Lymph node metastases in paediatric and young adult patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS): Findings from Children's Oncology Group (COG) study ARST0332.

PURPOSE: The aim of this paper is to better define the clinical features and outcomes of young patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) with regional and distant lymph node (LN) metastases treated in a standardised fashion, we analysed LN involvement in COG study ARST0332, which evaluated a risk-based treatment strategy for young patients with all stages of NRSTS. PATIENTS AND METHODS: Patients <30 years old with newly diagnosed NRSTS and LN metastases enrolled on ARST0332 were studied. Regional LN sampling was required for those with epithelioid sarcoma, clear cell sarcoma or clinically/radiographically enlarged LNs. Tumour features and extent of pre-enrolment resection determined treatment, including chemotherapy, radiotherapy, and delayed surgery. Recommendations for LN metastases included LN dissection at the time of primary tumour resection and dose-adapted radiotherapy based on extent of LN resection. RESULTS: Twenty of 529 eligible and evaluable ARST0332 patients with NRSTS had LN metastases; epithelioid sarcoma had the highest incidence (18%, 5 of 28). Pre-treatment imaging identified LN enlargement in 19 of 20 patients; 1 had no pre-treatment LN imaging. At 6.9 years median follow-up for surviving patients, 5-year overall survival was 85.7% (95% CI: 33.4%, 97.9%) for seven patients with isolated LN metastases and 15.4% (95% CI: 2.5%, 38.8%) for 13 patients with additional extranodal metastases. LN recurrence occurred in only one patient without LNs sampled at initial diagnosis. CONCLUSION: LN metastases occur in about 4% of paediatric/young adult NRSTS, are limited to a few histologic subtypes, and are rare in patients who did not have clinical or imaging evidence of lymphadenopathy, suggesting that biopsies of non-enlarged LNs are not necessary to identify occult involvement. Patients with isolated LN metastases have high 5-year overall survival (∼85%) and should be treated with curative intent. GOV REGISTRY NO: NCT00346164.

The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma.

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have direct clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.

Multi-site desmoplastic small round cell tumors are genetically related and immune-cold.

Desmoplastic small round cell tumor (DSRCT) is a highly aggressive soft tissue sarcoma that is characterized by the EWSR1-WT1 fusion protein. Patients present with hundreds of tumor implants in their abdominal cavity at various sites. To determine the genetic relatedness among these sites, exome and RNA sequencing were performed on 22 DSRCT specimens from 14 patients, four of whom had specimens from various tissue sites. Multi-site tumors from individual DSRCT patients had a shared origin and were highly related. Other than the EWSR1-WT1 fusion, very few secondary cancer gene mutations were shared among the sites. Among these, ARID1A, was recurrently mutated, which corroborates findings by others in DSRCT patients. Knocking out ARID1A in JN-DSRCT cells using CRISPR/CAS9 resulted in significantly lower cell proliferation and increased drug sensitivity. The transcriptome data were integrated using network analysis and drug target database information to identify potential therapeutic opportunities in EWSR1-WT1-associated pathways, such as PI3K and mTOR pathways. Treatment of JN-DSRCT cells with the PI3K inhibitor alpelisib and mTOR inhibitor temsirolimus reduced cell proliferation. In addition, the low mutation burden was associated with an immune-cold state in DSRCT. Together, these data reveal multiple genomic and immune features of DSRCT and suggest therapeutic opportunities in patients.

Examination of Intersectionality and the Pipeline for Black Academic Surgeons.

