CTNNB1 exon 3 mutations in metastatic solid pseudopapillary neoplasm of the pancreas.

BACKGROUND AND OBJECTIVES: Solid pseudopapillary neoplasm (SPN) of the pancreas demonstrates an indolent disease course; however, some patients present with a "malignant" phenotype, including distant metastases resistant to chemotherapy. This analysis identifies molecular drivers of metastatic SPN using the world's largest clinicogenomics database. METHODS: The American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange was queried for primary and metastatic SPN samples. Sample-level genomic alterations were compared. A pan-pancreatic cancer analysis assessed relevant mutations among all metastatic pancreatic malignancies. RESULTS: Among 28 SPN samples identified (n = 17 primary, n = 11 metastatic), the most commonly mutated gene was CTNNB1, (24/28 samples; 85.7%). Most mutations were missense (21/24; 87.5%) or in-frame deletions (3/24; 12.5%). The most common CTNNB1 mutations in primary SPN were exon 3 S37F/C missense mutations (6/16 profiled patients, 37.5%), contrasting exon 3 D32N/Y/H missense mutations in metastatic samples (6/11 profiled patients, 54.5%). Metastatic SPN had higher rates of CTNNB1 mutations than metastases from pancreatic ductal adenocarcinoma (72.7% vs. 1.1%; q < 0.0001), pancreatic neuroendocrine tumor (72.7% vs. 2.5%; q < 0.0001), and pancreatic acinar cell carcinoma (72.7% vs. 11.5%; q = 0.0254). CONCLUSIONS: Missense mutations along exon 3 of CTNNB1 predominate metastatic SPN, differentiating these patients from those with metastases from analogous pancreatic malignancies.

Concomitant Wilms tumor and autosomal dominant polycystic kidney disease.

BACKGROUND: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described. PROCEDURE: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. RESULTS: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT. CONCLUSION: Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies.

Feeding Performance and Outcomes in Infants With Robin Sequence Undergoing Mandibular Distraction Osteogenesis.

To describe perioperative feeding performance in infants with Robin sequence (RS) who underwent mandibular distraction osteogenesis (MDO).A retrospective study of infants that underwent MDO from May 2010 to December 2019.Tertiary pediatric hospital.A total of 40 patients underwent MDO and 20 met inclusion criteria. Of the included infants, 6 had an associated syndrome and 80% were male.Time to full oral feeds, rate of G-tube placement, and change in weight percentile following MDO.Average oral intake prior to MDO was 22.1% of individual goal feeds. Among the 15 (75%) children that did not require G-tube placement, mean time to full oral feeds after MDO was 11 days ± 5.7 days, with 80% of infants reaching full oral feeds within 2 weeks after extubation. The proportion of G-tube placement in patients with a syndrome was higher than in isolated RS (-0.6; 95% CI: -1.0, -0.2). Mean percentages of weight-for-age percentile decreased during the first 3 months after the procedure. This was followed by a mean upturn in weight starting after the third month after MDO with a recovery to preoperative mean weight-for-age percentiles by 6 months after surgery.This study suggests that infants with RS may achieve full oral feeds despite poor feeding performance before MDO. Infants with syndromic RS are more likely to require G-tube. These findings may be used to inform G-tube discussion and offer a timeline to work toward goal oral feeds for infants with RS after MDO.

The role of extracorporeal life support and timing of repair in infants with congenital diaphragmatic hernia.

Extracorporeal life support (ECLS) serves as a rescue therapy for patients with congenital diaphragmatic hernia (CDH) and severe cardiopulmonary failure, and only half of these patients survive to discharge. This costly intervention has a significant complication risk and is reserved for patients with the most severe disease physiology refractory to maximal cardiopulmonary support. Some contraindications to ECLS do exist such as coagulopathy, lethal chromosomal or congenital anomaly, very preterm birth, or very low birth weight, but many of these limits are being evaluated through further research. Consensus guidelines from the past decade vary in recommendations for ECLS use in patients with CDH but this therapy appears to have a survival benefit in the most severe subset of patients. Improved outcomes have been observed for patients treated at high-volume centers. This review details the evolving literature surrounding management paradigms for timing of CDH repair for patients receiving preoperative ECLS. Most recent data support early repair following cannulation to avoid non-repair which is uniformly fatal in this population. Longer ECLS runs are associated with decreased survival, and patient physiology should guide ECLS weaning and eventual decannulation rather than limiting patients to arbitrary run lengths. Standardization of care across centers is a major focus to limit unnecessary costs and improve short-term and long-term outcomes for these complex patients.

Wilms Tumor with Vena Caval Intravascular Extension: A Surgical Perspective.

Wilms tumor (WT) is the most common kidney tumor in pediatric patients. Intravascular extension of WT above the level of the renal veins is a rare manifestation that complicates surgical management. Patients with intravascular extension are frequently asymptomatic at diagnosis, and tumor thrombus extension is usually diagnosed by imaging. Neoadjuvant chemotherapy is indicated for thrombus extension above the level of the hepatic veins and often leads to thrombus regression, obviating the need for cardiopulmonary bypass in cases of cardiac thrombus at diagnosis. In cases of tumor extension to the retrohepatic cava, neoadjuvant therapy is not strictly indicated, but it may facilitate the regression of tumor thrombi, making resection safer. Hepatic vascular isolation and cardiopulmonary bypass increase the risk of bleeding and other complications when utilized for tumor thrombectomy. Fortunately, WT patients with vena caval with or with intracardiac extension have similar overall and event-free survival when compared to patients with WT without intravascular extension when thrombectomy is successfully performed. Still, patients with metastatic disease at presentation or unfavorable histology suffer relatively poor outcomes. Dedicated pediatric surgical oncology and pediatric cardiothoracic surgery teams, in conjunction with multimodal therapy directed by a multidisciplinary team, are preferred for optimized outcomes in this patient population.

