Imaging adjuvants in pediatric surgical oncology.

Surgery is a crucial component of pediatric cancer treatment, but conventional methods may lack precision. Image-guided surgery, including fluorescent and radioguided techniques, offers promise for enhancing tumor localization and facilitating precise resection. Intraoperative molecular imaging utilizes agents like indocyanine green to direct surgeons to occult deposits of tumor and to delineate tumor margins. Next-generation agents target tumors directly to improve specificity. Radioguided surgery, employing tracers like metaiodobenzylguanidine (MIBG), complements fluorescent techniques by allowing for detection of tumors at a greater depth. Dual-labeled agents combining both modalities are under development. Three-dimensional modeling and virtual/augmented reality aid in preoperative planning and intraoperative guidance. The above techniques show great promise to benefit patients with pediatric tumors, and their continued development will almost certainly improve surgical outcomes.

Long-term outcomes and patterns of relapse in patients with bilateral Wilms tumor or bilaterally predisposed unilateral Wilms tumor, a report from the COG AREN0534 study.

The objective of this study is to report the long-term timing and patterns of relapse for children enrolled in Children's Oncology Group AREN0534, a multicenter phase III clinical trial conducted from 2009 to 2015. Participants included children with bilateral Wilms tumor (BWT) or unilateral WT with genetic predisposition to develop BWT followed for up to 10 years. Smoothed hazard (risk) functions for event-free survival (EFS) were plotted so that the timing of events could be visualized, both overall and within pre-specified groups. Two hundred and twenty-two children (190 BWT and 32 unilateral WT with BWT predisposition) were followed for a median of 8.6 years. Fifty events were reported, of which 48 were relapse/progression. The overall 8-year EFS was 75% (95% confidence interval: 69%-83%). The highest risk for an EFS event was immediately after diagnosis with a declining rate over 2 years. A second peak of events was observed around 4 years after diagnosis, and a small number of events were reported until the end of the follow-up period. In subset analyses, later increases in risk were more commonly observed in patients with female sex, anaplastic histology, negative lymph nodes or margins, and favorable histology Wilms tumor patients with post-chemotherapy intermediate risk. Among relapses that occurred after 2 years, most were to the kidney. These patterns suggest that late events may be second primary tumors occurring more commonly in females, although more investigation is required. Clinicians may consider observation of patients with BWT beyond 4 years from diagnosis.

Youth Suicide and Preceding Mental Health Diagnosis.

Importance: Suicide is a leading cause of death among US youths, and mental health disorders are a known factor associated with increased suicide risk. Knowledge about potential sociodemographic differences in documented mental health diagnoses may guide prevention efforts. Objective: To examine the association of documented mental health diagnosis with (1) sociodemographic and clinical characteristics, (2) precipitating circumstances, and (3) mechanism among youth suicide decedents. Design, Setting, and Participants: This retrospective, cross-sectional study of youth suicide decedents aged 10 to 24 years used data from the Centers for Disease Control and Prevention National Violent Death Reporting System from 2010 to 2021. Data analysis was conducted from January to November 2023. Exposures: Sociodemographic characteristics, clinical characteristics, precipitating circumstances, and suicide mechanism. Main Outcomes and Measures: The primary outcome was previously documented presence of a mental health diagnosis. Associations were evaluated by multivariable logistic regression. Results: Among 40 618 youth suicide decedents (23 602 aged 20 to 24 years [58.1%]; 32 167 male [79.2%]; 1190 American Indian or Alaska Native [2.9%]; 1680 Asian, Native Hawaiian, or Other Pacific Islander [4.2%]; 5118 Black [12.7%]; 5334 Hispanic [13.2%]; 35 034 non-Hispanic; 30 756 White [76.1%]), 16 426 (40.4%) had a documented mental health diagnosis and 19 027 (46.8%) died by firearms. The adjusted odds of having a mental health diagnosis were lower among youths who were American Indian or Alaska Native (adjusted odds ratio [aOR], 0.45; 95% CI, 0.39-0.51); Asian, Native Hawaiian, or Other Pacific Islander (aOR, 0.58; 95% CI, 0.52-0.64); and Black (aOR, 0.62; 95% CI, 0.58-0.66) compared with White youths; lower among Hispanic youths (aOR, 0.76; 95% CI, 0.72-0.82) compared with non-Hispanic youths; lower among youths aged 10 to 14 years (aOR, 0.70; 95% CI, 0.65-0.76) compared with youths aged 20 to 24 years; and higher for females (aOR, 1.64; 95% CI, 1.56-1.73) than males. A mental health diagnosis was documented for 6308 of 19 027 youths who died by firearms (33.2%); 1691 of 2743 youths who died by poisonings (61.6%); 7017 of 15 331 youths who died by hanging, strangulation, or suffocation (45.8%); and 1407 of 3181 youths who died by other mechanisms (44.2%). Compared with firearm suicides, the adjusted odds of having a documented mental health diagnosis were higher for suicides by poisoning (aOR, 1.70; 95% CI, 1.62-1.78); hanging, strangulation, and suffocation (aOR, 2.78; 95% CI, 2.55-3.03); and other mechanisms (aOR, 1.59; 95% CI, 1.47-1.72). Conclusions and Relevance: In this cross-sectional study, 3 of 5 youth suicide decedents did not have a documented preceding mental health diagnosis; the odds of having a mental health diagnosis were lower among racially and ethnically minoritized youths than White youths and among firearm suicides compared with other mechanisms. These findings underscore the need for equitable identification of mental health needs and universal lethal means counseling as strategies to prevent youth suicide.

