Duhamel Versus Swenson Pull-Through for Total Colonic Aganglionosis: A Multi-Institutional Study.

BACKGROUND: Total colonic aganglionosis (TCA) is a rare variant of Hirschsprung disease (HD) where the colon and portion of distal ileum lack ganglion cells. Most pediatric use either a straight ileoanal (Swenson or Yancey-Soave) or a short Duhamel pull-through for TCA. There are no large studies comparing these techniques. We aimed to compare short-and medium-term outcomes between these approaches. METHOD: A retrospective review was performed among children with TCA from 2001 to 2019 undergoing a primary Duhamel or Swenson pull-through across three large children's hospitals. Patients undergoing redo and patients with greater than 30 % small bowel aganglionosis were excluded. We gathered data on demographics, operative approach, and outcomes at one, two, and three years. Continuous variables were analyzed with t-tests and categorical variables with Chi square or Fisher's tests. RESULTS: There were 54 patients, with 26 (48 %) undergoing Duhamel and 28 (52 %) undergoing Swenson pull-through. There were no differences in sex, age, medical comorbidities, or operative details, including age at pull-through, laparoscopic vs open, length of involved small bowel, and operative time. Length of stay and post-operative complications were not different. Three years after pull-through, patients undergoing Duhamel had fewer stools per day (1-3 stools 69.6 % vs 14.3 %, p = 0.003) and were less likely to be prescribed fiber supplementation (4.2 % vs 43.8 %, p = 0.003). There were no differences in irrigations, botulinum toxin administration, loperamide, or HD admissions. CONCLUSION: Both Duhamel and straight pull-throughs are safe for treatment of TCA, with acceptable short- and medium-term outcomes. Further studies on patient-reported outcomes are necessary to examine long-term differences. LEVEL OF EVIDENCE: III.

Synthetic augmentation of bilirubin metabolism in human pluripotent stem cell-derived liver organoids.

UGT1A1 (UDP glucuronosyltransferase family 1 member A1) is the primary enzyme required for bilirubin conjugation, which is essential for preventing hyperbilirubinemia. Animal models lack key human organic anion transporting polypeptides with distinct epigenetic control over bilirubin metabolism, necessitating a human model to interrogate the regulatory mechanism behind UGT1A1 function. Here, we use induced pluripotent stem cells to develop human liver organoids that can emulate conjugation failure phenotype. Bilirubin conjugation assays, chromatin immunoprecipitation, and transcriptome analysis elucidated the role of glucocorticoid antagonism in UGT1A1 activation. This antagonism prevents the binding of transcriptional repressor MECP2 at the expense of NRF2 with associated off-target effects. Therefore, we introduced functional GULO (L-gulonolactone oxidase) in human organoids to augment intracellular ascorbate for NRF2 reactivation. This engineered organoid conjugated more bilirubin and protected against hyperbilirubinemia when transplanted in immunosuppressed Crigler-Najjar syndrome rat model. Collectively, we demonstrate that our organoid system serves as a manipulatable model for interrogating hyperbilirubinemia and potential therapeutic development.

Fluorescent-guided surgery and the use of indocyanine green sentinel lymph node mapping in the pediatric and young adult oncology population.

BACKGROUND: Technetium-99 (99m Tc) lymphoscintigraphy with blue dye injection is an accepted method for sentinel lymph node (SLN) mapping, but blue dye has known adverse effects, and injection of 99m Tc may increase time under anesthesia for pediatric patients. Indocyanine green (ICG) may serve as an adjunct to assist with visibility and identification of SLNs. We hypothesized that sensitivity of ICG was similar to blue dye in SLN biopsies. METHODS: Thirty patients (36 procedures with 96 total specimens) underwent preoperative intradermal injection of 99m Tc, followed by intradermal injection of isosulfan blue and ICG. Test characteristics of blue dye, ICG, and 99m Tc included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: ICG had a sensitivity of 87% and PPV of 83% for detection of 99m Tc-hot lymph nodes; blue dye had a sensitivity of 44% and PPV of 97%. For detection of pathologically confirmed lymph nodes, ICG had a sensitivity of 84% and a positive predictive value (PPV) of 91%. 99m Tc had a sensitivity of 82% and a PPV of 94%. ICG had no significant difference in odds of being positive in pathology-confirmed lymph nodes compared to 99m Tc (odds ratio [OR], 0.818; 95% confidence interval [CI], 0.3-2.172; p = .823) and had higher odds than isosulfan blue (OR, 0.025, 95% CI, 0.001-0.148; p < .001). CONCLUSION: This study established the efficacy of ICG as an adjunct to SLNB in the pediatric and young adult population. ICG was safe, more efficacious than blue dye, and may obviate the need for lymphoscintigraphy in selected patients resulting in reduced time under anesthesia.

Quality of Life Outcomes for Patients Who Underwent Conventional Resection and Liver Transplantation for Locally Advanced Hepatoblastoma.