IMPORTANCE: The lack of underrepresented in medicine physicians within US academic surgery continues, with Black surgeons representing a disproportionately low number. OBJECTIVE: To evaluate the trend of general surgery residency application, matriculation, and graduation rates for Black trainees compared with their racial and ethnic counterparts over time. DESIGN, SETTING, AND PARTICIPANTS: In this nationwide multicenter study, data from the Electronic Residency Application Service (ERAS) for the general surgery residency match and Graduate Medical Education (GME) surveys of graduating general surgery residents were retrospectively reviewed and stratified by race, ethnicity, and sex. Analyses consisted of descriptive statistics, time series plots, and simple linear regression for the rate of change over time. Medical students and general surgery residency trainees of Asian, Black, Hispanic or Latino of Spanish origin, White, and other races were included. Data for non-US citizens or nonpermanent residents were excluded. Data were collected from 2005 to 2018, and data were analyzed in March 2021. MAIN OUTCOMES AND MEASURES: Primary outcomes included the rates of application, matriculation, and graduation from general surgery residency programs. RESULTS: Over the study period, there were 71 687 applicants, 26 237 first-year matriculants, and 24 893 graduates. Of 71 687 applicants, 24 618 (34.3%) were women, 16 602 (23.2%) were Asian, 5968 (8.3%) were Black, 2455 (3.4%) were Latino, and 31 197 (43.5%) were White. Women applicants and graduates increased from 29.4% (1178 of 4003) to 37.1% (2293 of 6181) and 23.5% (463 of 1967) to 33.5% (719 of 2147), respectively. When stratified by race and ethnicity, applications from Black women increased from 2.2% (87 of 4003) to 3.5% (215 of 6181) (P < .001) while applications from Black men remained unchanged (3.7% [150 of 4003] to 4.6% [284 of 6181]). While the matriculation rate for Black women remained unchanged (2.4% [46 of 1919] to 2.3% [52 of 2264]), the matriculation rate for Black men significantly decreased (3.0% [57 of 1919] to 2.4% [54 of 2264]; P = .04). Among Black graduates, there was a significant decline in graduation for men (4.3% [85 of 1967] to 2.7% [57 of 2147]; P = .03) with the rate among women remaining unchanged (1.7% [33 of 1967] to 2.2% [47 of 2147]). CONCLUSIONS AND RELEVANCE: Findings of this study show that the underrepresentation of Black physicians at every stage in surgical training pipeline persists. Black men are especially affected. Identifying factors that address intersectionality and contribute to the successful recruitment and retention of Black trainees in general surgery residency is critical for achieving racial and ethnic as well as gender equity.

Analysis of a Modified Two-Stage Approach to Ileal Pouch-Anal Anastomosis Without Fecal Diversion in Pediatric Patients.

BACKGROUND: Fecal diversion after ileal pouch anal anastomosis (IPAA) in children with ulcerative colitis (UC) remains controversial. We hypothesize that a modified two-stage IPAA omitting diverting ileostomy (DI) after IPAA, found to be safe in adults, would produce similar results in children. METHODS: Retrospective, single-institution study of children (≤18 years) undergoing staged total proctocolectomy with IPAA from 2014 to 2020. Traditional two-stage and three-stage approaches including DI after IPAA were compared to two-stage approach without DI. RESULTS: 32 patients were included; of these, 7 (22%), 14 (44%), and 11 (34%) patients underwent traditional two-stage, modified two-stage, or three-stage IPAA, respectively. Following IPAA, modified two-stage patients had shorter operative time, decreased opioid utilization, quicker return to regular diet, and shorter stoma duration. After IPAA, there was similar postoperative length of stay, complication rates, readmissions, visits to the emergency department, or unplanned return to the operating room (OR) within 30 days. Anastomotic leak occurred in 2 patients; both were managed nonoperatively without evidence of pouch dysfunction. CONCLUSION: Modified two-stage IPAA with omission of DI after the IPAA stage is safe to perform in pediatric UC patients. Prospective studies with larger sample sizes are needed to identify risk factors associated with operative complications.

Implementation of Electronic Clinical Decision Support Tools for Antibiotic Stewardship in Pediatric Appendicitis.

BACKGROUND: The efficacy of clinical decision support (CDS) tools to promote antibiotic stewardship in pediatric appendicitis remains poorly understood. Here, we developed an electronic order panel (OP) to assist with decreased utilization of extended spectrum antibiotics. METHODS: Retrospective review of patients (≤18 years) at a single institution from May 2018 to October 2019 treated with ≥1 dose of preferred (narrow) or nonpreferred (broad-spectrum) antibiotics was performed, and they were categorized as pre- (PIC) or postimplementation cohorts (PISC). RESULTS: Of 234 encounters, 170 (73%) and 107 (46%) received preferred and nonpreferred antibiotics, respectively. Postimplementation cohort encounters had a sustained 50% increase in preferred antibiotic use compared to PIC (92% vs 42%, P = .014). Order panel utilization accounted for 31% of overall encounters and 44% of PISC encounters. CONCLUSION: Despite sustained improvement in antibiotic stewardship, OP utilization remains low. The use of CDS tools may not be a good process measure for quality improvement.