Venous Thromboembolism Prophylaxis in High-Risk Pediatric Trauma Patients.

Importance: The indications, safety, and efficacy of chemical venous thromboembolism prophylaxis (cVTE) in pediatric trauma patients remain unclear. A set of high-risk criteria to guide cVTE use was recently recommended; however, these criteria have not been evaluated prospectively. Objective: To examine high-risk criteria and cVTE use in a prospective multi-institutional study of pediatric trauma patients. Design, Setting, and Participants: This cohort study was completed between October 2019 and October 2022 in 8 free-standing pediatric hospitals designated as American College of Surgeons level I pediatric trauma centers. Participants were pediatric trauma patients younger than 18 years who met defined high-risk criteria on admission. It was hypothesized that cVTE would be safe and reduce the incidence of VTE. Exposures: Receipt and timing of chemical VTE prophylaxis. Main Outcomes and Measures: The primary outcome was overall VTE rate stratified by receipt and timing of cVTE. The secondary outcome was safety of cVTE as measured by bleeding or other complications from anticoagulation. Results: Among 460 high-risk pediatric trauma patients, the median (IQR) age was 14.5 years (10.4-16.2 years); 313 patients (68%) were male and 147 female (32%). The median (IQR) Injury Severity Score (ISS) was 23 (16-30), and median (IQR) number of high-risk factors was 3 (2-4). A total of 251 (54.5%) patients received cVTE; 62 (13.5%) received cVTE within 24 hours of admission. Patients who received cVTE after 24 hours had more high-risk factors and higher ISS. The most common reason for delayed cVTE was central nervous system bleed (120 patients; 30.2%). There were 28 VTE events among 25 patients (5.4%). VTE occurred in 1 of 62 patients (1.6%) receiving cVTE within 24 hours, 13 of 189 patients (6.9%) receiving cVTE after 24 hours, and 11 of 209 (5.3%) who had no cVTE (P = .31). Increasing time between admission and cVTE initiation was significantly associated with VTE (odds ratio, 1.01; 95% CI, 1.00-1.01; P = .01). No bleeding complications were observed while patients received cVTE. Conclusions and Relevance: In this prospective study, use of cVTE based on a set of high-risk criteria was safe and did not lead to bleeding complications. Delay to initiation of cVTE was significantly associated with development of VTE. Quality improvement in pediatric VTE prevention may center on timing of prophylaxis and barriers to implementation.

Wilms tumor characteristics, surgical management, outcomes, and chronic kidney disease in children with WAGR syndrome: A report from the International WAGR Syndrome Association survey.