Hepatoblastoma is the most common malignant liver tumor of childhood, with liver transplant and extended resection used as surgical treatments for locally advanced tumors. Although each approach has well-described post-operative complications, quality-of-life outcomes have not been described following the two interventions. Long-term pediatric survivors of hepatoblastoma who underwent conventional liver resection or liver transplantation at a single institution from January 2000-December 2013 were recruited to complete quality-of-life surveys. Survey responses for the Pediatric Quality of Life Generic Core 4.0 (PedsQL, n = 30 patient and n = 31 parent surveys) and Pediatric Quality of Life Cancer Module 3.0 (PedsQL-Cancer, n = 29 patient and n = 31 parent surveys) were collected from patients and parents. The mean total patient-reported PedsQL score was 73.7, and the parent-reported score was 73.9. There were no significant differences in scores on the PedsQL between patients who underwent resection compared to those who underwent transplantation (p > 0.05 for all comparisons). On the PedsQL-Cancer module, procedural anxiety scores were significantly lower for patients who underwent resection as compared to transplant (M = 33.47 points less, CI [-60.41, -6.53], p-value 0.017). This cross-sectional study demonstrates that quality of life outcomes are overall similar among patients receiving transplants and resections. Patients who received a resection reported worse procedural anxiety.

10 Year Analysis of Pediatric Surgery Fellowship Match and Operative Experience: Concerning Trends?

OBJECTIVE: This paper aims to evaluate the pediatric surgery training pipeline vis-à-vis the pediatric surgery match and operative experience of pediatric surgery fellows. SUMMARY OF BACKGROUND DATA: Pediatric surgery remains a competitive surgical subspecialty. However, there is concern that operative experience for pediatric surgery fellows is changing. This paper examines the selectivity of the pediatric surgery match, along with the operative experience of pediatric surgery fellows to characterize the state of pediatric surgery training. METHODS: The pediatric surgery fellowship match was analyzed from the National Resident Matching Program data from 2010 to 2019. Selectivity among fellowships was compared using analysis of variance with Dunnett test. Operative log data for pediatric fellows was analyzed using the Accreditation Council for Graduate Medical Education case logs from 2009 to 2019. Linear regression analysis was used to evaluate trends in operative volume over time. RESULTS: Pediatric surgery had the highest proportion of unmatched applicants (47.2% ± 5.3%) and lowest proportion of unfilled positions (1.4% ± 1.6%) when compared to other National Resident Matching Program surgical fellowships. Accreditation Council for Graduate Medical Education case log analysis revealed a statistically significant decrease in cases for graduating fellows (-5.3 cases/year, P < 0.05). Total index cases decreased (-4.7 cases/year, P < 0.01, R 2 = 0.83) such that graduates in 2019 completed 59 fewer index operations than graduates in 2009. CONCLUSION: Although pediatric surgery fellowship remains highly selective there has been a decline in the operative experience for graduating fellows. This highlights the need for evaluation of training paradigms and operative exposure in pediatric surgery to ensure the training of competent pediatric surgeons.

The national rate of malignancy among Bethesda III, IV, and V thyroid nodules is higher than expected: A NSQIP analysis.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology was formalized in 2007 to stratify cytologic specimens based on their risk of malignancy. Several studies have reported significant variations between their institutional rate of malignancy compared to the Bethesda System for Reporting Thyroid Cytopathology. The objective of this study was to determine the national rate of malignancy for Bethesda III, Bethesda IV, and Bethesda V thyroid nodules. METHODS: From 2016 to 2019, patients with preoperative thyroid cytopathology and pathology results in National Surgical Quality Improvement database were included. The rate of malignancy was compared to the median the Bethesda System for Reporting Thyroid Cytopathology 2017, and risk factors associated with malignancy were identified for Bethesda III, Bethesda IV, and Bethesda V specimens. RESULTS: In total, 13,121 patients with preoperative cytopathology and postresection pathology were identified. The national rate of malignancy was significantly higher than the Bethesda System for Reporting Thyroid Cytopathology 2017 for Bethesda III (36.2% vs 12.0%, P < .01), Bethesda IV (36.7% vs 25.0%, P < .01), and Bethesda V (91.1% vs 52.5%, P < .01) specimens. Male sex was significantly associated with malignancy in Bethesda III, Bethesda IV, and Bethesda V nodules (Bethesda III, odds ratio: 1.20, [1.01-1.42]; Bethesda IV, odds ratio: 1.47, [1.27-1.71]; Bethesda V, odds ratio: 1.28, [1.03-1.58]). Younger age was associated with malignancy in Bethesda III patients under 55 (odds ratio: 1.23, [1.06-1.42]), Bethesda IV patients under 42 (odds ratio: 1.23, [1.06-1.43]), and Bethesda V patients aged less than 47 (odds ratio: 1.38, [1.15-1.67]). CONCLUSIONS: This is the largest cohort study to describe the national rate of malignancy for Bethesda III, IV, and V specimens in the United States. These results reveal the national rate of malignancy is higher than the implied rate of malignancy reported to patients based on the Bethesda System for Reporting Thyroid Cytopathology. We recommend counseling patients regarding this increased rate of malignancy to set appropriate expectations after surgical intervention.

Catching the red eye: A retrospective review of factors associated with retinal hemorrhage in child physical abuse.

