minimally invasive approaches but did not find a difference in the role of the surgeon under the INRG staging system.

Lymphatic malformations (LMs) are congenital abnormalities which result from disturbances in the embryologic development of the lymphatic system. We sought to determine the characteristics and treatment patterns for LMs in a rural setting, and the effect of a specialized vascular malformations clinic on triage and follow-up. This is a retrospective cohort study at a single tertiary care institution. Sixty-two patients were identified; chart review was completed to obtain demographic, surgery/sclerotherapy session and follow-up information. The head/neck region was the most predominant LM location (N = 26, 41.9%), followed by trunk (N = 16, 25.8%), extremity (N = 11, 17.7%), and intraabdominal/retroperitoneal (N = 7, 11.3%). Twenty-eight patients were managed non-surgically, while 21, 7 and 6 patients required surgery, sclerotherapy, or both. Head/neck LMs were the most likely to recur (73%, p = 0.028). Patients seen in specialty clinic had similar duration of follow-up and time to intervention, but were more often below 1 year of age (p = 0.030). Average LM volume among patients with available imaging was much larger in those referred to specialty clinic (73.2 cm3 versus 14.8 cm3, p = 0.022). Our experience reiterates not only the wide variety of clinical presentations of lymphatic malformations, but also demonstrates the necessity of multiple subspecialties and their collaboration to achieve prompt and efficacious treatment.

Background Minimally invasive surgery has broad applicability to pediatric diseases, including pediatric cancer resection. Neuroblastic tumors of childhood are highly variable in presentation, and so careful selection of appropriate candidates for minimally invasive resection is paramount to achieving safe and durable surgical and oncological outcomes. Methods The American Pediatric Surgical Association Cancer Committee developed questions seeking to better define the role of minimally invasive surgery for neuroblastic tumors. A search using PubMed, Medline, Embase, Web of Science, ProQuest Dissertations, and Clinical Trials was performed for articles published from 1998 to 2018 in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. Results The evidence identified is all retrospective in nature. Minimally invasive surgical resection of neuroblastic tumors is safe for carefully selected smaller (4-6 cm) image defined risk factor (IDRF)-negative abdominal tumors when oncologic principles are followed. Size is a less-well defined criterion for thoracic neuroblastic tumors. Open approaches for both abdominal and thoracic tumors may be preferable in the presence of IDRF's. Conclusion Small tumors without IDRF's are reasonable candidates for minimally invasive resection. Surgical oncologic guidelines should be closely followed. The quality of data supporting this systematic review is poor and highlights the need for refinement in the study of such surgical techniques to improve knowledge and outcomes for patients with neuroblastic tumors. Type of Study Systematic Review. Level of Evidence Level III and Level IV.

Background/Purpose Rhabdomyosarcoma is the most common soft tissue sarcoma in children and young adults and requires multimodality treatment. The purpose of this review is to present an update on risk stratification as well as surgical and medical management strategies in pediatric rhabdomyosarcoma. Methods A comprehensive review of the current literature on pediatric rhabdomyosarcoma, including the most recent Children's Oncology Group studies and several international collaboratives, was performed by the authors and key findings were summarized in the manuscript. Results FOXO1 fusion status is a stronger prognostic factor than histology and is now used for risk stratification in treatment protocols. For assessment of regional nodal involvement, FDG-PET-CT shows poor sensitivity and specificity to detect histologically confirmed nodal metastasis. Thus, surgical assessment of regional lymph nodes is required for rhabdomyosarcoma of the extremities or trunk as well as paratesticular rhabdomyosarcoma in patients ≥ 10 years of age, although adherence to surgical guidelines remains poor. Hemiscrotectomy performed for scrotal violation in paratesticular rhabdomyosarcoma has not shown an improvement in event free survival and is not recommended. Conclusions Surgical and medical treatment strategies for rhabdomyosarcoma in children continue to evolve. This review provides current evidence-based treatment standards with an emphasis on surgical care. Type of Study Review. Level of Evidence Level IV.