Factors associated with inguinal hernia repair in premature infants during neonatal admission.

INTRODUCTION: Timing of inguinal hernia repair (IHR) in premature infants is variable and influenced by surgeon preference and complication profile. The purpose of this study was to evaluate factors related to early IHR, defined as hernia repair during initial neonatal admission, in premature infants. METHODS: Neonatal hospitalizations of premature infants (gestational age at birth < 37 weeks and ≤ 28 days old at admission), with a diagnosis of inguinal hernia from 2010 to 2017 in HCUP National Inpatient Sample and Kid's Inpatient Sample databases were evaluated. Multivariable Cox proportional hazard models was used to estimate associations between demographics, additional procedures, hospital characteristics, and early IHR. RESULTS: Overall, 30,298 neonatal hospitalizations of premature infants with inguinal hernia were identified; 13,228 (43.3%) underwent early IHR. Early IHR was more likely with older gestational age at birth (35-36 weeks vs < 24 weeks, HR 6.05, 95% CI 4.17, 8.79), female sex (HR 1.20, 95% CI 1.07, 1.34), and undergoing concomitant gastrostomy (HR 2.51, 95% CI 1.72, 3.66). Non-Hispanic Black infants (HR 0.84, 95% CI 0.75, 0.95), infants at urban non-teaching hospitals (HR 0.15, 95% CI 0.07, 0.33), and infants at rural hospitals (HR 0.81, 95% CI 0.70, 0.97) were less likely to undergo early IHR. CONCLUSIONS: Using a nationally representative database, early IHR in premature neonates was more commonly performed in non-Hispanic White, female neonates and at urban teaching hospitals. Patient race and hospital type were determinants of early IHR in premature neonates. There is a need to further evaluate the impact of race and socioeconomic factors on outcomes of common pediatric operations like inguinal hernia repairs. LEVEL OF EVIDENCE: Level III.

Characteristics and predictors of mortality in-hospital mortality following burn injury in infants in a resource-limited setting.

PURPOSE: Burn outcome data in infants is lacking from sub-Saharan Africa. We, therefore, sought to assess the characteristics and predictors of in-hospital burn mortality in a resource-limited setting. METHODS: We performed a retrospective study of the prospectively collected Burn Injury Surveillance database from June 2011 to December 2019. We performed bivariate analysis and Poisson regression to assess risk factors for mortality in our infant burn population. RESULTS: 115 (7.3%) infants met inclusion criteria. The median age of 8 months (IQR: 6-10) and primarily male (n = 67, 58.8%). Most burns were from scald (n = 62, 53.9%). Infant burn mortality was 12.2%. Poisson multivariable regression to determine burn mortality risk in infants showed that increased %TBSA burns (RR 1.04, 95% CI 1.01-1.07) and flame burns (RR 3.08, 95%CI 1.16-8.16) had a higher risk of mortality. Having surgery reduced the relative risk of death for infants with burns. CONCLUSION: We show that factors that increase infant burn mortality risk include percent total body surface area burn, flame burn mechanism, and lack of operative intervention. Increasing burn operative capability, particularly for infants and other children, is imperative.

The Impact of General Surgeons on Pediatric Surgical Practice in North Carolina: The Reality of Pediatric Surgical Care Delivery.