BACKGROUND/PURPOSE: Accurate identification of child physical abuse is crucial during the evaluation of injured children. Retinal hemorrhages (RH) are used for diagnosis, but clear criteria for screening with direct fundoscopic exam are lacking. We sought to identify key factors associated with RH to guide evaluations. METHODS: Electronic medical records for patients <1 year of age presenting to a Level I Pediatric Trauma Center with unwitnessed head injury from January 2015 to December 2018 were retrospectively reviewed. Multivariable logistic regression was used to identify factors associated with RH. RESULTS: Two hundred and seventy-six patients were included; 63% underwent direct fundoscopic examination, of which 23% were positive and 77% were negative for RH. Unscreened patients tended to be older and have isolated skull fractures. Multivariable regression analysis revealed that abnormal GCS and subdural hemorrhage were positively associated with a diagnosis of retinal hemorrhage, while isolated skull fracture was negatively associated. CONCLUSIONS: Children under 1 year of age with subdural hemorrhage have a greater risk of associated RH and should undergo routine screening with direct fundoscopic examination. Conversely, those with isolated skull fractures may not require an ophthalmology consultation. Standardized screening protocols may help reduce the risk of missing child physical abuse. LEVEL OF EVIDENCE: III (Diagnostic Test).

Thoracoscopy vs thoracotomy for the management of metastatic osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

Complete surgical resection of pulmonary metastatic disease in patients with osteosarcoma is crucial to long-term survival. Open thoracotomy allows palpation of nodules not identified on imaging but the impact on survival is unknown. The objective of this study was to compare overall survival (OS) and pulmonary disease-free survival (DFS) in children who underwent thoracotomy vs thoracoscopic surgery for pulmonary metastasectomy. A multi-institutional collaborative group retrospectively reviewed 202 pediatric patients with osteosarcoma who underwent pulmonary metastasectomy by thoracotomy (n = 154) or thoracoscopy (n = 48). Results were analyzed by Kaplan-Meier survival estimates and multivariate Cox proportional hazard regression models. With median follow-up of 45 months, 135 (67.5%) patients had a pulmonary relapse and 95 (47%) patients were deceased. Kaplan-Meier analysis showed no significant difference in 5-year pulmonary DFS (25% vs 38%; P = .18) or OS (49% vs 42%, P = .37) between the surgical approaches of thoracotomy and thoracoscopy. In Cox regression analysis controlling for other factors impacting outcome, there was a significantly increased risk of mortality (HR 2.11; P = .027; 95% CI 1.09-4.09) but not pulmonary recurrence (HR 0.96; P = .90; 95% CI 0.52-1.79) with a thoracoscopic approach. However, in the subset analysis limited to patients with oligometastatic disease, thoracoscopy had no increased risk of mortality (HR 1.16; P = .62; 0.64-2.11). In conclusion, patients with metastatic osteosarcoma and limited pulmonary disease burden demonstrate comparable outcomes after thoracotomy and thoracoscopy for metastasectomy. While significant selection bias in these surgical cohorts limits the generalizability of the conclusions, clinical equipoise for a randomized clinical trial in patients with oligometastatic disease is supported.

Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event.

Improved molecular understanding is needed for rational treatment of diffuse intrinsic pontine gliomas (DIPG). Here, using multi-focal paired tumor and germline exome DNA and RNA sequencing, we uncovered phosphatase and tensin homolog (PTEN) loss as a clonal mutation in the case of a 6-year-old boy with a diffuse intrinsic pontine glioma, and incorporated copy number alteration analyses to provide a more detailed understanding of clonal evolution in diffuse intrinsic pontine gliomas. As well, using the PedcBioPortal, we found alterations in PTEN in 16 of 326 (4.9%) cases of pediatric high-grade glioma (3 of 154 (1.9%) brainstem) for which full sequencing data was available. Our data strengthens the association with PTEN loss in diffuse intrinsic pontine gliomas and provides further argument for the inclusion of PTEN in future targeted sequencing panels for pediatric diffuse intrinsic pontine gliomas and for the development and optimization of mTOR/PI3K inhibitors with optimal central nervous system penetration.

Using the bias from flow to elucidate single DNA repair protein sliding and interactions with DNA.

We perform single-molecule spatial tracking measurements of a DNA repair protein, the C-terminal domain of Ada (C-Ada) from Escherichia coli, moving on DNA extended by flow. The trajectories of single proteins labeled with a fluorophore are constructed. We analyze single-protein dwell times on DNA for different flow rates and conclude that sliding (with essentially no hopping) is the mechanism of C-Ada motion along stretched DNA. We also analyze the trajectory results with a drift-diffusion Langevin equation approach to elucidate the influence of flow on the protein motion; systematic variation of the flow enables one to estimate the microscopic friction. We integrate the step-size probability distribution to obtain a version of the fluctuation theorem that articulates the relation between the entropy production and consumption under the adjustable drag (i.e., bias) from the flow. This expression allows validation of the Langevin equation description of the motion. Comparison of the rate of sliding with recent computer simulations of DNA repair suggests that C-Ada could conduct its repair function while moving at near the one-dimensional diffusion limit.