Opsoclonus Myoclonus Syndrome (OMS, or Opsoclonus Myoclonus Ataxia) is a rare condition that presents with saccadic movements of the eyes, cerebellar ataxia, and choreiform movements of the limbs. While previous reports have described the use of ultrasound, CT, FDG-PET and traditional focused MRI for localization of OMS-associated masses, whole body MRI has not previously been reported for this purpose. Here we describe a 16-year-old patient who exhibited OMS and underwent whole body MRI to rule out the more commonly associated neuroblastoma. An ovarian mass was discovered, resected, and pathology confirmed benign teratoma - there was subsequent resolution of symptoms after complete surgical resection. Whole body MRI should be considered in pediatric cases of OMS due to the paraneoplastic nature of the disease with associated tumor, high sensitivity of disease detection, lack of ionizing radiation, excellent tissue resolution and demonstrated effectiveness in pediatric imaging. Keywords: Opsoclonus myoclonus syndrome, Ataxia, Teratoma, Pediatric, Paraneoplastic, Whole body magnetic resonance imaging (MRI)

Introduction: Foreign body ingestions are a common problem managed by pediatric surgeons. Although the majority of ingested objects lead to no significant clinical consequence and often do...

Background/Aim: Neuroblastoma is clinically and molecularly heterogeneous, with poor outcomes despite multimodal treatment strategies. The primary tumor site is an independent predictor of survival; adrenal tumors have the worst outcomes, while posterior mediastinum tumors carry a more favorable prognosis. Materials and Methods: To elucidate the role of the primary tumor microenvironment in mediating survival outcomes, we developed a mouse model for the study of extra-adrenal neuroblastoma by injecting luciferase-tagged cells into either the subpleural space of the posterior chest or the adrenal gland. Results: Solid tumors developed in the thoracic cavity at the same rate and efficiency as the adrenal as early as one week post-surgery. The survival rate following surgery was equivalent, though the physiological tolerance for large tumors was lower in the thoracic group. Conclusion: This novel mouse model of survivable extra-adrenal neuroblastoma will enable future investigations of the distinct tumor microenvironments between the adrenal gland and posterior mediastinum.

The currently utilized International Neuroblastoma Risk Group (INRG) staging system developed in 2009 uses image-defined risk factors as a measure of surgical risk, separating resectable neuroblastoma from those best preceded by chemotherapy. The previous International Neuroblastoma Staging System was based primarily on surgical findings. We hypothesized there would be a change to the role of the surgeon in neuroblastoma treatment in the more recent decade.This is a single center 20-year retrospective analysis of 104 patients with International Classification of Diseases-9 and -10 codes for neuroblastoma. Patient demographics, tumor site, cancer treatment modality, survival, biopsy technique, surgical intervention, and pathology staging were collected. Data was analyzed by analysis of variance (ANOVA) and Student's t test.There was a decrease in open surgeries for extra-adrenal neuroblastomas in the later decade (77%, 31%, P = 0.01). There was a narrowing of the time interval to surgery in the later cohort, likely as a result of uniformity in surgical timing on treatment protocols relying on INRG staging.Our findings mirror changes in practice patterns globally. We found an increase in minimally invasive approaches but did not find a difference in the role of the surgeon under the INRG staging system.

Background Historically, choledochal cyst excision has been performed as an open procedure. Controversy remains regarding managing this technically challenging entity in a minimally invasive fashion. Methods A novel mechanically-designed intuitive, articulating instrument is used to facilitate intracorporeal suturing when there is limited working space. The mechanical design of the three-axis Gimbal cuff facilitates intracorporeal suturing by providing intuitive wristed function to the surgeon by translating the surgeon's wrist movement to the end effector. Results We describe the adoption of a novel articulating instrument to facilitate a primary hepaticoduodenostomy within the limited space of a pediatric porta and a redo hepaticojejunostomy. Conclusions These cases demonstrate the use of a novel articulating needle driver to sew an intracorporeal bilio-enteric anastomosis which obviates the need for robotic technology while expanding a laparoscopic surgeon's armamentarium.