OBJECTIVE: The aim of this study was to define the training background of the actual surgical workforce providing care to pediatric patients in North Carolina (NC). BACKGROUND: Due to database limitations, pediatric surgical workforce studies have not included general surgeons (GS) who operate on children. Defining the role of GS in care delivery affects policy for clinical care and general and pediatric surgical training. METHODS: We performed a retrospective review of the NC Hospital Discharge Database (2011-2017), including pediatric patients (<18 years) undergoing the most frequent general surgery procedures. Descriptive and correlational analysis over surgical provider [Pediatric Surgeon (PS), GS], and other specialties (OSS), was performed using logistic regression modeling to identify factors associated with surgery by a PS. RESULTS: Of the 57,265 discharges analyzed, pediatric, general, and other specialty surgeons operated on 25,514 (44.6%), 18,581 (32.5%), and 9049 (15.8%), respectively. In a logistic regression model, PS had lower odds of operating on older patients [odds ratio (OR) 0.9, 95% confidence interval (CI) 0.90-0.91]. However, PS were more likely to operate on female patients (OR 1.58, 95% CI 1.53-1.65), Black (OR 1.49, 95% CI 1.43-1.56), and other minority patients (OR 1.23, 95% CI 1.17-1.29) when compared to white patients. PS were also more likely to operate on patients with private insurance (OR 1.38, 95% CI 1.33-1.43) compared to government insurance, and patients undergoing emergency surgery (OR 1.44, 95% CI 1.38-1.50). CONCLUSION: In NC, general surgeons performed a third of the operations on children. After controlling for covariates, pediatric surgeons in NC are more likely to operate on minority and emergency surgery patients, and this is the first study to describe this important practice pattern.

Surgical outcomes and survival rates of colon cancer in children and young adults.

INTRODUCTION: Colon cancer in children and young adults is rare. We sought to compare outcomes and survival between patients ≤and>25 years of age with colon cancer. METHODS: Using the National Cancer Database, patients with colon cancer between 2004 and 2016 were identified. We included patients with histological codes consistent with invasive colon adenocarcinoma and excluded those missing data about treatment. Post-surgical outcomes and survival were compared. RESULTS: Of 531,462 patients meeting criteria, 947 were ≤25 years. Patients ≤25 had more advanced disease (stage III:44.4%vs33.4%, stage IV:27.5%vs.15.3%) and higher rates of total colectomy (8.9%vs.2.7%) and proctocolectomy (5.0%vs.0.0%) than those >25 years. Stage for stage, 5-year survival was higher in patients ≤25 than those >25years. On multivariate regression, age was not associated with increased risk of mortality while male sex and uninsured status were. CONCLUSIONS: Despite presenting with more advanced disease, patients ≤25 years with colon cancer had better survival than those >25 years.

Local Control For High-Grade Nonrhabdomyosarcoma Soft Tissue Sarcoma Assigned to Radiation Therapy on ARST0332: A Report From the Childrens Oncology Group.

PURPOSE: The ARST0332 trial for pediatric and young adults with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) used risk-based treatment including primary resection with lower-than-standard radiation doses to optimize local control (LC) while minimizing long-term toxicity in those requiring radiation therapy (RT). RT for high-grade NRSTS was based on extent of resection (R0: negative margins, R1: microscopic margins, R2/U: gross disease/unresectable); those with >5 cm tumors received chemotherapy (CT; ifosfamide/doxorubicin). This analysis evaluates LC for patients assigned to RT and prognostic factors associated with local recurrence (LR). METHODS AND MATERIALS: Patients aged <30 years with high-grade NRSTS received RT (55.8 Gy) for R1 ≤5 cm tumor (arm B); RT (55.8 Gy)/CT for R0/R1 >5 cm tumor (arm C); or neoadjuvant RT (45 Gy)/CT plus delayed surgery, CT, and postoperative boost to 10.8 Gy R0 <5 mm margins/R1 or 19.8 Gy for R2/unresected tumors (arm D). RESULTS: One hundred ninety-three eligible patients had 24 LRs (arm B 1/15 [6.7%], arm C 7/65 [10.8%], arm D 16/113 [14.2%]) at median time to LR of 1.1 years (range, 0.11-5.27). Of 95 eligible for delayed surgery after neoadjuvant therapy, 89 (93.7%) achieved R0/R1 margins. Overall LC after RT were as follows: R0, 106 of 109 (97%); R1, 51 of 60 (85%); and R2/unresectable, 2 of 6 (33%). LR predictors include extent of delayed resection (P <.001), imaging response before delayed surgery (P < .001), histologic subtype (P <.001), and no RT (P = .046). The 5-year event-free survival was significantly lower (P = .0003) for patients unable to undergo R0/R1 resection. CONCLUSIONS: Risk-based treatment for young patients with high-grade NRSTS treated on ARST0332 produced very high LC, particularly after R0 resection (97%), despite lower-than-standard RT doses. Neoadjuvant CT/RT enabled delayed R0/R1 resection in most patients and is preferred over adjuvant therapy due to the lower RT dose delivered.

