Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children's Oncology Group.

PURPOSE: Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS: Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS: Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION: Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.

Appendectomy by Pediatric Surgeons in North Carolina is Associated With Higher Charge Than General Surgeons.

INTRODUCTION: The delivery of pediatric surgical care for acute appendicitis involves general surgeons (GS) and pediatric surgeons (PS), but the differences in clinical practice are primarily undescribed. We examined charge differences between GS and PS for the treatment of pediatric acute appendicitis. METHODS: We performed a retrospective review of the North Carolina hospital discharge database (2013-2017) in pediatric patients (≤18 y) who had surgery for appendiceal pathology (acute or chronic appendicitis and other appendiceal pathology). We performed a bivariate analysis of surgical charges over the type of surgical providers (GS, PS, other specialty, and unassigned surgeons). RESULTS: Over the study period, 21,049 patients had appendicitis or other diseases of the appendix, and 15,230 (72.4%) underwent appendectomy. Patients who were operated on by PS were younger (10 y, interquartile range (IQR): 6-13 versus 13 y, IQR: 9-16, P < 0.001). Acute appendicitis was diagnosed in 2860 (44.3%) and 3173 (49.2%) of the PS and GS cohorts, respectively, P = 0.008. PS compared to GS performed a higher percentage of laparoscopic (n = 2,697, 89.4% versus n = 2,178, 65.5%) than open appendectomies (n = 280, 9.3% versus n = 1,118, 33.6%), P < 0.001. The overall hospital charges were $28,081 (IQR: $21,706-$37,431) and $24,322 (IQR: $17,906-$32,226) for PS and GS, respectively, P < 0.001. Surgical charges where higher for PS than GS, $12,566 (IQR: $9802-$17,462) and $8051 (IQR: $5872-$2331), respectively. When controlling for diagnosis, surgical approach, emergent status, age, and surgical cost of appendiceal surgery, and hospital charges following appendiceal surgery were $4280 higher for PS than GS (95% CI: 3874-4687). CONCLUSIONS: The total charge for operations for appendiceal disease is significantly higher for PS compared to GS. Pediatric surgeons had increased surgical charges compared to GS but decreased radiology charges. The specific reasons for these differences are not clearly delineated in this data set and persist after controlling for relevant covariates. However, these data demonstrate that increasing value in pediatric appendicitis may require specialty-based targets.

Anesthesia and pain management of pediatric cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy has shown to improve survival in patients with extensive or refractory abdominal tumors of many different histologies. Postoperative pain control can be challenging as the surgical procedure is performed through a midline laparotomy incision from xiphoid to symphysis pubis, and patients are usually nothing by mouth for the first 8-10 postoperative days. AIMS: We present the anesthetic management and postoperative pain control strategies for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy using a multimodal, opioid-sparing, and total intravenous anesthetic technique with a tunneled thoracic epidural. METHODS: A single institution retrospective review of anesthetic management, intraoperative fluid and blood administration, and postoperative pain control for pediatric patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy between July 2018 and December 2020 was conducted. We employed a novel anesthetic and analgesia protocol consisting of premedication with gabapentin followed by intraoperative infusions of propofol, dexmedetomidine, ketamine, and cisatracurium. A tunneled thoracic epidural catheter was placed for management of pain. RESULTS: We reviewed and analyzed the first 25 patient records. The most common diagnosis was desmoplastic small round cell tumor (n = 12). Median age of patients was 14 years (range 21 months-22 years). All patients were extubated in the operating room and no patients required reintubation. There were no incidences of acute kidney injury. Epidural infusions were used for a median of 8 days (range 2-14 days). Median postoperative intravenous opioid use (morphine equivalent) through postoperative day 10 was 0.02 mg/kg/day (range 0-0.86 mg/kg/day) administered for a median of 2 days (range 0-17 days). Nine patients (36%) did not require any intravenous opioids in the postoperative period. CONCLUSIONS: Utilizing a multimodal, opioid-sparing, total intravenous anesthetic technique in conjunction with a tunneled thoracic epidural catheter, we were able to avoid the need for postoperative mechanical ventilation and minimize both intraoperative and postoperative opioid requirements.