Background/Purpose Cancer predisposition syndromes (CPS) are a heterogeneous group of inherited disorders that greatly increase the risk of developing malignancies. CPS are particularly relevant to pediatric surgeons since nearly 10% of cancer diagnoses are due to inherited genetic traits, and CPS often contribute to cancer development during childhood. Materials/Methods The English language literature was searched for manuscripts, practice guidelines, and society statements on “cancer predisposition syndromes in children”. Following review of these manuscripts and cross-referencing of their bibliographies, tables were created to summarize findings of the most common CPS associated with surgically treated pediatric solid malignancies. Results Pediatric surgeons should be aware of CPS as the identification of one of these syndromes can completely change the management of certain tumors, such as WT. The most common CPS associated with pediatric solid malignancies are outlined, with an emphasis on those most often encountered by pediatric surgeons: neuroblastoma, Wilms’ tumor, hepatoblastoma, and medullary thyroid cancer. Frequently associated non-tumor manifestations of these CPS are also included as a guide to increase surgeon awareness. Screening and management guidelines are outlined, and published genetic testing and counseling guidelines are included where available. Conclusion Pediatric surgeons play an important role as surgical oncologists and are often the first point of contact for children with solid tumors. In their role of delivering a diagnosis and developing a follow-up and treatment plan as part of a multidisciplinary team, familiarity with common CPS will ensure evidence-based practices are followed, including important principles such as organ preservation and intensified surveillance plans. This review defines and summarizes the CPS associated with common childhood solid tumors encountered by the pediatric surgeon, as well as common non-cancerous disease stigmata that may help guide diagnosis. Type of study Summary paper. Level of evidence 5.

Although high-risk neuroblastoma (HR-NB) is clinically heterogeneous, it is treated in a similar fashion without additional risk stratification. Based on the 4 copy-number profiles with 556 HR-NB subjects and 14 potential risk factors of neuroblastoma, we develop an interpretable machine learning model with L 0 penalized global AUC summary ( L 0 GAUCS) maximization, and identify 6 and 4 molecular factors associated with overall and event-free survivals (OS and EFS) of HR-NB, respectively. We further construct a six-factor model for OS and a four-factor model for EFS, and categorize HR-NB patients into 4 subtypes (Excellent, Good, Fair, and Poor) for both OS ( P = 1 . 59 e − 11 ) and EFS ( P = 1 . 73 e − 06 ). Particularly, 14.05% and 6.75% HR-NB patients are in the Excellent (I) and Poor subtype (IV) with median OS times of 137. and 14.5 months, respectively. Patients from such distinct subtypes may be assigned to different experimental therapies in future trials. Furthermore, although it is well known that infants (children less than 1 year) has significantly better prognosis in neuroblastoma, we discover that infants with MYCN amplification (MNA+) has unfavorable OS and EFS in HR-NB. Infants with MNA+ have the hazard ratio of 2.9 (95% CI: 1 . 33 − 6 . 34 ) and P value of 3 . 67 e − 06 for OS, and hazard ratio of 2.61 (95% CI: 1 . 05 − 6 . 48 ) and P value of 0.0007 for EFS. The unexpected but important finding that the survival of infants with MNA+ has significantly worse prognosis in HR-NB may have clinical implications.

Neuroblastoma is a common cancer in children, affected by a number of genes that interact with each other through intricate but coordinated networks. Traditional approaches can only reconstruct a single regulatory network that is topologically not informative enough to explain the complexity of neuroblastoma risk. We implemented and modified an advanced model for recovering informative, omnidirectional, dynamic, and personalized networks (idopNetworks) from static gene expression data for neuroblastoma risk. We analyzed 3439 immune genes of neuroblastoma for 217 high-risk patients and 30 low-risk patients by which to reconstruct large patient-specific idopNetworks. By converting these networks into risk-specific representations, we found that the shift in patients from a low to high risk or from a high to low risk might be due to the reciprocal change of hub regulators. By altering the directions of regulation exerted by these hubs, it may be possible to reduce a high risk to a low risk. Results from a holistic, systems-oriented paradigm through idopNetworks can potentially enable oncologists to experimentally identify the biomarkers of neuroblastoma and other cancers.

