Preoperative spinal angiography decreases risk of spinal ischemia in pediatric posterior thoracic tumor resection.

PURPOSE: Resection of pediatric posterior thoracic tumors (PTTs) can be complicated by Artery of Adamkiewicz (AKA) injury. Post-op spinal ischemia occurs in approx. 3.2% of patients, typically due to iatrogenic vascular injury. Pre-op angiography (PSA) may help to avoid this complication. Herein, we aim to evaluate outcomes after initiation of routine PSA prior to PTT resection. METHODS: A single-institution retrospective review identified 25 children (< 18 years) treated for PTTs from 2009 to 2021. PTTs included: posterior mediastinum, paraspinal thorax and posterior chest wall tumors. PSA patients were compared to those without pre-operative angiography (NA). Demographics, perioperative and long-term outcomes and event-free survival (EFS) were assessed. RESULTS: Prior to 2012, eleven patients were treated without PSA. However, the last developed post-operative paraplegia secondary to spinal ischemia. Since this event, PSA has become routine for all PTTs (n = 14) identifying six AKAs and nine accessory spinal arteries. Resection was performed in ten (90.1%) NA patients and eight (57.1%) PSA patients. Based on PSA findings, resection was not offered to six patients and planned partial resection was performed in three patients. Five PSA patients required radiation therapy for local control vs two NA patients. There were no differences in recurrence or overall EFS. CONCLUSION: PSA aids in identifying patients with high-risk thoracic vascular anatomy and may prevent risk of post-operative paraplegia associated with PTT resection.

Migration, invasion, and metastasis are mediated by P-Rex1 in neuroblastoma.

Neuroblastoma accounts for approximately 15% of pediatric cancer-related deaths despite intensive multimodal therapy. This is due, in part, to high rates of metastatic disease at diagnosis and disease relapse. A better understanding of tumor biology of aggressive, pro-metastatic phenotypes is necessary to develop novel, more effective therapeutics against neuroblastoma. Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) has been found to stimulate migration, invasion, and metastasis in several adult malignancies. However, its role in neuroblastoma is currently unknown. In the present study, we found that P-Rex1 is upregulated in pro-metastatic murine models of neuroblastoma, as well as human neuroblastoma metastases. Correspondingly, silencing of P-Rex1 was associated with decreased migration and invasion in vitro. This was associated with decreased AKT-mTOR and ERK2 activity, dysregulation of Rac, and diminished secretion of matrix metalloproteinases. Furthermore, increased P-Rex1 expression was associated with inferior relapse-free and overall survival via tissue microarray and Kaplan-Meier survival analysis of a publicly available clinical database. Together, these findings suggest that P-Rex1 may be a novel therapeutic target and potential prognostic factor in neuroblastoma.

Social Determinants of Outcomes Disparity among Pediatric Patients with Solid Tumor.

BACKGROUND: Socioeconomic factors have a significant impact on healthcare outcomes. Metrics such as area deprivation index (ADI) are used to quantify the anticipated influence of these factors. Here, we sought to assess the impact of socioeconomic factors on clinical outcomes among pediatric patients with solid tumor in our region. STUDY DESIGN: We identified 3,863 pediatric patients who were diagnosed with a malignant solid tumor in the Texas Cancer Registry between 1995 and 2019. ADI was used to quantify socioeconomic determinants of health. These outcome variables were determined: stage of disease at diagnosis, time between diagnosis and treatment initiation, and overall mortality. Statistical analysis was performed using logistic regression, linear regression, Cox proportional hazards regression, and Kaplan-Meier survival curves. RESULTS: A total of 53.5% of patients were male and the average age at diagnosis was 4.5 years. Forty-seven percent of patients were White, 13.3% were Black, 36.2% were Hispanic, 1.7% were Asian, and other rare minority groups made up 1.8%. On multivariable analysis, increased risk of death was associated with Black race, rare minority race, residence in a border county, and increasing ADI score, with the risk of death at 5 years rising 4% with each increasing ADI point. CONCLUSIONS: Social determinants of health are associated with disparate outcomes among pediatric patients with solid tumor. Our results suggest that patients who are part of racial minority groups and those who reside in socioeconomically disadvantaged neighborhoods or regions near the Texas-Mexico border are at an increased risk of death. This information may be useful in strategizing outreach and expanding resources to improve outcomes in at-risk communities.

Outcomes of Extracorporeal Life Support Utilization for Pediatric Patients With COVID-19 Infections.

