The Utility of Prophylactic Antibiotics for Laparoscopic Pyloromyotomy.

INTRODUCTION: Laparoscopic pyloromyotomy (LP) for the treatment of infantile hypertrophic pyloric stenosis (IHPS) is a clean case with low expected rates of postoperative surgical site infection (SSI). Previous studies have shown a low risk of SSI following LP but also large variations in the utilization of prophylactic antibiotics. The goal of this study was to review the use of preoperative antibiotics for LP and to compare this with SSI incidence. METHODS: We performed a retrospective single-center analysis of patients undergoing LP for infantile hypertrophic pyloric stenosis at a large quaternary children's hospital from January 2017 to June 2020. Subjects were <4 mo old. Exclusion criteria were those lost to follow-up within 30 d postoperatively and those who required open conversion intraoperatively. Statistical analysis was performed using Fisher's exact test, two-tailed independent t-tests, and descriptive statistics. RESULTS: Two-hundred twenty-seven patients were included, mean population age was 5.7 wk, and 81.1% were male. Preoperative antibiotics were administered in 39% of patients. Only 1.3% (n = 3) of all patients developed an SSI within 30 d of their operation. Analysis between patients who received preoperative antibiotics and those who did not revealed no difference in age (5.72 wk versus 5.72 wk, t (225) = 0.38, P = 0.70), sex (41% of males versus 32% of females, P = 0.39), length of stay (t(225) = -0.94, P = 0.35), or postoperative SSI (1.1% versus 1.4%, P > 0.999). Large variability was noted in antibiotic utilization by surgeon. CONCLUSIONS: In patients undergoing LP, there was no difference in SSI rates whether or not patients received preoperative antibiotics and, there is large variation in utilization. Measures are needed to decrease usage of prophylactic antibiotics before LP.

Survival outcomes in pediatric patients with metastatic Ewing sarcoma who achieve a rapid complete response of pulmonary metastases.

PURPOSE: Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non-RCR). PATIENTS AND METHODS: This retrospective cohort study included children under 20 years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi-square tests were conducted for differences among groups. Kaplan-Meier curves were generated for OS and pulmonary relapse. RESULTS: Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five-year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR (p = .04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17-0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16-0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non-RCR groups (p = .14). Five-year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non-RCR (47.0%, p = .13), or WLI (38.8%) versus no WLI (46.0%, p = .32). DISCUSSION: Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.

Management of undifferentiated embryonal sarcoma of the liver: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence-based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi-institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative. METHODS: Data were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event-free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively. RESULTS: Seventy-eight patients were identified with a median age of 9.9 years [interquartile range [IQR): 7-12]. Twenty-seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6 cm [IQR: 0.0-4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04-0.6]. At a median follow-up of 4 years [IQR: 2-8], the EFS was 70.0% [95% CI: 60%-82%] and OS was 83% [95% CI: 75%-93%]. CONCLUSION: Complete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

Management and Outcomes of Wilms Tumor With Suprarenal Intravascular Extension: A Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: The purpose of this study was to describe management and outcomes from a contemporary cohort of children with Wilms tumor complicated by inferior vena caval thrombus. BACKGROUND: The largest series of these patients was published almost 2 decades ago. Since then, neoadjuvant chemotherapy has been commonly used to manage these patients, and outcomes have not been reported. METHODS: Retrospective review of 19 North American centers between 2009 and 2019. Patient and disease characteristics, management, and outcomes were investigated and analyzed. RESULTS: Of 124 patients, 81% had favorable histology (FH), and 52% were stage IV. IVC thrombus level was infrahepatic in 53 (43%), intrahepatic in 32 (26%), suprahepatic in 14 (11%), and cardiac in 24 (19%). Neoadjuvant chemotherapy using a 3-drug regimen was administered in 82% and postresection radiation in 90%. Thrombus level regression was 45% overall, with suprahepatic level showing the best response (62%). Cardiopulmonary bypass (CPB) was potentially avoided in 67%. The perioperative complication rate was significantly lower after neoadjuvant chemotherapy [(25%) vs upfront surgery (55%); P =0.005]. CPB was not associated with higher complications [CPB (50%) vs no CPB (27%); P =0.08]. Two-year event-free survival was 93% and overall survival was 96%, higher in FH cases (FH 98% vs unfavorable histology/anaplastic 82%; P =0.73). Neither incomplete resection nor viable thrombus cells affected event-free survival or overall survival. CONCLUSIONS: Multimodal therapy resulted in excellent outcomes, even with advanced-stage disease and cardiac extension. Neoadjuvant chemotherapy decreased the need for CPB to facilitate resection. Complete thrombectomy may not always be necessary.

Comparison of Outcomes Between Surveillance Ultrasound and Completion Lymph Node Dissection in Children and Adolescents With Sentinel Lymph Node-Positive Cutaneous Melanoma.