High risk neuroblastoma (HR-NB) remains difficult to treat, and its overall survival (OS) is still below 50%. Although HR-NB is a heterogeneous disease, HR-NB patients are currently treated in a similar fashion. Through unsupervised biclustering, we further stratified HR-NB patients into two reproducible and clinically distinct subtypes, including an ultra-high risk neuroblastoma (UHR-NB) and high risk neuroblastoma (HR-NB). The UHR-NB subtype consistently had the worst OS in multiple independent cohorts ( P &lt, 0 . 008 ). Out of 283 neuroblastoma-specific immune genes that were used for stratification, 39 of them were differentiated in UHR-NB, including four upregulated and 35 downregulated, as compared to HR-NB. The four UHR-NB upregulated genes (ADAM22, GAL, KLHL13 and TWIST1) were all upregulated in MYCN amplified neuroblastoma in 5 additional cohorts. TWIST1 and ADAM22 were also positively correlated with cancer stage, while GAL was an independent OS predictor in addition to MYCN and age. Furthermore, we identified 26 commonly upregulated and 311 downregulated genes in UHR-NB from all 4723 immune-related genes. While 43 KEGG pathways with molecular functions were enriched in the downregulated immune-related genes, only the P53 signaling pathway was enriched in the upregulated ones, which suggested that UHR-NB was a TP53 related subtype with reduced immune activities.

Background/purpose Lymphadenopathy is a common complaint in children. Pediatric surgeons are often called upon to evaluate, treat, and/or biopsy enlarged lymph nodes. With many nonsurgical causes in the differential diagnosis, the surgeon plays the important role of providing reassurance and timely diagnosis while minimizing the pain and morbidity associated with surgical interventions in children. The purpose of this summary paper is to provide a management guide for surgeons working up children with lymphadenopathy. Materials/methods The English language literature was searched for “lymphadenopathy in children”. All manuscript types were considered for review, regardless of medical specialty, with emphasis placed on published guidelines, algorithms, and reviews. After thorough review of these manuscripts and cross-referencing of their bibliographies, the attached algorithm was developed, with emphasis on the role and timing of surgical intervention. Results The APSA Cancer Committee developed the attached algorithm to fill a gap in the surgical literature. It outlines lymphadenopathy workup and treatment with emphasis on the role and timing of surgical intervention. Conclusion This review defines and summarizes the common etiologies and presentations of lymphadenopathy in children, and offers a straightforward algorithm for evaluation of and treatment with an emphasis on malignancy risk and surgical management. Type of study Summary paper. Level of evidence Level V.

Pediatric soft tissue sarcomas comprise a small proportion of pediatric solid malignancies and may arise in numerous anatomic locations such as the head and neck, trunk, extremities, and the genitourinary tract. Here, we present a case of rhabdomyosarcoma (RMS) arising from an unusual location, the urachus. The 3-year-old patient initially presented with signs of small bowel obstruction. On diagnostic laparoscopy, an infraumbilical mass was discovered and removed by laparotomy. Analysis of the specimen confirmed embryonal RMS (ERMS). The patient was treated with a regimen of postoperative chemotherapy and radiation therapy. Although rare, prompt diagnostic evaluation and treatment of RMS may improve the long-term morbidity and mortality of these patients.

Neuroblastoma is a heterogenous disease, with solid tumors arising in the adrenal gland or paraspinal regions in young children. Neuroblastoma is unique, with varied presentation and prognosis based on primary location and tumor stage. Tumor behavior and response to treatment ranges from spontaneous regression to disseminated, lethal disease depending on the individual biology of a patient's tumor. Stratification of the disease has changed, with patients now placed in low, intermediate, and high-risk categories depending on age, stage, and tumor biology. Long-term survival for the high-risk subset of patients with metastatic disease is