INTRODUCTION: Children with WAGR (Wilms tumor, aniridia, genitourinary anomalies, and range of development delays) syndrome are predisposed to Wilms tumor (WT) and intrinsic kidney disease. Using the comprehensive International WAGR Syndrome Association (IWSA) survey of children with WAGR syndrome, we analyzed tumor characteristics, treatment and congenital risk factors, and kidney function in children with WAGR and WT. METHODS: Descriptive statistics were utilized including demographics, treatment strategies, and patient outcomes. Comparisons were made between patients with WAGR and WT to those with WAGR alone. A multivariable logistic regression was completed for risk of developing WT and to identify predictors of chronic kidney disease (CKD). RESULTS: Sixty-four of 145 children with WAGR developed WT (44.1%). Three relapsed and one died. CKD developed in five children with WAGR without WT (5/81, 6.2%), and in 34 with WAGR and WT (34/64, 28.3%). Children with WAGR and WT were younger (p = .017), and had a greater association with CKD than WAGR children without WT (p < .0001). Two children with WT required hemodialysis, and one underwent kidney transplantation. By univariate analysis, CKD at any stage was associated with complete nephrectomy for the WT surgery (p < .0001), chemotherapy duration greater than 12 months, and three-drug therapy. Upon multivariate analysis, prior nephrectomy was the only significant variable (p = .0002). CONCLUSIONS: Epidemiological analysis of children with WAGR demonstrated favorable oncologic outcomes, but high rate of early CKD in those who developed WT. Further study of the use of nephron-sparing surgery in children with WAGR and strategies to delay or treat early CKD are needed.

Current surgical approaches to pediatric renal tumors.

Pediatric renal tumors are among the most common pediatric solid malignancies. Surgical resection is a key component in the multidisciplinary therapy for children with kidney tumors. Therefore, it is imperative that surgeons caring for children with renal tumors fully understand the current standards of care in order to provide appropriate surgical expertise within this multimodal framework. Fortunately, the last 60 years of international, multidisciplinary pediatric cancer cooperative group studies have enabled high rates of cure for these patients. This review will highlight the international surgical approaches to pediatric patients with kidney cancer to help surgeons understand the key differences and similarities between the European (International Society of Pediatric Oncology) and North American (Children's Oncology Group) recommendations.

Central Venous Catheter Consideration in Pediatric Oncology: A Systematic Review and Meta-analysis From the American Pediatric Surgical Association Cancer Committee.

BACKGROUND: Tunneled central venous catheters (CVCs) are the cornerstone of modern oncologic practice. Establishing best practices for catheter management in children with cancer is essential to optimize care, but few guidelines exist to guide placement and management. OBJECTIVES: To address four questions: 1) Does catheter composition influence the incidence of complications; 2) Is there a platelet count below which catheter placement poses an increased risk of complications; 3) Is there an absolute neutrophil count (ANC) below which catheter placement poses an increased risk of complications; and 4) Are there best practices for the management of a central line associated bloodstream infection (CLABSI)? METHODS: Data Sources: English language articles in Ovid Medline, PubMed, Embase, Web of Science, and Cochrane Databases. STUDY SELECTION: Independently performed by 2 reviewers, disagreements resolved by a third reviewer. DATA EXTRACTION: Performed by 4 reviewers on forms designed by consensus, quality assessed by GRADE methodology. RESULTS: Data were extracted from 110 manuscripts. There was no significant difference in fracture rate, venous thrombosis, catheter occlusion or infection by catheter composition. Thrombocytopenia with minimum thresholds of 30,000-50,000 platelets/mcl was not associated with major hematoma. Limited evidence suggests a platelet count <30,000/mcL was associated with small increased risk of hematoma. While few studies found a significant increase in CLABSI in CVCs placed in neutropenic patients with ANC<500Kcells/dl, meta-analysis suggests a small increase in this population. Catheter removal remains recommended in complicated or persistent infections. Limited evidence supports antibiotic, ethanol, or hydrochloric lock therapy in definitive catheter salvage. No high-quality data were available to answer any of the proposed questions. CONCLUSIONS: Although over 15,000 tunneled catheters are placed annually in North America into children with cancer, there is a paucity of evidence to guide practice, suggesting multiple opportunities to improve care. LEVEL OF EVIDENCE: III. This study was registered as PROSPERO 2019 CRD42019124077.

Bilateral Wilms tumor with anaplasia: A report from the Children's Oncology Group Study AREN0534.

INTRODUCTION: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. METHODS: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. RESULTS: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months. CONCLUSION: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.

Limited English Proficiency can Negatively Impact Disease/Treatment in Children With Cancer Compared to Those Who are English Proficient-an Institutional Study.

BACKGROUND: In 2013, 25.5 million people in the United States self-identified as having limited English proficiency (LEP). LEP in adults has been associated with longer hospital stays, increased adverse events, increased emergency room visits, and decreased understanding of medications prescribed. This study aims to define the relationship between LEP and outcomes in a pediatric oncologic population. METHODS: We performed a matched case-control study utilizing data from our institutional cancer database (children

Treatment and outcomes of clear cell sarcoma of the kidney: A report from the Children's Oncology Group studies AREN0321 and AREN03B2.