Outcomes of pediatric patients who received extracorporeal life support (ECLS) for COVID-19 remain poorly described. The aim of this multi-institutional retrospective observational study was to evaluate these outcomes and assess for prognostic factors associated with in-hospital mortality. Seventy-nine patients at 14 pediatric centers across the United States who received ECLS support for COVID-19 infections between January 2020 and July 2022 were included for analysis. Data were extracted from the electronic medical record. The median age was 14.5 years (interquartile range [IQR]: 2-17 years). Most patients were female (54.4%) and had at least one pre-existing comorbidity (84.8%), such as obesity (44.3%, median body mass index percentile: 97% [IQR: 67.5-99.0%]). Venovenous (VV) ECLS was initiated in 50.6% of patients. Median duration of ECLS was 12 days (IQR: 6.0-22.5 days) with a mean duration from admission to ECLS initiation of 5.2 ± 6.3 days. Survival to hospital discharge was 54.4%. Neurological deficits were reported in 16.3% of survivors. Nonsurvivors were of older age (13.3 ± 6.2 years vs. 9.3 ± 7.7 years, p = 0.012), more likely to receive renal replacement therapy (63.9% vs. 30.2%, p = 0.003), demonstrated longer durations from admission to ECLS initiation (7.0 ± 8.1 days vs. 3.7 ± 3.8 days, p = 0.030), and had higher rates of ECLS-related complications (91.7% vs. 69.8%, p = 0.016) than survivors. Pediatric patients with COVID-19 who received ECLS demonstrated substantial morbidity and further investigation is warranted to optimize management strategies.

Pediatric robotic surgery: An overview.

Pediatric robotic surgery offers children a minimally invasive approach with numerous advantages over open or thoracoscopic and laparoscopic surgery. However, despite its widespread adoption for adult patients, the utilization of robotic surgery within pediatrics has been relatively slower to progress. This paper provides an overview of pediatric robotic surgery and discusses benefits, limitations, and strategies for successful implementation of robotics within pediatric surgical practice.

High-Risk Neuroblastoma: A Surgical Perspective.

High-risk neuroblastoma requires multimodal treatment including systemic chemotherapy, surgical resection, radiation therapy, stem cell transplant, and immunotherapy. Surgeons play a vital role in obtaining local control of neuroblastoma and must therefore be knowledgeable about this complex pathology. This article provides a review of the optimal timing and extent of resection, the impact of various image-defined risk factors on surgical planning, and surgical approaches and techniques to enhance the resection of tumors in different anatomic locations.

Robotic repair of pediatric hernias: Current techniques and practices.

The use of minimally invasive surgical techniques has gained popularity in pediatric surgery due to decreased length of stay, improved post-operative pain and smaller incisions. Laparoscopic assisted robotic surgical procedures are becoming more common in adults as they carry all of the benefits of traditional MIS but also allow for improved dexterity, visualization and surgeon ergonomics. In adults, hernia repairs are one of the most commonly performed robotic cases but adaption to pediatric repairs has been slower. Case reports and small case series have described a number of various types of pediatric hernia repairs including congenital diaphragmatic hernias, paraesophageal hernias and inguinal hernias. These cases have demonstrated that robotic repair of pediatric hernias is safe and feasible with minimal documented post-operative complications or recurrence. Future directions should focus on larger patient volume in order to assess outcomes between traditional laparoscopic and robotic approaches.

Utilization of robotics in pediatric surgical oncology.

Despite increasing implementation of robotic surgery and minimally invasive techniques within adult surgical oncology and pediatric general surgery, the utilization of robotic-assisted resections for pediatric tumors has been met with controversy. The robotic platform affords numerous advantages over conventional surgical techniques. However, limited data and guidelines regarding patient selection, indications for the robotic approach, and long-term oncologic outcomes have delayed the widespread adoption of robotic-assisted resection of pediatric tumors. This paper reviews the benefits, limitations, and existing guidelines and data regarding the utilization of robotics in pediatric surgical oncology.

Induction of serine hydroxymethyltransferase 2 promotes tumorigenesis and metastasis in neuroblastoma.