Background & Aims For patients with short-bowel syndrome, intestinal adaptation is required to achieve enteral independence. Although adaptation has been studied extensively in animal models, little is known about this process in human intestine. We hypothesized that analysis of matched specimens with and without luminal flow could identify new potential therapeutic pathways. Methods Fifteen paired human ileum samples were collected from children aged 2–20 months during ileostomy-reversal surgery after short-segment intestinal resection and diversion. The segment exposed to enteral feeding was denoted as fed, and the diverted segment was labeled as unfed. Morphometrics and cell differentiation were compared histologically. RNA Sequencing and Gene Ontology Enrichment Analysis identified over-represented and under-represented pathways. Immunofluorescence staining and Western blot evaluated proteins of interest. Paired data were compared with 1-tailed Wilcoxon rank-sum tests with a P value less than .05 considered significant. Results Unfed ileum contained shorter villi, shallower crypts, and fewer Paneth cells. Genes up-regulated by the absence of mechanoluminal stimulation were involved in digestion, metabolism, and transport. Messenger RNA expression of LGR5 was significantly higher in unfed intestine, accompanied by increased levels of phosphorylated signal transducer and activator of transcription 3 protein, and CCND1 and C-MYC messenger RNA. However, decreased proliferation and fewer LGR5+, OLFM4+, and SOX9+ intestinal stem cells (ISCs) were observed in unfed ileum. Conclusions Even with sufficient systemic caloric intake, human ileum responds to the chronic absence of mechanoluminal stimulation by up-regulating brush-border enzymes, transporters, structural genes, and ISC genes LGR5 and ASCL2. These data suggest that unfed intestine is primed to replenish the ISC population upon re-introduction of enteral feeding. Therefore, the elucidation of pathways involved in these processes may provide therapeutic targets for patients with intestinal failure. RNA sequencing data are available at Gene Expression Omnibus series GSE82147., Graphical abstract

Background Differentiated thyroid carcinomas (DTCs) are rare in young children but represent almost 10% of all malignancies diagnosed in older adolescents. Methods This article reviews the recent literature describing surgical therapeutic approaches to pediatric DTC, associated complications, and long-term recurrence and survival outcomes. Results Similar to adult thyroid cancers, pediatric DTCs are more common in females and are associated with thyroid nodules, family history of thyroid cancer, radiation exposure, iodine deficiency, autoimmune thyroid disease, and genetic syndromes. Management of thyroid cancers in children involves ultrasound imaging, fine needle aspiration, and surgical resection with treatment decisions based on clinical and radiological features, cytology and risk assessment. Conclusions Total thyroidectomy and compartment based resection of clinically involved lymph node basins form the cornerstone of treatment of DTC. There is an evolving literature regarding the use of molecular genetics to inform treatment strategies and the use of targeted therapies to treat iodine refractory and surgically unresectable progressive disease. Type of study Summary review. Level of evidence This is a review article of previously published Level 1–5 articles that includes expert opinion (Level 5).

Purpose To evaluate efficacy of sclerotherapy with doxycycline versus sodium tetradecyl sulfate (STS) for treatment of macrocystic and mixed lymphatic malformations (LMs). Materials and Methods This single-center retrospective review identified 41 children (17 boys; 24 girls; age range, 1 month to 15.4 y) who underwent sclerotherapy with doxycycline (n = 32) or STS (n = 9) for macrocystic (n = 31) or mixed (n = 10) LMs. There were 114 treatments performed, averaging 2.8 treatments (range, 1–8 treatments) per patient. Average follow-up time was 10 months (range, 1–59 months). Clinical response was deemed excellent or moderate if > 90% or > 50% of LMs resolved based on visual estimate. Results With doxycycline, 87% of patients (28 of 32) had excellent or moderate response with an average of 2.8 treatments (range, 1–7 treatments); 13% required subsequent resection. With 3% STS monotherapy, only 55% of patients (5 of 9) had excellent or moderate response with an average of 2.8 treatments (range, 1–8 treatments), and 33% required subsequent resection. Significantly fewer patients treated with STS responded well compared with patients treated with doxycycline ( P = .03). Patients treated with STS had significantly longer follow-up than patients treated with doxycycline (27 months vs 6 months, P = .0001). Conclusions Doxycycline monotherapy resulted in a high rate of excellent clinical outcomes after a few treatments without increased need for subsequent operative resection. These results support use of doxycycline sclerotherapy as primary treatment for macrocystic and mixed LMs in children.

As surgical outcomes and survival of patients with cancer improves, in particular patients with head and neck cancer would often develop multiple primaries. The limitations of radiation for repeated local therapy leave radical surgery as the only local option for some of these patients. Given the complexity of the issues at hand, these patients should be evaluated by a multidisciplinary team with expertise in otolaryngology, radiation oncology, medical oncology, and thoracic surgery. Mediastinal tracheostomy is rarely used, but it can be a useful tool in the management of these complex patients. When esophagectomy is performed in combination with pharyngolaryngectomy, a minimally invasive transhiatal approach can be used. Transhiatal esophageal mobilization is technically feasible with laparoscopy, and it obviates the need for thoracic incisions and patient repositioning in this already complex morbid procedure. Additionally, for cervical esophageal tumors, neither margins nor completeness of lymphadenectomy are sacrificed. We describe several critical steps of mediastinal tracheostomy and minimally invasive transhiatal esophagectomy for the management of these complex patients.