Costs and recurrence of inguinal hernia repair in premature infants during neonatal admission.

BACKGROUND: Timing of inguinal hernia repair (IHR) in premature infants remains variable, yet the impact of IHR timing on procedure costs and recurrence is unclear. We sought to compare cost and recurrence rates of IHR in premature infants based on timing of repair. METHODS: We performed a retrospective cohort study using MarketScan insurance claims data from 2007 to 2018 to evaluate IHR occurring within 365 days of birth in preterm infants (gestational age [GA]<37 weeks at birth). Patients were stratified based on timing of IHR: those occurring during and after neonatal discharge. Hernia recurrences within one year following IHR were identified. Patient demographic characteristics and costs were compared between groups. Time to recurrence and cumulative recurrence hazards were estimated using Kaplan Meier analysis and Cox proportional hazards regression. RESULTS: We identified 3,662 preterm infants with IHR within 365 days of birth; 1,054(28.8%) occurred early. Infants with IHR during NICU stay were more likely to have GA at birth≤32 weeks (74.7% vs. 37.2%; p<0.01) and birthweight<1500 g (83.0% vs. 40.3%; p<0.01) compared to post-NICU IHR. The hernia recurrence rate was higher and total procedure costs lower in early IHR. Early IHR (HR:1.86, 95% CI: 1.56-2.22), incarcerated/strangulated hernia (HR:1.86, 95% CI:1.49-2.32), GA≤32 weeks (HR: 1.40, 95% CI: 1.19-1.65), and congenital anomalies (HR: 1.32, 95% CI: 1.12-1.57) were predictors of hernia recurrence. CONCLUSION: Using insurance claims data, IHR performed during initial neonatal admission was associated with lower cost, but higher recurrence rate, when compared to delayed repairs in preterm infants. TYPE OF STUDY: Retrospective study LEVEL OF EVIDENCE: Level III.

Cost of Pediatric Trauma: A Comparison of Non-Accidental and Accidental Trauma in Pediatric Patients.

BACKGROUND: Nonaccidental trauma (NAT) affects >100,000 children in the United States every year and is associated with significant mortality and morbidity. Little is known about the financial burden of NAT, particularly in comparison to accidental trauma (AT). We sought to compare hospital charges and outcomes between children presenting with NAT and AT. METHODS: Pediatric (<16 y) trauma hospitalizations from 2006 to 2018 were identified using the Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (NIS) and Kid's Inpatient Sample (KID) databases. Hospitalizations were identified as NAT or AT based on ICD codes. Discharge weights were used to obtain national estimates and standardize them across the different sampling structures. Outcomes (hospital charges, length of stay (LOS), and mortality) were compared, and multivariate regression analyses were used to assess independent predictors of hospital charges and mortality. RESULTS: Fifty-eight Thousand Two Hundred Seventy-five pediatric hospitalizations were included with 17,954 (0.3%) categorized as NAT. Children with NAT were younger, more female, less likely to identify as White, and more under public insurance than those with AT. Hospital charges were significantly higher in patients with NAT ($27,100 versus $19,900, P < 0.0001). Mortality (4.9% versus 0.0%, P < 0.0001) and LOS (3.2 d versus 1.5 d, P < 0.0001) were significantly higher among patients with NAT. Multivariable regression analyses identified NAT as a predictor of higher hospital charges, mortality, and LOS. CONCLUSIONS: Nonaccidental trauma in pediatric patients is associated with significantly higher hospital charges, mortality, and LOS than accidental trauma. Ongoing research focused on the relative impact of known risk factors and resource utilization is needed.

Childhood Drownings: An Opportunity for Injury Prevention in a Resource-Limited Setting.

