Evolution and Variations of the Ovine Model of Spina Bifida.

Spina bifida is the most common congenital anomaly of the central nervous system and the first non-fatal fetal lesions to be addressed by fetal intervention. While research in spina bifida has been performed in rodent, nonhuman primate, and canine models, sheep have been a model organism for the disease. This review summarizes the history of development of the ovine model of spina bifida, previous applications, and translation into clinical studies. Initially used by Meuli et al. [Nat Med. 1995;1(4):342-7], fetal myelomeningocele defect creation and in utero repair demonstrated motor function preservation. The addition of myelotomy in this model can reproduce hindbrain herniation malformations, which is the leading cause of mortality and morbidity in humans. Since inception, the ovine models have been validated numerous times as the ideal large animal model for fetal repair, with both locomotive scoring and spina bifida defect scoring adding to the rigor of this model. The ovine model has been used to study different methods of myelomeningocele defect repair, the application of various tissue engineering techniques for neuroprotection and bowel and bladder function. The results of these large animal studies have been translated into human clinical trials including Management of Meningocele Study (MOMS) trial that established current standard of care for prenatal repair of spina bifida defects, and the ongoing trials including the Cellular Therapy for In Utero Repair of Myelomeningocele (CuRe) trial using a stem cell patch for repair. The advancement of these life savings and life-altering therapies began in sheep models, and this notable model continues to be used to further the field including current work with stem cell therapy.

Prenatal Rupture of Hydrocolpos in a Cloacal Malformation.

INTRODUCTION: Cloacal dysgenesis occurs from failure of embryological division of urogenital sinus and hindgut, leading to a single common perineal opening for genitourinary and gastrointestinal tracts. The prenatal diagnosis of cloacal malformation is imprecise, but the clinical correlation of postnatal findings to prenatal history can help reveal explanations for unusual pathological findings in patients with urogenital abnormalities. CASE PRESENTATION: A 21-year-old woman was referred after her 20-week ultrasound demonstrated anhydramnios and concern for dilated fetal bowel. Fetal MRI confirmed anhydramnios and a dilated fetal colon, in addition to hydronephrosis and a pelvic cyst. Repeat ultrasound at 27 weeks showed unexpected complete resolution of her anhydramnios but new fetal ascites. The newborn girl was postnatally diagnosed with a cloacal malformation and an unusual near-complete fusion of her labia. She underwent proximal sigmoid colostomy and a tube vaginostomy at birth followed by cloacal reconstruction at 1.5 years old. CONCLUSION: In female fetus with a pelvic cyst, one should have a high index of suspicion for cloacal anomaly and consider the possibility of urinary obstruction leading to alteration in amniotic fluid.

Comparison of retroperitoneal and transperitoneal robotic partial nephrectomy for Pentafecta perioperative and renal functional outcomes.

BACKGROUND: We compared quality outcomes between transperitoneal (TRPN) and retroperitoneal robotic partial nephrectomy (RRPN). METHODS: Two-center retrospective analysis of TRPN and RRPN from 10/2009 to 10/2015. Perioperative/renal function outcomes were analyzed. Primary endpoint was Pentafecta, a composite measure of quality [negative margin, no 30-day complication, ischemia time ≤25 min, return of glomerular filtration rate (eGFR) to >90% from baseline at last follow-up, and no chronic kidney disease upstaging]. Multivariable analysis (MVA) for factors associated with lack of optimal outcome was performed. RESULTS: 404 patients (TRPN 263, RRPN 141) were analyzed. Comparing TRPN vs. RRPN, mean tumor size (3.1 vs. 2.9 cm, p = 0.122) and RENAL score (7.4 vs. 7.2, p = 0.503) were similar. Most TRPN were anterior (65.0%) and most RRPN posterior (65.3%, p < 0.001). Operative time (p = 0.001) was less for RRPN. No significant differences between TRPN vs. RRPN were noted for ischemia time (23.1 vs. 22.8 min, p = 0.313), blood loss (p = 0.772), positive margins (p = 0.590), complications (p = 0.537), length of stay (p = 0.296), ΔeGFR (p = 0.246), eGFR recovery to >90% (55.9 vs. 57.4%, p = 0.833), and lack of CKD upstaging (84.0 vs. 87.2%, p = 0.464). Pentafecta rates were not significantly different (TRPN 33.9 vs. RRPN 43.3%, p = 0.526). MVA revealed increasing RENAL score (OR 1.5, p < 0.001) and decreasing baseline eGFR (OR 2.4, p = 0.017) as predictive for lack of Pentafecta. CONCLUSIONS: TRPN and RRPN have similar quality outcomes, though RRPN may offer modest benefit for operative time and have utility in posterior tumors. Association of increasing RENAL score and decreased baseline eGFR with lack of Pentafecta suggests dominant role of non-modifiable factors.