Neuroblastomas arise from neural crest cells of the paraspinal ganglia and the adrenal medulla, leading to heterogeneity in tumor presentation and location. Outcomes remain poor despite intensified multimodality treatment strategies. Primary tumor site is an independent predictor of survival in all risk groups independent of MYCN amplification status. Adrenal tumors have the worst outcomes; thoracic and cervical tumors carry a more favorable prognosis. We hypothesized that factors specific to the adrenal microenvironment enhance tumor invasion and metastasis. To identify factors that account for the survival differential of neuroblastoma based on primary tumor site, we queried the publicly available national database (TARGET) of human neuroblastoma tumors. 1,076 tumors were categorized by primary tumor site. Children with thoracic tumors had a much more favorable outcome than adrenal primary tumors. Gene expression patterns were significantly different between tumor sites for the 229 patients with microarray data. In general, upregulated genes in the thorax were associated with improved survival, and those in the adrenal gland with poor survival. Enrichment clustering revealed most genes differentially expressed were related to cell-cell junctions. We developed a model system for the study of extra-adrenal neuroblastoma. Luciferin-tagged 9464D neuroblastoma cells suspended in Matrigel were injected into the subpleural space in the left posterior chest of C57/Bl6 mice after thoracotomy. In the comparison group, 9464D cells were injected into the left adrenal gland as previously described in the literature. Mice were imaged weekly using IVIS. Solid tumors developed in the thoracic cavity at the same rate and efficiency as in the adrenal as early as one week following surgery. The survival rate from the surgery is equivalent, though the physiologic tolerance for large tumors after three weeks was lower in the thorax group. The human end point due to large tumor burden was 4 weeks for thoracic implants, compared to 6 weeks for adrenal. Our model makes it possible for the first time to investigate the distinct tumor microenvironments of the adrenal gland and the posterior mediastinum. Using our innovative mouse model, future studies will investigate the role of the differentially expressed genes in tumorigenesis, particularly those related to the cytoskeleton and cell-cell adhesion. Identification of the mechanisms by which cell adhesion molecules affect neuroblastoma initiation, growth, and metastasis in different tumor locations will help explain the differences in clinical outcomes between groups and will open innovative new avenues for therapeutic targeting. Citation Format: Christa N. Grant, Lidan Sun, Zhenqiu Liu, Hong-Gang Wang. Development of a survivable thoracic neuroblastoma mouse model for the study of the extra-adrenal tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A24.

Short bowel syndrome (SBS) is a devastating condition in which insufficient small intestinal surface area results in malnutrition and dependence on intravenous parenteral nutrition. There is an increasing incidence of SBS, particularly in premature babies and newborns with congenital intestinal anomalies. Tissue-engineered small intestine (TESI) offers a therapeutic alternative to the current standard treatment, intestinal transplantation, and has the potential to solve its biggest challenges, namely donor shortage and life-long immunosuppression. We have previously demonstrated that TESI can be generated from mouse and human small intestine and histologically replicates key components of native intestine. We hypothesized that TESI also recapitulates native small intestine function. Organoid units were generated from mouse or human donor intestine and implanted into genetically identical or immunodeficient host mice. After 4 wk, TESI was harvested and either fixed and paraffin embedded or immediately subjected to assays to illustrate function. We demonstrated that both mouse and human tissue-engineered small intestine grew into an appropriately polarized sphere of intact epithelium facing a lumen, contiguous with supporting mesenchyme, muscle, and stem/progenitor cells. The epithelium demonstrated major ultrastructural components, including tight junctions and microvilli, transporters, and functional brush-border and digestive enzymes. This study demonstrates that tissue-engineered small intestine possesses a well-differentiated epithelium with intact ion transporters/channels, functional brush-border enzymes, and similar ultrastructural components to native tissue, including progenitor cells, whether derived from mouse or human cells.