High-risk neuroblastoma (NB) remains an extremely difficult subgroup to cure and is associated with MYCN amplification. Serine hydroxymethyltransferase 2 (SHMT2) regulates serine metabolism in a myc-dependent manner; it is upregulated in several cancers and is associated with tumor aggressiveness. Akt-2, an important regulator of MYCN via the PI3K/Akt pathway, induces metastatic potential in NB. The association between SHMT2 and PI3K/Akt in hepatocyte regeneration has been well established but its mechanistic interaction in cancer has yet to be clearly elucidated. Herein, we evaluated the exact role of SHMT2 on the PI3K/Akt pathway, in addition to NB tumorigenesis and metastatic potential in vitro. SHMT2 gene expression and overall survival (OS) were assessed. Two human NB cell lines were examined. SHMT2 silencing and overexpression were performed. The downstream effects were analyzed with immunoblotting, RT-qPCR and functional assays were performed. We found SHMT2 gene expression is associated with decreased OS and MYCN amplification. SHMT2 protein and mRNA expression are increased in MYCN-amplified cells. SHMT2 expression has a direct interaction with Akt-2 and MYCN. Induction of SHMT2 increased cellular proliferation, colony formation and cellular migration and SHMT2 expression was increased in metastatic NB cells. We conclude that SHMT2 regulates N-Myc via phosphorylation of Akt-2 and plays an important role in NB tumorigenesis by contributing to cell growth, migration, colony formation and metastasis in vitro.

Combination bromo- and extraterminal domain and poly (ADP-ribose) polymerase inhibition synergistically enhances DNA damage and inhibits neuroblastoma tumorigenesis.

PURPOSE: JQ1 is a bromo- and extraterminal (BET) domain inhibitor that downregulates MYC expression and impairs the DNA damage response. Poly (ADP-ribose) polymerase (PARP) inhibitors prevent DNA damage sensing and repair. We hypothesized that JQ1 would promote a DNA repair-deficient phenotype that sensitizes neuroblastoma cells to PARP inhibition. METHODS: Four human neuroblastoma cell lines were examined: two MYCN-amplified (BE(2)-C and IMR-32), and two non-MYCN-amplified (SK-N-SH and SH-SY5Y). Cells were treated with JQ1 (BET inhibitor), Olaparib (PARP inhibitor), or in combination to assess for therapeutic synergy of JQ1 and Olaparib. Treated cells were harvested and analyzed. Quantitative assessment of combination treatment synergy was performed using the median effect principle of Chou and Talalay. RESULTS: Combination treatment with Olaparib decreased the IC50 of JQ1 by 19.9-fold, 2.0-fold, 12.1-fold, and 2.0-fold in the BE(2)-C, IMR-32, SK-N-SH, and SH-SY5Y cell lines, respectively. In the MYCN-amplified cell lines, BE(2)-C and IMR-32, combination treatment decreased gene expression of MYCN relative to single-drug treatment alone or control. Combination treatment decreased protein expression of DNA repair proteins Ku80 and RAD51, led to accumulation of DNA damage marker phospho-histone H2A.X, and increased caspase activity. In the non-MYCN-amplified cell lines, SK-N-SH and SH-SY5Y, combination treatment induced G0/G1 cell cycle arrest. CONCLUSIONS: Combination BET and PARP inhibition synergistically inhibited neuroblastoma tumorigenesis in vitro. In MYCN-amplified neuroblastoma cells, this effect may be induced by downregulation of MYCN transcription, defects in DNA repair, accumulation of DNA damage, and apoptosis. In non-MYCN-amplified cell lines, combination treatment induced cell cycle arrest.

Pediatric Normokinetic Biliary Dyskinesia: Pain with Cholecystokinin on Hepatobiliary Iminodiacetic Acid Scan Predictive of Symptom Resolution After Cholecystectomy.