Trends and outcomes following intentional injuries in pediatric patients in a resource-limited setting.

INTRODUCTION: Intentional injuries pose a significant, yet underreported threat to children in sub-Saharan Africa. We sought to evaluate intentional injuries trends and compare outcomes between unintentional and intentional injuries in pediatric patients presenting to a tertiary care facility in Malawi. METHODS: We performed a review of pediatric (≤15 years old) trauma patients presenting to Kamuzu Central Hospital, Lilongwe, Malawi, from 2009 to 2018. Patient characteristics and outcomes were compared based on the injury intent, using bivariate and multivariate regression analysis. RESULTS: We included 42,600 pediatric trauma patients in the study. Intentional injuries accounted for 5.9% of all injuries. Children with intentional injuries were older (median, 10 vs. 6 years, p < 0.001), more likely to be male (68.4% vs. 63.9%, p < 0.001), and had significantly lower mortality (0.8% vs. 1.4%, p = 0.02) than those with unintentional injuries There was no significant change in the incidence of or mortality associated with intentional injuries. On multivariable regression, increasing age, head and cervical spine injury, night-time presentation, penetrating injury, and alcohol use were associated with increased risk of intentional harm. CONCLUSION: Intentional injury remains a significant cause of pediatric trauma in Malawi without decreasing hospital presentation incidence or mortality. In sub-Saharan Africa, there is a need to develop comprehensive plans and policies to protect children. LEVEL OF EVIDENCE: II.

Metabolic response as assessed by 18 F-fluorodeoxyglucose positron emission tomography-computed tomography does not predict outcome in patients with intermediate- or high-risk rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

BACKGROUND: Strategies to optimize management in rhabdomyosarcoma (RMS) include risk stratification to assign therapy aiming to minimize treatment morbidity yet improve outcomes. This analysis evaluated the relationship between complete metabolic response (CMR) as assessed by 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET) imaging and event-free survival (EFS) in intermediate-risk (IR) and high-risk (HR) RMS patients. METHODS: FDG-PET imaging characteristics, including assessment of CMR and maximum standard uptake values (SUVmax) of the primary tumor, were evaluated by central review. Institutional reports of SUVmax were used when SUVmax values could not be determined by central review. One hundred and thirty IR and 105 HR patients had FDG-PET scans submitted for central review or had SUVmax data available from institutional report at any time point. A Cox proportional hazards regression model was used to evaluate the relationship between these parameters and EFS. RESULTS: SUVmax at study entry did not correlate with EFS for IR (p = 0.32) or HR (p = 0.86) patients. Compared to patients who did not achieve a CMR, EFS was not superior for IR patients who achieved a CMR at weeks 4 (p = 0.66) or 15 (p = 0.46), nor for HR patients who achieved CMR at week 6 (p = 0.75) or 19 (p = 0.28). Change in SUVmax at week 4 (p = 0.21) or 15 (p = 0.91) for IR patients or at week 6 (p = 0.75) or 19 (p = 0.61) for HR patients did not correlate with EFS. CONCLUSION: Based on these data, FDG-PET does not appear to predict EFS in IR or HR-RMS. It remains to be determined whether FDG-PET has a role in predicting survival outcomes in other RMS subpopulations.

Sclerosing Encapsulating Peritonitis in a Pediatric Patient Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Sclerosing encapsulating peritonitis (SEP) is a rare chronic inflammatory condition characterized by small bowel encapsulation by a thick fibrocollagenous membrane. Patients with SEP often present with nonspecific symptoms, such as abdominal pain and distension, however some patients may present with symptoms suggestive of intestinal obstruction. Secondary SEP has been reported in patients undergoing peritoneal dialysis and has been recently described in adults following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). OBSERVATIONS: We report a clinical case of a 13-year-old female who presented with worsening abdominal pain and distension and persistent emesis who was found to have SEP 13 months following CRS and HIPEC for management of desmoplastic small round cell tumor and subsequently required operative intervention. CONCLUSION: Although there have been published reports of adult patients experiencing cases of SEP following CRS/HIPEC, this is the first published case of secondary SEP occurring in a pediatric oncology patient.