We report an unusual case of small bowel obstruction caused by an intestinal cast in an 8-year-old female who developed intestinal graft-versus-host disease (GVHD) following two unrelated bone marrow transplants for aplastic anemia, and highlight the pathophysiology, common presentations, and surgical complications of intestinal GVHD from the surgeons' perspective.

Tissue engineering is a promising potential candidate for treating intestinal failure resulting from necrotizing enterocolitis. This requires the acquisition, preparation and implantation of autologous organoid units. This may be affected by the complexities of periods of storage of viable donor tissue and delayed implantation. This chapter addresses the development, methodology, and application of tissue-engineered intestine in the experimental and clinical setting. Tissue engineering has the potential of avoiding the inherent toxicities of intestinal transplantation and prolonged immunosuppression.

Intestinal malrotation occurs in approximately 1 per 1200 live births. However, it is not known if monozygotic twins have a differential risk for malrotation. Therefore, it is unclear whether an asymptomatic identical twin of an infant with known intestinal malrotation should undergo a formal screening evaluation. We describe a case of the diagnosis of malrotation in an asymptomatic identical twin of a baby who had been treated for malrotation with volvulus and review the relevant medical literature.

Introduction The incidence of intestinal stricture is low for most conditions requiring a primary small bowel stoma in infants. Routine performance of contrast enemas (CE) prior to stoma closure adds cost and radiation exposure. We hypothesized that routine CE prior to ostomy reversal is not necessary in all infants, and sought to identify a subset of patients who may benefit from preoperative CE. Methods Medical records of infants under age 1 (N=161) undergoing small bowel stoma reversal at a single institution between 2003 and 2013 were retrospectively reviewed. Student's T-test was used to compare groups. Results Contrast enemas were performed on 80% of all infants undergoing small bowel ostomy reversal during the study period. Infants with necrotizing enterocolitis (NEC) were more likely to have a CE than those with intestinal atresia (p=0.03) or those with all other diagnoses combined (p=0.03). Nine strictures were identified on CE. Of those, 8 (89%) were in patients with NEC, and only 4 were clinically significant and required operative resection. The overall relevant stricture rate was 2.5%. No patient that underwent ostomy takedown without CE had a stricture diagnosed intraoperatively or an unrecognized stricture that presented clinically after stoma takedown. Conclusions Routine CE is not required prior to small bowel ostomy reversal in infants. We recommend judicious use of enema studies in patients with NEC and high likelihood of stricture.

Loss of significant intestinal length from congenital anomaly or disease may lead to short bowel syndrome (SBS); intestinal failure may be partially offset by a gain in epithelial surface area, termed adaptation. Current in vivo models of SBS are costly and technically challenging. Operative times and survival rates have slowed extension to transgenic models. We created a new reproducible in vivo model of SBS in zebrafish, a tractable vertebrate model, to facilitate investigation of the mechanisms of intestinal adaptation. Proximal intestinal diversion at segment 1 (S1, equivalent to jejunum) was performed in adult male zebrafish. SBS fish emptied distal intestinal contents via stoma as in the human disease. After 2 wk, S1 was dilated compared with controls and villus ridges had increased complexity, contributing to greater villus epithelial perimeter. The number of intervillus pockets, the intestinal stem cell zone of the zebrafish increased and contained a higher number of bromodeoxyuridine (BrdU)-labeled cells after 2 wk of SBS. Egf receptor and a subset of its ligands, also drivers of adaptation, were upregulated in SBS fish. Igf has been reported as a driver of intestinal adaptation in other animal models, and SBS fish exposed to a pharmacological inhibitor of the Igf receptor failed to demonstrate signs of intestinal adaptation, such as increased inner epithelial perimeter and BrdU incorporation. We describe a technically feasible model of human SBS in the zebrafish, a faster and less expensive tool to investigate intestinal stem cell plasticity as well as the mechanisms that drive intestinal adaptation.

Pyloric atresia with epidermolysis bullosa (EB) dystrophica is a rare entity that may not be immediately recognized. We describe the fourth confirmed case of pyloric atresia associated with the dystrophic subtype of EB diagnosed by standard pathologic measures, and discuss the clinical disease features and recent advances in the pathophysiology.