Introduction: Biliary dyskinesia is typically defined as a gallbladder ejection fraction (EF) <35% on hepatobiliary iminodiacetic acid scan with cholecystokinin stimulation (CCK-HIDA) testing. Cholecystectomy often leads to resolution of associated biliary colic symptoms. Alternatively, there is a subset of symptomatic patients with normal gallbladder EF on CCK-HIDA. It has been proposed that pain with CCK injection is more predictive of symptom resolution after cholecystectomy than low gallbladder EF. We reviewed our experience with pediatric patients with positive CCK provocation testing and a normal gallbladder EF in the absence of gallstones. Materials and Methods: We retrospectively reviewed the records of all pediatric patients with normal hepatobiliary iminodiacetic acid EFs (35%-80%) and pain with CCK injection at a tertiary care center between 2016 and 2020. Age, gender, body mass index (BMI), CCK-HIDA results, and pathology analysis were noted. Short- and long-term resolution of symptoms was determined by patient self-reporting at a mean of 3 weeks and 46 months, respectively. Results: Seventeen patients met inclusion criteria. Average age was 15.1 years (range, 12-17 years) with median BMI 24.9 (± 4.9 kg/m2). Mean CCK-HIDA EF was 56.3% (± 11.4%). In total, 62.5% of patients had evidence of chronic cholecystitis and/or cholesterolosis on pathology analysis. Of patients available for short-term and long-term postoperative follow-up, 80% and 83% reported complete or near complete resolution of symptoms, respectively. Conclusions: Normokinetic biliary dyskinesia is poorly understood but appears to be associated with chronic inflammation and cured by surgical intervention. Laparoscopic cholecystectomy results in resolution of symptoms for a majority of patients and should be considered in those with pain with CCK injection despite normal imaging studies. Clinical Trial Registration Number: 1657640-2.

Multimodality treatment of pediatric Ewing sarcoma: A single-center 10-year analysis of outcomes.

BACKGROUND: Ewing sarcoma, a malignancy originating from the bone or soft tissues most commonly diagnosed in adolescents, requires multimodality therapy. Although both surgical resection and radiation therapy are effective local control modalities, there are limited data comparing outcomes in patients treated with surgery versus radiation. We sought to determine whether there were differences in 5-year local failure-free survival, event-free survival, and overall survival based on the modality used for local control. METHODS: Patients treated for Ewing sarcoma at a single tertiary pediatric hospital between 2010 and 2020 were included for retrospective analysis. Patient and tumor demographics, treatment information, and patient response to therapies were collected from the medical record. Outcome measures were local failure-free survival, event-free survival, and overall survival at 5 years from diagnosis. RESULTS: Sixty-one patients met inclusion criteria. All patients received chemotherapy, and 68.9% of patients presented with localized disease. Of these, 23.8% were treated with radiation alone; the remaining 76.2% underwent resection ± radiation. A total of 52.4% of patients with localized disease achieved R0 resection. Only 3 patients experienced local progression; there was no difference between treatment groups. There was no significant association between local control modality and event-free survival or overall survival in patients with localized disease, regardless of margin status. CONCLUSION: There was no significant difference in 5-year local failure-free survival, event-free survival, or overall survival in Ewing sarcoma patients treated with radiation versus surgery ± radiation, regardless of whether or not R0 resection was achieved. Future directions include a multi-institutional study to allow for further subgroup analysis and increased sample size.

Ethnic Disparities in the Management of Pediatric Subcutaneous Abscesses.

(1) Background: Significant racial and ethnic disparities affect access to pediatric Emergency Department (ED) and surgical care across the United States. The present study sought to assess the role of racial and ethnic disparities in the management of pediatric subcutaneous abscesses. (2) Methods: A retrospective chart review was performed including ED visits for subcutaneous abscesses in patients < 18 years of age, over a 12-month period. The effects of self-reported ethnicity (Hispanic versus non-Hispanic) and race (Hispanic, Black, Caucasian and Asian) on the diagnosis and management of subcutaneous abscesses were analyzed. (3) Results: 192 patients were identified with an average age of 4.7 ± 5.3 years and 43.8% identified as Hispanic. Non-Hispanic patients were significantly more likely to receive treatment of their SSTI prior to the ED and to be admitted, compared to Hispanic patients. There was no difference in bedside versus operating room incision and drainage (I&D); however, significantly more non-Hispanic patients received procedural sedation for bedside I&D compared to Hispanic patients. There were no differences in outcomes such as recurrence or re-admission based on ethnicity or race. (4) Conclusions: Ethnic and racial disparities exist in the management of subcutaneous abscesses in the United States. Further studies are needed to address the systemic causes of these disparities such as access to tertiary healthcare facilities and systems-based analyses of unconscious bias in healthcare.

Impact of Cryoablation on Pectus Excavatum Repair in Pediatric Patients.