The APSA Board of Governors enthusiastically endorses the position paper ``Diversity, Equity, and Inclusion: A Strategic Priority for the American Pediatric Surgical Association''.

This Commentary by the APSA Board of Governors enthusiastically endorses the position paper "Diversity, Equity, and Inclusion: A Strategic Priority for the American Pediatric Surgical Association".

An enhanced recovery after surgery pathway in pediatric colorectal surgery improves patient outcomes.

INTRODUCTION: Enhanced recovery after surgery (ERAS) pathways in adult colorectal surgery are known to reduce complications, readmissions, and length of stay (LOS). However, there is a paucity of ERAS data for pediatric colorectal surgery. METHODS: A 2014-2018 single-institution, retrospective cohort study was performed on pediatric colorectal surgery patients (2-18 years) pre- and post-ERAS pathway implementation. Bivariate analysis and linear regression were used to determine if ERAS pathway implementation reduced total morphine milligram equivalents per kilogram (MME/kg), LOS, and time to oral intake. RESULTS: 98 (70.5%) and 41 (29.5%) patients were managed with ERAS and non-ERAS pathways, respectively. There was no statistical difference in age, sex, diagnosis, or use of laparoscopic technique between cohorts. The ERAS cohort experienced a significant reduction in total MME/kg, Foley duration, time to oral intake, and LOS with no increase in complications. The presence of an ERAS pathway reduced the total MME/kg (-0.071, 95% CI -0.10, -0.043) when controlling for covariates. CONCLUSION: The use of an ERAS pathway reduces opioid utilization, which is associated with a reduction in LOS and expedites the initiation of oral intake, in colorectal pediatric surgery patients. Pediatric ERAS pathways should be incorporated into the care of pediatric patients undergoing colorectal surgery. LEVEL OF EVIDENCE: Level III evidence. TYPE OF STUDY: Retrospective cohort study.

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone. METHODS: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867. FINDINGS: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related. INTERPRETATION: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up. FUNDING: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.

Colon Cancer in Patients Under 25 Years Old: A Different Disease?

BACKGROUND: The aim of this study was to compare the stage-for-stage overall (OS) and recurrence-free (RFS) survival between adult and pediatric/adolescent colon cancer patients. STUDY DESIGN: A retrospective review of pediatric/adolescent patients less than 25 years old, treated between 1991 and 2017 at University of Texas MD Anderson Cancer Center, was compared with a prospectively maintained database of adult patients. Outcomes variables were compared, and OS and RFS were estimated using the Kaplan-Meier method and compared between groups using the log rank test and multivariable Cox models. RESULTS: The cohort contained 94 pediatric patients and 765 adult patients. Overall, the 3-year OS rates for adult and pediatric patients, respectively, were 90% and 41.92% (95% CI 87% to 92%) (p < 0.0001), and the 3-year RFS rates were 78% and 32% (p < 0.0001). The stage-for-stage 5-year OS rates for adult vs pediatric patients were: Stage 1: 96% vs 100% (p = 0.793); stage 2: 90% vs 64% (p < 0.0001); stage 3: 85% vs 58% (p < 0.0001); stage 4; 55% vs 16% (p < 0.0001). The stage-for-stage 5-year RFS rates for adults vs children were: stage 1: 95% vs 100%; stage 2: 85% vs 55% (p = 0.0002); stage 3: 73% vs 31% (p < 0.0001); stage 4: 27% vs 5% (p < 0.0001). Pediatric/adolescent patients had a higher risk of recurrence or death than adult patients on multivariate analysis (hazard ratio [HR] 2.312, 95% CI: 1.615 to 3.313 (p < 0.0001). Peritoneal metastasis was significantly higher in pediatric patients. (p = 0.00001) CONCLUSIONS: Stage-for-stage, pediatric/adolescent patients had shorter 3- and 5-year OS and RFS rates than adult patients. Peritoneal disease and carcinomatosis were significantly higher in pediatric, adolescent, and young adult patients less than 25 years old. Predisposing conditions, such as polyposis or congenital colon disease, did not contribute to this difference.