BACKGROUND: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5-year event-free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk-adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH-1). Patients who had stage II/III disease received regimen I with RT. METHODS: Four-year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage-appropriate chemotherapy. RESULTS: Eighty-two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4-year EFS rate was 82.7% (95% confidence interval [CI], 74.8%-91.4%) for AREN0321 and 89.6% (95% CI, 81.3%-98.7%) for AREN03B2 only (p = .28). When combining studies, the 4-year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%-100.0%), 93.4% (95% CI, 86.4%-100.0%), 82.8% (95% CI, 74.1%-92.6%), and 58.3% (95% CI, 34%-100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. CONCLUSIONS: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin-containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced-stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365).

Clinical relevance of inflammation on rectal biopsy for Hirschsprung disease: An outcomes analysis.

OBJECTIVES: Inflammation on diagnostic rectal biopsy for children with suspected Hirschsprung disease (HSCR) is reported on pathology, and its significance is unknown. We describe the management and outcomes of a cohort with inflammation on rectal biopsy compared to those without. Specifically, to address the hypothesis that inflammation on diagnostic biopsy is associated with increased complication rates irrespective of intervention type and timing. METHODS: A single institution retrospective review of children with HSCR who underwent biopsy and endorectal pull-through (ERPT) from 2010 to 2020 was performed. The primary outcome was overall complications at 30-days following ERPT. Secondary outcomes included timing and type of operative intervention as well as postoperative enterocolitis diagnosed within 6-months of ERPT. RESULTS: Forty-nine children were identified; inflammation was present on diagnostic biopsy for 17 children. Those with inflammation were more likely to have clinical evidence of enterocolitis at the time of biopsy (p = 0.001) and were more likely to undergo leveling colostomy before ERPT (p = 0.01). Children with inflammation had a higher anastomotic leak rate (p = 0.04). Subgroup analysis of patients with inflammation undergoing primary ERPT versus leveling colostomy demonstrated no significant difference in outcomes following definitive ERPT. CONCLUSIONS: Our study suggests inflammation on diagnostic rectal biopsy for HSCR is associated with increased anastomotic leak rates. While additional prospective studies are indicated, attention to methods of mitigating inflammation and confirming its resolution before definitive pull-through may be of benefit for improving clinical outcomes in patients found with inflammation on diagnostic rectal biopsy.

Race and Ethnic Group Enrollment and Outcomes for Wilms Tumor: Analysis of the Current Era Children's Oncology Group Study, AREN03B2.

BACKGROUND: To review race and ethnic group enrollment and outcomes for Wilms tumor (WT) across all 4 risk-assigned therapeutic trials from the current era Children's Oncology Group Renal Tumor Biology and Risk Stratification Protocol, AREN03B2. STUDY DESIGN: For patients with WT enrolled in AREN03B2 (2006 to 2019), disease and biologic features, therapeutic study-specific enrollment, and event-free (EFS) and overall (OS) 4-year survival were compared between institutionally reported race and ethnic groups. RESULTS: Among 5,146 patients with WT, no statistically significant differences were detected between race and ethnic groups regarding subsequent risk-assigned therapeutic study enrollment, disease stage, histology, biologic factors, or overall EFS or OS, except the following variables: Black children were older and had larger tumors at enrollment, whereas Hispanic children had lower rates of diffuse anaplasia WT and loss of heterozygosity at 1p. The only significant difference in EFS or OS between race and ethnic groups was observed among the few children treated for diffuse anaplasia WT with regimen UH-1 and -2 on high-risk protocol, AREN0321. On this therapeutic arm only, Black children showed worse EFS (hazard ratio = 3.18) and OS (hazard ratio = 3.42). However, this finding was not replicated for patients treated with regimen UH-1 and -2 under AREN03B2 but not on AREN0321. CONCLUSIONS: Race and ethnic group enrollment appeared constant across AREN03B2 risk-assigned therapeutic trials. EFS and OS on these therapeutic trials when analyzed together were comparable regarding race and ethnicity. Black children may have experienced worse stage-specific survival when treated with regimen UH-1 and -2 on AREN0321, but this survival gap was not confirmed when analyzing additional high-risk AREN03B2 patients.

Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children's Oncology Group AREN18B5-Q.

Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.