Short bowel syndrome causes significant morbidity and mortality. Tissue-engineered intestine may serve as a viable replacement. Tissue-engineered small intestine (TESI) has previously been generated in the mouse model from donor cells that were harvested and immediately reimplanted; however, this technique may prove impossible in children who are critically ill, hemodynamically unstable, or septic. We hypothesized that organoid units (OU), multicellular clusters containing epithelium and mesenchyme, could be cryopreserved for delayed production of TESI.OU were isolated from3 wk-old mouse or human ileum. OU were then cryopreserved by either standard snap freezing or vitrification. In the snap freezing protocol, OU were suspended in cryoprotectant and transferred directly to -80°C for storage. The vitrification protocol began with a stepwise increase in cryoprotectant concentration followed by liquid supercooling of the OU solution to -13°C and nucleation with a metal rod to induce vitrification. Samples were then cooled to -80°C at a controlled rate of -1°C/min and subsequently plunged into liquid nitrogen for long-term storage. OU from both groups were maintained in cryostorage for at least 72 h and thawed in a 37°C water bath. Cryoprotectant was removed with serial sucrose dilutions and OU were assessed by Trypan blue assay for post-cryopreservation viability. Via techniques previously described by our laboratory, the thawed murine or human OU were either cultured in vitro or implanted on a scaffold into the omentum of a syngeneic or irradiated Nonobese Diabetic/Severe Combined Immunodeficiency, gamma chain deficient adult mouse. The resultant TESI was analyzed by histology and immunofluorescence.After cryopreservation, the viability of murine OU was significantly higher in the vitrification group (93 ± 2%, mean ± standard error of the mean) compared with standard freezing (56 ± 6%) (P 0.001, unpaired t-test, n = 25). Human OU demonstrated similar viability after vitrification (89 ± 2%). In vitro culture of thawed OU produced expanding epithelial spheres supported by a layer of mesenchyme. TESI was successfully generated from the preserved OU. Hematoxylin and eosin staining demonstrated a mucosa composed of a simple columnar epithelium whereas immunofluorescence staining confirmed the presence of both progenitor and differentiated epithelial cells. Furthermore, beta-2-microglobulin confirmed that the human TESI epithelium originated from human cells.We demonstrated improved multicellular viability after vitrification over conventional cryopreservation techniques and the first successful vitrification of murine and human OU with subsequent TESI generation. Clinical application of this method may allow for delayed autologous implantation of TESI for children in extremis.

The ultimate goal of therapies for intestinal failure is to replace the structure and function of the absent region of the intestine. Intestinal failure is the inability to independently maintain nutrition via enteral absorption and has many causes, including genetic and metabolic abnormalities. Short bowel syndrome (SBS) is one form of intestinal failure caused by the anatomical loss of intestinal length. While patients with SBS are able to survive with intravenous nutrition, quality of life is poor, and morbidity is high. Liver failure and sepsis are the most common morbidities. Intestine and multivisceral transplantation have salvaged many children but also come at a high human and financial cost. With complications from necessary immunosuppression and significant graft failure rates, alternative therapies are needed. Recent advances in intestinal stem cell (ISC) and developmental biology have led to the identification and analysis of multiple putative ISCs and progenitor cells. Concurrent growth in the fields of material bioengineering and cell biology has augmented the growth of the field of tissue engineering. By replicating and manipulating the normal developmental and regenerative processes, it has been possible to grow tissue-engineered intestine. Further study to refine the processes and generate larger quantities of engineered tissue will be necessary in order to employ tissue-engineered intestine as a viable future strategy for intestinal replacement in patients with intestinal failure.

METHODS: Organoid units were generated and implanted as previously reported from mouse (C57/BL6) and human donor small intestine. After four weeks, resulting TESI was harvested and fixed. Immunofluorescence confocal microscopy for Na+/K+ ATPase, CFTR, NHE1, NHE3 and aquaporin 7 was performed on paraffin-embedded sections. TESI sections were rehydrated and blocked, exposed to Vector Red Alkaline Phosphatase Substrate in for 30 minutes and imaged by confocal microscopy. Adult C57/BL6 and human small intestine served as controls.