BACKGROUND: Minimally invasive repair of pectus excavatum (MIRPE) involves placement of a transthoracic, retrosternal support bar under thoracoscopic guidance. Despite its minimally invasive technical approach, postoperative pain is a significant morbidity that often results in increased length of stay. Multi-modal pain control strategies have been used in the past with limited success. Recently, the use of intraoperative intercostal nerve cryoablation (CA) has been added. In the present study, we aim to evaluate the effects of CA on postoperative pain control, opioid requirements, and perioperative outcomes. STUDY DESIGN: A single-center, retrospective chart review of all patients (less than 18 years old) who underwent MIRPE from 2009 to 2020 was performed. CA was started in June 2018. Data collection included demographics, preoperative characteristics, intraoperative findings, and postoperative outcomes. We hypothesized that CA would be associated with improved pain scores, lower doses of total inpatient opioid requirement, and shorter length of stay (LOS). RESULTS: One hundred sixty-one patients met inclusion criteria: 75 underwent intraoperative CA and 86 underwent MIRPE without CA (NCA group). CA significantly decreased median LOS from 4 days in NCA to 2 days; the use of CA was the only significant predictor of LOS on linear regression. CA was also associated with decreased total PCA, intravenous opioid, and oral opioid dosages. There was no difference in inpatient pain scores and a slight increase in mean procedure time. However, CA was associated with significantly decreased postoperative complications. CONCLUSIONS: The use of cryoablation during MIRPE significantly decreases LOS, perioperative opioid requirements, and postoperative complications, with a minimal increase in operative time. Cryoablation is an effective pain control modality in the surgical management of chest wall deformities in children.

Anti-GRP-R monoclonal antibody antitumor therapy against neuroblastoma.

Standard treatment for patients with high-risk neuroblastoma remains multimodal therapy including chemoradiation, surgical resection, and autologous stem cell rescue. Immunotherapy has demonstrated success in treating many types of cancers; however, its use in pediatric solid tumors has been limited by low tumor mutation burdens. Gastrin-releasing peptide receptor (GRP-R) is overexpressed in numerous malignancies, including poorly-differentiated neuroblastoma. Monoclonal antibodies (mAbs) to GRP-R have yet to be developed but could serve as a potential novel immunotherapy. This preclinical study aims to evaluate the efficacy of a novel GRP-R mAb immunotherapy against neuroblastoma. We established four candidate anti-GRP-R mAbs by screening a single-chain variable fragment (scFv) library. GRP-R mAb-1 demonstrated the highest efficacy with the lowest EC50 at 4.607 ng/ml against GRP-R expressing neuroblastoma cells, blocked the GRP-ligand activation of GRP-R and its downstream PI3K/AKT signaling. This resulted in functional inhibition of cell proliferation and anchorage-independent growth, indicating that mAb-1 has an antagonist inhibitory role on GRP-R. To examine the antibody-dependent cellular cytotoxicity (ADCC) of GRP-R mAb-1 on neuroblastoma, we co-cultured neuroblastoma cells with natural killer (NK) cells versus GRP-R mAb-1 treatment alone. GRP-R mAb-1 mediated ADCC effects on neuroblastoma cells and induced release of IFNγ by NK cells under co-culture conditions in vitro. The cytotoxic effects of mAb-1 were confirmed with the secretion of cytotoxic granzyme B from NK cells and the reduction of mitotic tumor cells in vivo using a murine tumor xenograft model. In summary, GRP-R mAb-1 demonstrated efficacious anti-tumor effects on neuroblastoma cells in preclinical models. Importantly, GRP-R mAb-1 may be an efficacious, novel immunotherapy in the treatment of high-risk neuroblastoma patients.

A narrative review of gastroesophageal reflux in the pediatric patient.

Gastroesophageal reflux (GER) is the retrograde passage of gastric contents into the esophagus. It is a physiologic condition that is common in neonates, typically resolves spontaneously, and does not result in clinically significant complications. When pathologic, gastroesophageal reflux disease (GERD) can cause numerous complications including persistent emesis, failure to thrive, aspiration, and respiratory symptoms. While a diagnosis can often be made from a thorough history and physical, some patients may require further testing. In general, many clinicians will reserve extensive investigation such as multiple intraluminal impedance and pH monitoring for patients with a confounding clinical picture or relative contraindications to medical or surgical management. Whereas most pediatric GER resolves spontaneously, medical management including lifestyle changes, changes to feeds, and the use of H2-antagonists and/or proton pump inhibitors (PPIs) can be utilized to alleviate symptoms. Surgical treatment is reserved for patients who are refractory to medical management or have suffered significant complications as a consequence of GER. In this article we seek to provide a concise but detailed review of recent updates in the understanding, work up and management of GER in the pediatric patient. A summary of new technologies used in the diagnostic and therapeutic arms of this disease are included.