Impact of tumor histology and grade on treatment success of percutaneous renal cryoablation.

BACKGROUND: We analyzed oncological outcomes in patients who underwent percutaneous renal cryoablation (PRC) with documented renal cell carcinoma (RCC) by perioperative biopsy. METHODS: Multicenter retrospective analysis of 153 patients [median follow-up 48 months] who underwent PRC from 09/2005 to 08/2014 was performed. We divided the cohort into patients who developed recurrence versus no recurrence. Kaplan-Meier analyses examined recurrence-free survival (RFS) according to grade and histology. Multivariable analysis (MVA) was performed to identify factors associated with tumor recurrence. RESULTS: One hundred and fifty-three patients were analyzed [18 patients (11.8 %) with recurrence and 135 (88.2 %) patients without recurrence]. There were no differences between the groups with respect to demographics, RENAL score, and number of probes utilized. Recurrence group had larger tumor size (3.1 vs. 2.4 cm; p = 0.011), upper pole tumor location (p = 0.016), and greater proportions of high-grade tumor (33 vs. 0.7 %; p < 0.001) and clear cell histology (77.8 vs. 45.9 %; p = 0.011). Four-year RFS was 100 versus 80 % for grade 1 versus grade 2/3 tumors (p = 0.0002), and 97 versus 88 % for other RCC versus clear cell RCC (p = 0.07). MVA demonstrated tumor size >3 cm (OR 2.46; p = 0.019), clear cell histology (OR 2.12; p = 0.027), and high tumor grade (OR 2.33, p < 0.001) as independent risk factors associated with tumor recurrence. CONCLUSIONS: Association of higher grade and clear cell histology with recurrence and progression suggests need for increased emphasis on preoperative risk stratification by biopsy, with grade 1 and non-clear cell RCC being associated with improved treatment success than higher grade and clear cell RCC.

Development of a Simple and Reproducible Cell-derived Orthotopic Xenograft Murine Model for Neuroblastoma.

BACKGROUND/AIM: Neuroblastoma is a common childhood cancer with poor survival for children with high-risk disease, and ongoing research to improve outcomes is needed. Patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) are reliable models for oncologic research; however, they are resource-intensive, expensive, and require significant expertise to develop and maintain. We developed an orthotopic xenograft murine model of neuroblastoma that utilizes cryopreserved banks of human neuroblastoma cell lines, requires minimal equipment, and is easily reproducible. MATERIALS AND METHODS: The neuroblastoma cell line NB1643 was obtained from the Children's Oncology Group (COG) Childhood Cancer Repository. Nod-SCID-gamma (NSG) mice underwent orthotopic injection of 2x106 NB1643 cells suspended in 10 µl of collagen hydrogel directly into the adrenal gland via an open retroperitoneal surgical approach. Mice were monitored by ultrasound and in vivo imaging system (IVIS) until the tumor reached the volume of the ipsilateral kidney. Tumor identity was confirmed by necropsy and histologic analysis. RESULTS: A total of 55 mice underwent surgery. Eight died due to anesthetic or surgical complications. 39/47 (78%) survivors grew primary adrenal tumors. Average anesthesia time was 30 min. Ultrasound and IVIS successfully characterized tumor growth in all mice. Average time to target tumor size was 5 weeks (range=3-9). Gross pathologic and histologic analysis confirmed adrenal tumors consistent with neuroblastoma in all mice with adrenal masses. CONCLUSION: A cell-derived orthotopic xenograft murine model can be successfully used to create an in vivo model of neuroblastoma. This model can be utilized in environments where PDX or GEMM models are not feasible.

Proliferative Effects of Mesenchymal Stromal Cells on Neuroblastoma Cell Lines: Are They Tumor Promoting or Tumor Inhibiting?