INTRODUCTION: Drowning is a public health problem that is under-reported in Africa. We sought to evaluate the epidemiology and risk factors for drownings in Malawi. METHODS: We performed a retrospective review of all pediatric (≤15 years old) patients who presented following a drowning incident to Kamuzu Central Hospital in Lilongwe, Malawi, from 2009-19. Demographics and outcomes were compared between survivors and non-survivors. Logistic multivariate regression analysis was used to identify factors associated with increased odds of mortality. RESULTS: There were 156 pediatric drowning victims during the study period. The median age at presentation was 3 (IQR: 2-7 years). Survivors were younger [median age: 2 years (IQR: 2-5) vs. 5 years (IQR: 2-10), p = 0.004], with a higher proportion of drownings occurring at home (85.6% vs. 58.3%, p = 0.001) compared to non-survivors. Patients who had a drowning event at a public space had increased odds of mortality (OR 8.17, 95% CI 2.34-28.6). Patients who were transferred (OR 0.03, 95% CI 0.003-0.25) and had other injuries (OR 0.20, 95% CI 0.06-0.70) had decreased odds of mortality following drowning. CONCLUSION: Over half of pediatric drowning victims at a tertiary-care facility in Malawi survived. Drowning survivors were significantly younger, more likely to have drowned at home, and transported by private vehicles and minibus than non-survivors. There is a need for scalable, cost-effective drowning prevention strategies that focus on water safety education and training community members and police officers in basic life support and resuscitation.

Retrospective observational studies in ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society (CTOS) community of experts on the minimum requirements for the evaluation of activity of systemic treatments.

BACKGROUND: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. METHODS: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021). RESULTS: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. CONCLUSIONS: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.

Systematic Improvement in the Patient Transfer Process to a Tertiary Care Children's Hospital.

OBJECTIVE: Interfacility transfer of pediatric patients to a children's hospital is a complex process that can be time consuming and dissatisfying for referring providers. We aimed to improve the efficiency of communication and acceptance for interfacility transfers to our hospital. METHODS: We implemented iterative improvements to the process in 2 phases from 2013 to 2016 (pediatric medicine) and 2019 to 2022 (pediatric critical care and surgery). Key interventions included creation of a hospitalist position to manage transfers with broad ability to accept patients and transition to direct phone access for transfer requests to streamline connection. Effective initiatives from Phase 1 were adapted and spread to the other services in Phase 2. Data were manually extracted monthly from call transcripts and monitored by using statistical process control (SPC) charts. Primary outcome measures were time from call to connection to a provider and number of providers added to the call before making a disposition decision. RESULTS: Average time from call initiation to provider connection for pediatric medicine calls decreased from 11 minutes to 5 minutes. The average number of internal physicians on each call before acceptance decreased from 2.1 to 1.3. In Phase 2, time to provider connection decreased from 11 to 4 minutes for pediatric critical care calls and 16 to 5 minutes for pediatric surgery calls. CONCLUSIONS: We streamlined the process of accepting incoming transfer requests throughout our children's hospital. Prioritizing direct communication led to efficient disposition decisions and progression toward transfer and was effective for multiple service lines.

Surgical outcomes and survival of adrenocortical carcinoma between children and adults.

INTRODUCTION: Adrenocortical carcinoma (ACC) is associated with poor outcomes. We compared surgical outcomes between children and adult; and identified factors independently associated with survival. METHODS: Using the National Cancer Database, children and adults with ACC who underwent surgery between 2004 and 2016 were identified. We compared outcomes and survival between groups. Cox regression analysis was performed to identify predictors of survival. RESULTS: Of 2553 patients, 2.8% were children. A higher proportion of children were Hispanic (19.1%vs.6.6%) and covered by government insurance (45.1%vs.35.8%) than adults. More pediatric patients received lymphadenectomy and chemotherapy than adults. Pediatric patients had better survival at 1 -(91.4%; 95%CI: 81.2%-96.0% vs.79.6%; 95%CI: 77.9%-81.1%) and 5-years (60.6%; 95%CI:47.5%-71.3% vs.44.9%; 95%CI 42.7%- 47.0) (p = 0.0016). Age≥18 (HR: 2.21(1.50-3.27)), metastatic disease at diagnosis (HR: 3.51(3.04-4.04)), and receipt of lymphadenectomy (HR: 1.30(1.14-1.48)) were independently associated with worse survival. CONCLUSIONS: Children with ACC had better survival than adults. Factors independently associated with worse survival included older age, metastatic disease, and receipt of lymph node surgery.