OBJECTIVE: To determine the impact of nodal basin ultrasound (US) surveillance versus completion lymph node dissection (CLND) in children and adolescents with sentinel lymph node (SLN) positive melanoma. BACKGROUND: Treatment for children and adolescents with melanoma are extrapolated from adult trials. However, there is increasing evidence that important clinical and biological differences exist between pediatric and adult melanoma. METHODS: Patients ≤18 years diagnosed with cutaneous melanoma between 2010 and 2020 from 14 pediatric hospitals were included. Data extracted included demographics, histopathology, nodal basin strategies, surveillance intervals, and survival information. RESULTS: Of 252 patients, 90.1% (n=227) underwent SLN biopsy (SLNB), 50.9% (n=115) had at least 1 positive node. A total of 67 patients underwent CLND with 97.0% (n=65/67) performed after a positive SLNB. In contrast, 46 total patients underwent US observation of nodal basins with 78.3% (n=36/46) of these occurring after positive SLNB. Younger patients were more likely to undergo US surveillance (median age 8.5 y) than CLND (median age 11.3 y; P =0.0103). Overall, 8.9% (n=21/235) experienced disease recurrence: 6 primary, 6 nodal, and 9 distant. There was no difference in recurrence (11.1% vs 18.8%; P =0.28) or death from disease (2.2% vs 9.7%; P =0.36) for those who underwent US versus CLND, respectively. CONCLUSIONS: Children and adolescents with cutaneous melanoma frequently have nodal metastases identified by SLN. Recurrence was more common among patients with thicker primary lesions and positive SLN. No significant differences in oncologic outcomes were observed with US surveillance and CLND following the identification of a positive SLN.

Multi-institutional assessment of the prevalence of neuroendocrine tumors in children undergoing laparoscopic appendectomy for acute appendicitis in the United States.

As non-operative management of acute appendicitis in children has become more common, missed incidental appendiceal pathology can be an unintended consequence. We assessed the prevalence of neuroendocrine tumors in appendectomy specimens from eight US children's hospitals from 2012 to 2021. The prevalence of neuroendocrine tumors (NET) was found to be 1:271, with a median age of 14 years and 62% female. Most tumors were small (median 6 mm; interquartile range [IQR]: 3-10), and no recurrence was noted during the follow-up period (median 22.5 months; IQR: 3-53). The possibility of delayed diagnosis of these tumors should be part of the discussion for non-operative management of pediatric acute appendicitis.

Incidence and management of pleural effusions in patients with Wilms tumor: A Pediatric Surgical Oncology Research Collaborative study.

Wilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi-institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P = .004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event-free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage-specific treatment regimens.

Handheld PET Probe for Pediatric Cancer Surgery.

18F-fluorodeoxyglucose (FDG) is a glucose analog that acts as a marker for glucose uptake and metabolism. FDG PET scans are used in monitoring pediatric cancers. The handheld PET probe localization of FDG-avid lesions is an emerging modality for radio-guided surgery (RGS). We sought to assess the utility of PET probe in localizing occult FDG-avid tumors in pediatric patients. PET probe functionality was evaluated by using a PET/CT scan calibration phantom. The PET probe was able to detect FDG photon emission from simulated tumors with an expected decay of the radioisotope over time. Specificity for simulated tumor detection was lower in a model that included background FDG. In a clinical model, eight pediatric patients with FDG-avid primary, recurrent or metastatic cancer underwent a tumor excision, utilizing IV FDG and PET probe survey. Adequate tissue for diagnosis was present in 16 of 17 resected specimens, and pathology was positive for malignancy in 12 of the 17 FDG-avid lesions. PET probe gamma counts per second were higher in tumors compared with adjacent benign tissue in all operations. The median ex vivo tumor-to-background ratio (TBR) was 4.0 (range 0.9-12). The PET probe confirmed the excision of occult FDG-avid tumors in eight pediatric patients.

Hyperlactatemia as a prognostic indicator for contemporary left ventricular assist device implantation.