BACKGROUND: Neuroblastoma is a common pediatric malignancy with poor survival for high-risk disease. Mesenchymal stromal cells (MSCs) have innate tumor-homing properties, enabling them to serve as a cellular delivery vehicle, but MSCs have demonstrated variable effects on tumor growth. We compared how placental MSCs (PMSCs) and bone marrow-derived MSCs (BM-MSCs) affect proliferation of neuroblastoma (NB) cells in vitro. METHODS: Indirect co-culture assessed proliferative effects of 18 MSCs (early-gestation PMSCs (n = 9), term PMSCs (n = 5), BM-MSCs (n = 4) on three high-risk NB cell lines (NB1643, SH-SY5Y, and CHLA90). Controls were NB cells cultured in media alone. Proliferation was assessed using MTS assay and measured by fold change (fc) over controls. PMSCs were sub-grouped by neuroprotective effect: strong (n = 7), intermediate (n = 3), and weak (n = 4). The relationship between MSC type, PMSC neuroprotection, and PMSC gestational age on NB cell proliferation was assessed. RESULTS: NB cell proliferation varied between MSC groups. BM-MSCs demonstrated lower proliferative effects than PMSCs (fc 1.18 vs 1.44, p < 0.001). Neither gestational age nor neuroprotection significantly predicted degree of proliferation. Proliferative effects of MSCs varied among NB cell lines. BM-MSCs had less effect on CHLA90 (fc 1.01) compared to NB1643 (fc 1.33) and SH-SY5Y (fc 1.20). Only NB1643 showed a difference between early and term PMSCs (p = 0.04). CONCLUSION: Effects of MSCs on NB cell proliferation vary by MSC source and NB cell line. BM-MSCs demonstrated lower proliferative effects than most PMSCs. MSC neuroprotection was not correlated with proliferation. Improved understanding of MSC proliferation-promoting mechanisms may provide valuable insight into selection of cells best suited as drug delivery vehicles. LEVEL OF EVIDENCE: N/A. TYPE OF STUDY: Original Research.

Gender Disparity in Pediatric Surgery: An Evaluation of Pediatric Surgery Conference Participation.

BACKGROUND: Leadership in academic conferences is an important factor for academic advancement. Underrepresentation of women in academic surgical conferences has been demonstrated in other subspecialties, but it has not been well-studied in pediatric surgery. METHODS: This retrospective descriptive study analyzes conference participation at 2 national pediatric surgery annual conference programs from 2003 to 2022. Moderator, speakers, and research presenter sex was collected. The primary outcome was the proportion of female participants in each of these roles. Mann-Kendall trend test was conducted to assess for significance. RESULTS: Across 29 meetings, a total of 523 sessions were examined. Overall, female participation in all roles increased from 2003 to 2022. There were statistically positive trends of female participation in leadership roles as moderator (p = 0.003) and speaker (p = 0.01), with moderator role demonstrating the largest proportional female increase over time - with a 7-fold increase from 7.1% in 2003 to 50.0% in 2022. There was also a significant increasing trend in female participation as research presenters (p < 0.01) from 25.4% to 46.4%. CONCLUSION: Gender representation in pediatric surgery conferences has improved over the last two decades. Women now represent approximately half of all participatory roles, and efforts to continue providing equal opportunities for women at pediatric surgery academic conferences should continue. LEVEL OF EVIDENCE: N/A. TYPE OF STUDY: Retrospective Descriptive.

Spina Bifida: A Review of the Genetics, Pathophysiology and Emerging Cellular Therapies.

Spina bifida is the most common congenital defect of the central nervous system which can portend lifelong disability to those afflicted. While the complete underpinnings of this disease are yet to be fully understood, there have been great advances in the genetic and molecular underpinnings of this disease. Moreover, the treatment for spina bifida has made great advancements, from surgical closure of the defect after birth to the now state-of-the-art intrauterine repair. This review will touch upon the genetics, embryology, and pathophysiology and conclude with a discussion on current therapy, as well as the first FDA-approved clinical trial utilizing stem cells as treatment for spina bifida.

Genetic and Molecular Determinants of Lymphatic Malformations: Potential Targets for Therapy.

Lymphatic malformations are fluid-filled congenital defects of lymphatic channels occurring in 1 in 6000 to 16,000 patients. There are various types, and they often exist in conjunction with other congenital anomalies and vascular malformations. Great strides have been made in understanding these malformations in recent years. This review summarize known molecular and embryological precursors for lymphangiogenesis. Gene mutations and dysregulations implicated in pathogenesis of lymphatic malformations are discussed. Finally, we touch on current and developing therapies with special attention on targeted biotherapeutics.