Severity of respiratory disease is correlated with time of first oral feeding and need for a gastrostomy tube at discharge in premature infants born at <30 weeks of gestation.

BACKGROUND: Premature infants who cannot achieve full oral feeds may need a gastrostomy tube (GT) to be discharged from the neonatal intensive care unit (NICU). We previously developed a model to predict which infants born <30 weeks (w) gestational age (GA) will require a GT before discharge. Here we report the detailed respiratory variable data to describe the general respiratory course for infants in the NICU < 30 w GA at birth and the association between different levels of respiratory support with postmenstrual age (PMA) at the time of first oral feeding attempt (PMAff), including later need for GT for discharge. METHODS: Retrospective chart review of 391 NICU admissions comprising test (2015-2016) and validation (2017-2018) cohorts. Data, including respiratory support, were collected on 204 infants, 41 GT and 163 non-GT, in the test cohort, and 187 infants, 37 GT, and 150 non-GT, in the validation cohort. RESULTS: Respiratory data were significantly different between GT and non-GT infants. Infants who required GT for discharge were on significantly higher respiratory support at 30 days of age, 32 w PMA, and 36 w PMA. Respiratory parameters were highly correlated with PMAff. CONCLUSION: Respiratory status predicts PMAff, which was the variable in our previously described model that was most predictive of failure to achieve full oral feeding. These data provide a catalyst to develop strategies for improving oral feeding outcome for infants requiring prolonged respiratory support in the NICU.

A predictive model for preterm babies born < 30 weeks gestational age who will not attain full oral feedings.

OBJECTIVE: Develop a model to predict gastrostomy tube (GT) for feeding at discharge in infants born < 30 weeks' (w) gestational age (GA). STUDY DESIGN: A single-center retrospective study at academic NICU. Total of 391 (78 GT, 313 non-GT) infants < 30 w GA admitted in 2015-2018 split into test (15-16) and validation (17-18) cohorts. Classification and regression tree analysis was used to identify predictive factors for GT. RESULTS: Several factors were associated with GT requirements. Four factors included in the model were postmenstrual age (PMA) at first oral feeding, birth GA, high-frequency ventilation exposure, necrotizing enterocolitis stage II/III. Area under the receiver operator characteristic curve was 0.944 in the test cohort, 0.815 in the validation cohort. Implementation plan based on the model was developed. CONCLUSIONS: We developed a predictive model to risk-stratify infants born < 30 w GA for failing full oral feeding. We hope implementation at 38 w PMA will result in earlier placement of needed GT and discharge.

Gastrojejunocolic fistula: case report of a rare late complication of laparoscopic Roux-en-Y gastric bypass and review of the literature.

INTRODUCTION: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is known as the weight loss surgery to which other bariatric procedures are compared. While morbidity and mortality of this procedure are low, serious complications do exist which can be life-threatening and sometimes require surgical correction. CASE PRESENTATION: A 63-year-old woman underwent LRYGB outside of the United States, later complicated by biliary colic treated with cholecystectomy and upper gastrointestinal bleeding secondary to H. pylori-related ulcer at her gastrojejunostomy. Following adequate treatment of the patients marginal ulcer, the patient experienced several months of progressive severe abdominal pain, frequent vomiting and diarrhea, and unintentional weight loss refractory to pharmacologic therapy. The patient underwent multiple medical and endoscopic evaluations unrevealing of an organic cause of her symptoms. At presentation, the patient was found to be profoundly weak, dehydrated and malnourished with metabolic derangements and was subsequently diagnosed with a gastrojejunocolic fistula via upper endoscopy and radiography. We provided excluded stomach gastrostomy tube feeding to the patient for three months to improve the patients nutritional status before definitive surgical correction was successfully performed. DISCUSSION: Large bowel fistulas are a rare and highly morbid late complication following LRYGB and are likely secondary to marginal ulcers and/or instrumentation such as endoscopy. Surgery represents the definitive treatment. CONCLUSION: LRYGB is typically a safe and effective intervention for obesity. Large bowel fistulas are rare complications following this surgery. We highlight difficulties in diagnosing and treating this condition.

The role of RNase H2 in processing ribonucleotides incorporated during DNA replication.

Saccharomyces cerevisiae RNase H2 resolves RNA-DNA hybrids formed during transcription and it incises DNA at single ribonucleotides incorporated during nuclear DNA replication. To distinguish between the roles of these two activities in maintenance of genome stability, here we investigate the phenotypes of a mutant of yeast RNase H2 (rnh201-RED; ribonucleotide excision defective) that retains activity on RNA-DNA hybrids but is unable to cleave single ribonucleotides that are stably incorporated into the genome. The rnh201-RED mutant was expressed in wild type yeast or in a strain that also encodes a mutant allele of DNA polymerase ε (pol2-M644G) that enhances ribonucleotide incorporation during DNA replication. Similar to a strain that completely lacks RNase H2 (rnh201Δ), the pol2-M644G rnh201-RED strain exhibits replication stress and checkpoint activation. Moreover, like its null mutant counterpart, the double mutant pol2-M644G rnh201-RED strain and the single mutant rnh201-RED strain delete 2-5 base pairs in repetitive sequences at a high rate that is topoisomerase 1-dependent. The results highlight an important role for RNase H2 in maintaining genome integrity by removing single ribonucleotides incorporated during DNA replication.