BACKGROUND: This study evaluates the impact of early post-operative hyperlactatemia on outcomes after left ventricular assist device (LVAD) implantation. METHODS: Adults undergoing contemporary LVAD implantation between 2009 to 2018 were included. Peak post-operative (within 24-h) lactate level was analyzed. The cohort was stratified into patients with and without post-operative hyperlactatemia, which was defined as peak > 3.5 mMol/L. The primary outcome was survival, and secondary outcomes included post-implant adverse events. Sub-analysis was performed to evaluate the impact of time for lactate normalization, define as lactate < 2 mMol/L. Multivariable cox regression was used for risk-adjustment. RESULTS: A total of 190 patients were included. 49.5% experienced early post-operative hyperlactatemia. Patients with post-operative hyperlactatemia had significantly higher rates of post-implant complications including re-operation, renal failure, and hepatic dysfunction (all, p ≤ 0.05). The post-operative hyperlactatemia group also had significantly higher 90-day and 1-year mortality rates following LVAD implantation (both, p ≤ 0.05). In multivariable analysis, post-operative hyperlactatemia (HR 1.69, 95% CI 1.09-2.60, p = 0.02) was an independent predictor of overall mortality following LVAD implantation. Increased time for normalization of lactate also adversely impacted risk-adjusted overall mortality following implantation as a continuous variable (HR 1.02, 95% CI 1.01-1.03, p < .001). CONCLUSIONS: This study demonstrates early post-operative hyperlactatemia is associated with increased morbidity and mortality following LVAD implantation. Even early post-operative lactate trends within the first 24 post-operative hours appear to have a useful role in predicting longitudinal survival following implantation. Careful monitoring of post-operative lactate with measures to normalize levels should be considered in the early care of LVAD patients.

Assessment of Leptomeningeal Carcinomatosis Diagnosis, Management and Outcomes in Patients with Solid Tumors Over a Decade of Experience.

OBJECTIVE: Leptomeningeal carcinomatosis (LMC), a common complication of advanced malignancies, is associated with high morbidity and mortality, yet diagnosis and treatment decisions remain challenging. This study describes the diagnostic and treatment modalities for LMC and identifies factors associated with overall survival (OS). MATERIALS AND METHODS: We performed a single-institution retrospective study (registration #: OSU2016C0053) of 153 patients diagnosed with LMC treated at The Ohio State University, Comprehensive Cancer Center, (OSUCCC)-James between January 1, 2010 and December 31, 2015. RESULTS: Median age at diagnosis was 55.7 years, and 61% had Eastern Cooperative Oncology Group baseline performance status ≤1. Most common primary tumors were breast (43%), lung (26%), and cutaneous melanoma (10%). At presentation, most patients were stage III-IV (71%) with higher grade tumors (grade III: 46%). Metastases to bone (36%), brain (33%), and lung (12%) were the most common sites with a median of 0.5 years (range, 0-14.9 years) between the diagnosis of first metastasis and of LMC. 153 (100%) patients had MRI evidence of LMC. Of the 67 (44%) who underwent lumbar puncture (LP), 33 (22%) had positive cerebrospinal fluid (CSF) cytology. Most patients received radiotherapy for LMC (60%) and chemotherapy (93%) for either the primary disease or LMC. 28 patients received intrathecal chemotherapy, 22 of whom had a primary diagnosis of breast cancer. 98% died with median OS of all patients was 1.9 months (95% CI: 1.3-2.5 months). CONCLUSION: Despite improved treatments and targeted therapies, outcomes of LMC remain extremely poor. Positive CSF cytology was associated with lower OS in patients who had cytology assessed and specifically in patients with breast cancer. CSF cytology serves as an important indicator for prognosis and helps aid in developing individualized therapeutic strategies for patients with LMC.

Appendectomy Versus Observation for Appendicitis in Neutropenic Children With Cancer.

BACKGROUND: Optimal management of neutropenic appendicitis (NA) in children undergoing cancer therapy remains undefined. Management strategies include upfront appendectomy or initial nonoperative management. We aimed to characterize the effect of management strategy on complications and length of stay (LOS) and describe implications for chemotherapy delay or alteration. METHODS: Sites from the Pediatric Surgery Oncology Research Collaborative performed a retrospective review of children with NA over a 6-year period. RESULTS: Sixty-six children, with a median age of 11 years (range 1-17), were identified with NA while undergoing cancer treatment. The most common cancer diagnoses were leukemia (62%) and brain tumor (12%). Upfront appendectomy was performed in 41% of patients; the remainder had initial nonoperative management. Rates of abscess or perforation at diagnosis were equivalent in the groups (30% vs 24%; P = .23). Of patients who had initial nonoperative management, 46% (17 of 37) underwent delayed appendectomy during the same hospitalization. Delayed appendectomy was due to failure of initial nonoperative management in 65% (n = 11) and count recovery in 35% (n = 6). Cancer therapy was delayed in 35% (n = 23). Initial nonoperative management was associated with a delay in cancer treatment (46% vs. 22%, P = .05) and longer LOS (29 vs 12 days; P = .01). Patients who had initial nonoperative management and delayed appendectomy had a higher rate of postoperative complications (P < .01). CONCLUSIONS: In pediatric patients with NA from oncologic treatment, upfront appendectomy resulted in lower complication rates, reduced LOS, and fewer alterations in chemotherapy regimens compared to initial nonoperative management.

Successful Liver Transplantation for Adolescent Patient With Pyruvate Kinase Deficiency-induced Cirrhosis.