Corrigendum to "Collision Tumor With Renal Cell Carcinoma and Plasmacytoma: Further Evidence of a Renal Cell and Plasma Cell Neoplasm Relationship?" [Urology Case Reports 6 (2017) 50-52].

[This corrects the article DOI: 10.1016/j.eucr.2016.03.005.].

Statin utilization improves oncologic and survival outcomes in patients with dyslipidemia and surgically treated renal cell carcinoma.

BACKGROUND: We evaluated the role of statins in patients who underwent surgery for renal cell carcinoma (RCC) and who had dyslipidemia, as use of statins has been suggested to improve outcomes in RCC. METHODS: Two-center retrospective study of patients with dyslipidemia who underwent surgery for RCC from 7/1995 to 6/2005. Patients were managed by statins or ezetimibe, fibrate agents, or cholestyramine. Analysis was conducted between patients who received statin therapy versus those that did not. Primary outcome was progression-free survival (PFS). Secondary outcomes were cancer-specific (CSS) and overall survival (OS). Multivariable analysis was performed to identify risk factors associated with disease progression. RESULTS: In this study 283 patients were analyzed (180 statin, 103 non-statin, median follow-up 68 months). There were no significant demographic differences. Median duration of antidyslipidemia therapy was similar (statin 31 months vs. non-statin 28 months, P=0.413). Tumor size (statin 5.4 cm vs. non-statin 5.6 cm, P=0.569), stage distribution (P=0.591), histology (P=0.801), and grade (P=0.807) were similar. Kaplan-Meier analysis demonstrated higher 5-yr PFS (91% vs. 70%, P<0.001), CSS (88% vs. 69%, P<0.001), and OS (71% vs. 67%, P=0.025) in statin vs. non-statin patients. Multivariable analysis for factors associated with disease progression found absence of statin therapy (OR 2.41, P<0.001), higher stage (OR 2.01-3.86 P<0.001), and higher grade tumors (OR 2.07, P=0.006) to be predictive. CONCLUSIONS: In RCC patients with dyslipidemia, statin use was associated with improved survival outcomes, and was an independent predictor of PFS. Further investigations are requisite to determine utility of statins in RCC patients.

Collision Tumor With Renal Cell Carcinoma and Plasmacytoma: Further Evidence of a Renal Cell and Plasma Cell Neoplasm Relationship?

Renal solitary extramedullary plasmacytomas belong to a group of plasma cell neoplasms, which generally have been associated with renal cell carcinoma. We present a case report of a patient with collision tumor histology of extramedullary plasmacytoma and clear cell renal cell carcinoma, the first in the known literature. Standard work-up for a plasma cell neoplasm was conducted and the mass was resected. The patient remains disease-free at 28 months post-surgery. The report calls into question pre-surgical renal mass biopsy protocol and suggests a relationship between renal cell carcinoma and plasma cell neoplasms.

Gastrointestinal tract access for urological natural orifice transluminal endoscopic surgery.

We conducted a literature review of natural orifice transluminal endoscopic surgery (NOTES), focusing on urologic procedures with gastrointestinal tract access, to update on the development of this novel surgical approach. As part of the methods, a comprehensive electronic literature search for NOTES was conducted using PubMed and Cochrane Library from March 2002 to February 2016 for papers reporting urologic procedures performed utilizing gastrointestinal tract access. A total of 11 peer-reviewed studies examining utility of gastrointestinal access for NOTES urologic procedures were noted, with the first report in 2007. The procedures reported in the studies were total/radical nephrectomy, partial nephrectomy, adrenalectomy, and prostatectomy. The transgastric approach was identified in five studies examining total/radical nephrectomy (n = 2), partial nephrectomy (n = 1), partial cystectomy (n = 1), and adrenalectomy (n = 1). Six studies evaluated transrectal approach for NOTES, describing total/radical nephrectomy (n = 3), partial nephrectomy (n = 1), robotic nephrectomy with adrenalectomy (n = 1) and prostatectomy (n = 1). Feasibility was reported in all studies. Most studies were preclinical and acute, and limited by concerns regarding restricted instrumentation and infection risk. We concluded that gastrointestinal access for urologic NOTES demonstrates promise as described by outlined feasibility studies in preclinical models. Nonetheless, clinical application awaits further advancements in surgical technology and concerns regarding infectious potential.