We present the case of a successful liver transplant in a young adult patient with cholestasis and cirrhosis secondary to severe pyruvate kinase (PK) deficiency. Liver transplant resulted in resolution of liver dysfunction, decreased need for blood transfusions and eligibility for bone marrow transplantation. This case represents the third reported patient in the literature with severe PK deficiency who successfully underwent liver transplant as a result of profound cholestasis and liver failure. Explant pathology demonstrated a lack of significant iron deposition indicating that PK deficiency predisposes the liver to injury independent of transfusion-related iron overload.

Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways.

BACKGROUND: Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis. METHODS: We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13-cis-retinoic acid on intracellular signalling. RESULTS: Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRß and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13-cis-retinoic acid demonstrates enhanced efficacy compared with regorafenib alone. CONCLUSIONS: The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13-cis-retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.

Multifocal Appendiceal Carcinoid Tumor in an Adolescent: A Case Report and Review of the Literature.

Appendiceal carcinoid tumors in children and adolescents are rare. This report describes a case of a multifocal appendiceal carcinoid tumor identified incidentally following appendectomy in an adolescent. In this report, we describe the staging process and surgical management for focal and locally invasive appendiceal carcinoid tumors and highlight the rarity of multifocality in this location. The diagnostic and pathologic challenges for this case are presented.

AR-13 reduces antibiotic-resistant bacterial burden in cystic fibrosis phagocytes and improves cystic fibrosis transmembrane conductance regulator function.

BACKGROUND: There are no effective treatments for Burkholderia cenocepacia in patients with cystic fibrosis (CF) due to bacterial multi-drug resistance and defective host killing. We demonstrated that decreased bacterial killing in CF is caused by reduced macrophage autophagy due to defective cystic fibrosis transmembrane conductance regulator (CFTR) function. AR-12 is a small molecule autophagy inducer that kills intracellular pathogens such as Francisella. We evaluated the efficacy of AR-12 and a new analogue AR-13 in reducing bacterial burden in CF phagocytes. METHODS: Human CF and non-CF peripheral blood monocyte-derived macrophages, neutrophils, and nasal epithelial cells were exposed to CF bacterial strains in conjunction with treatment with antibiotics and/or AR compounds. RESULTS: AR-13 and not AR-12 had growth inhibition on B. cenocepacia and methicillin-resistantStaphylococcus aureus (MRSA) in media alone. There was a 99% reduction in MRSA in CF macrophages, 71% reduction in Pseudomonas aeruginosa in CF neutrophils, and 70% reduction in non-CF neutrophils using AR-13. Conversely, there was no reduction in B. cenocepacia in infected CF and non-CF macrophages using AR-13 alone, but AR-13 and antibiotics synergistically reduced B. cenocepacia in CF macrophages. AR-13 improved autophagy in CF macrophages and CF patient-derived epithelial cells, and increased CFTR protein expression and channel function in CF epithelial cells. CONCLUSIONS: The novel AR-12 analogue AR-13, in combination with antibiotics, reduced antibiotic-resistant bacterial burden in CF phagocytes, which correlated with increased autophagy and CFTR expression. AR-13 is a novel therapeutic for patients infected with B. cenocepacia and other resistant organisms that lack effective therapies.

Cysteamine-mediated clearance of antibiotic-resistant pathogens in human cystic fibrosis macrophages.

Members of the Burkholderia cepacia complex are virulent, multi-drug resistant pathogens that survive and replicate intracellularly in patients with cystic fibrosis (CF). We have discovered that B. cenocepacia cannot be cleared from CF macrophages due to defective autophagy, causing continued systemic inflammation and infection. Defective autophagy in CF is mediated through constitutive reactive oxygen species (ROS) activation of transglutaminase-2 (TG2), which causes the sequestration (accumulation) of essential autophagy initiating proteins. Cysteamine is a TG2 inhibitor and proteostasis regulator with the potential to restore autophagy. Therefore, we sought to examine the impact of cysteamine on CF macrophage autophagy and bacterial killing. Human peripheral blood monocyte-derived macrophages (MDMs) and alveolar macrophages were isolated from CF and non-CF donors. Macrophages were infected with clinical isolates of relevant CF pathogens. Cysteamine caused direct bacterial growth killing of live B. cenocepacia, B. multivorans, P. aeruginosa and MRSA in the absence of cells. Additionally, B. cenocepacia, B. multivorans, and P. aeruginosa invasion were significantly decreased in CF MDMs treated with cysteamine. Finally, cysteamine decreased TG2, p62, and beclin-1 accumulation in CF, leading to increased Burkholderia uptake into autophagosomes, increased macrophage CFTR expression, and decreased ROS and IL-1ß production. Cysteamine has direct anti-bacterial growth killing and improves human CF macrophage autophagy resulting in increased macrophage-mediated bacterial clearance, decreased inflammation, and reduced constitutive ROS production. Thus, cysteamine may be an effective adjunct to antibiotic regimens in CF.