Modern surgical strategies in pediatric neuroblastoma: Evolving approaches and treatment principles.

Neuroblastoma, the most common extracranial solid tumor in children under the age of 5, has been described as early as the 19th century, and its complexity has continued to intrigue researchers, as well as medical and surgical specialists. At one end of the phenotypic spectrum, neuroblastoma is self-limiting with minimal to no intervention required, while on the opposite end exists the challenge of refractory disease despite aggressive management and toxic systemic treatments. The goal of this review is to describe a comprehensive surgical perspective and contemporary approach to neuroblastoma.

A Comparison of Commonly Utilized Diagnostic Biopsy Techniques for Pediatric Patients With Cancer: A Systematic Review by the APSA Cancer Committee.

BACKGROUND: Historically, surgical biopsy (SB) for diagnosis of pediatric solid tumors was considered necessary to provide adequate tissue for histologic and molecular analysis. Less invasive biopsy techniques such as image-guided core needle biopsy (CNB), have shown comparable accuracy with decreased morbidity in some adult studies. However, data regarding the safety and efficacy of CNB in pediatric tumors is limited. This study's aim was to assess the overall rate of successful diagnosis and safety of CNB compared to SB in children with malignancies. METHODS: A PRISMA compliant systematic review was performed in MEDLINE via PubMed, Embase and CINAHL Plus database searches from 2010 to 2023. Studies were included with relevance to the following clinical question: For children with concern for malignancy requiring biopsy for diagnosis, how does CNB compare to open or laparoscopic/thoracoscopic SB in terms of safety and diagnostic efficacy? Data for patients ≤21 years requiring biopsy for diagnosis of liver tumors, neuroblastoma (NB), soft tissue sarcoma (STS), and lymphoma were included. RESULTS: Twenty-seven studies including 2477 patients met inclusion criteria, with 2065 undergoing CNB and 412 SB. Of the 2477 patients, 820 patients had NB, 307 liver tumors, 96 STS, 151 lymphoma, and 1103 patients were from studies that included multiple diagnoses. The average complication rate for CNB was 2.9% compared to 21.4% for SB (p < 0.001). Bleeding was the most common complication in both groups, but significantly higher after SB (22.1% vs 2.3%) (p < 0.001). CNB was diagnostic in 90.8% of patients compared to 98.8% who underwent SB (p < 0.001). CONCLUSIONS: Rates of successful diagnosis were greater than 90% for both CNB and SB, though significantly higher for SB. Conversely, complication rates were close to ten times higher after SB compared to CNB. Given its relatively lower risk profile, CNB can be a safe and useful diagnostic tool for children with solid malignancies. Research focused on enhancing CNB's diagnostic accuracy while maintaining low morbidity should be further explored. LEVEL OF EVIDENCE: Treatment study, Level III.

Evaluation of Image-Defined Risk Factor (IDRF) Assessment in Patients With Intermediate-risk Neuroblastoma: A Report From the Children's Oncology Group Study ANBL0531.

BACKGROUND: The International Neuroblastoma Risk Group (INRG) classifier utilizes a staging system based on pretreatment imaging criteria in which image-defined risk factors (IDRFs) are used to evaluate the extent of locoregional disease. Children's Oncology Group (COG) study ANBL0531 prospectively examined institutional determination of IDRF status and compared that to a standardized central review. METHODS: Between 9/2009-6/2011, patients with intermediate-risk neuroblastoma were enrolled on ANBL0531 and had IDRF assessment at treating institutions. Paired COG pediatric surgeons and radiologists performed blinded central review of diagnostic imaging for the presence or absence of IDRFs. Second blinded review was performed in cases of discordance. Comparison of local and central review was performed using the Kappa coefficient to determine concordance in IDRF assessment. RESULTS: 211 patients enrolled in ANBL0531 underwent IDRF assessment; 3 patients were excluded due to poor image quality. Central reviewer pairs agreed on the presence or absence of any IDRF in 170/208 (81.7%; κ = 0.48) cases. Thirteen (6.3%) cases could not be adjudicated after second blinded review. Radiologists were more likely to identify IRDFs as present than surgeons (p < 0.001). Local and central reviewers agreed on the presence or absence of any IDRF in only108/208 (51.9%; κ = 0.06) cases. CONCLUSIONS: Among experienced pediatric surgeons and radiologists participating in central review, concordance was moderate, with agreement in 81.7% of cases. On comparison of local and central assessment of IDRFs, concordance was poor. These data indicate that greater standardization, education, technology, and training are needed to improve the assessment of IDRFs in children with neuroblastoma. LEVEL OF EVIDENCE: Treatment Study, Level III.

Neuroblastoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Neuroblastoma is the most common extracranial solid tumor diagnosed in children. This inaugural version of the NCCN Guidelines for Neuroblastoma provides recommendations for the diagnosis, risk classification, and treatment of neuroblastoma. The information in these guidelines was developed by the NCCN Neuroblastoma Panel, a multidisciplinary group of representatives with expertise in neuroblastoma, consisting of pediatric oncologists, radiologists, pathologists, surgeons, and radiation oncologists from NCCN Member Institutions. The evidence-based and consensus recommendations contained in the NCCN Guidelines are intended to guide clinicians in selecting the most appropriate treatments for their patients with this clinically heterogeneous disease.

Contemporary Approaches to Peripheral Nerve Surgery.

"State of the Art" Learning Objectives: This manuscript serves to provide the reader with a general overview of the contemporary approaches to peripheral nerve reconstruction as the field has undergone considerable advancement over the last 3 decades. The learning objectives are as follows: To provide the reader with a brief history of peripheral nerve surgery and some of the landmark developments that allow for current peripheral nerve care practices.To outline the considerations and management options for the care of patients with brachial plexopathy, spinal cord injury, and lower extremity peripheral nerve injury.Highlight contemporary surgical techniques to address terminal neuroma and phantom limb pain.Review progressive and future procedures in peripheral nerve care, such as supercharge end-to-side nerve transfers.Discuss rehabilitation techniques for peripheral nerve care.

Le présent manuscrit vise à fournir au lecteur un aperçu général des approches contemporaines de la reconstruction des nerfs périphériques puisque le domaine a beaucoup progressé depuis trois décennies. Les objectifs d'apprentissage s"établissent comme suit : Fournir au lecteur un bref historique de la chirurgie des nerfs périphériques et quelques-unes des avancées historiques qui ont donné lieu aux pratiques de soins actuelles des nerfs périphériques.Décrire les considérations et les possibilités de prise en charge pour les soins des patients ayant une plexopathie brachiale, une lésion médullaire ou une lésion des nerfs périphériques des membres inférieurs.Souligner les techniques chirurgicales contemporaines pour traiter les neurones terminaux et les douleurs des membres fantômes.Examiner les interventions progressives et futures pour les soins des nerfs périphériques, comme l'amplification du transfert du nerf terminal au nerf latéral.Parler des techniques de réadaptation pour les soins des nerfs périphériques.

Assessing patient autonomy in the context of TeamBirth, a quality improvement intervention to improve shared decision-making during labor and birth.

BACKGROUND: Respectful maternity care includes shared decision-making (SDM). However, research on SDM is lacking from the intrapartum period and instruments to measure it have only recently been developed. TeamBirth is a quality improvement initiative that uses team huddles to improve SDM during labor and birth. Team huddles are structured meetings including the patient and full care team when the patient's preferences, care plans, and expectations for when the next huddle will occur are reviewed. METHODS: We used patient survey data (n = 1253) from a prospective observational study at four U.S. hospitals to examine the relationship between TeamBirth huddles and SDM. We measured SDM using the Mother's Autonomy in Decision-Making (MADM) scale. Linear regression models were used to assess the association between any exposure to huddles and the MADM score and between the number of huddles and the MADM score. RESULTS: In our multivariable model, experiencing a huddle was significantly associated with a 3.13-point higher MADM score. When compared with receiving one huddle, experiencing 6+ huddles yielded a 3.64-point higher MADM score. DISCUSSION: Patients reporting at least one TeamBirth huddle experienced significantly higher SDM, as measured by the MADM scale. Our findings align with prior research that found actively involving the patient in their care by creating structured opportunities to discuss preferences and choices enables SDM. We also demonstrated that MADM is sensitive to hospital-based quality improvement, suggesting that future labor and birth interventions might adopt MADM as a patient-reported experience measure.

Incidence and prevalence of hepatitis C and B infections among men who have sex with men and transgender women enrolled in a United States HIV vaccine trial.

Background: Rising hepatitis C and B virus (HCV and HBV) rates have been reported in men who have sex with men (MSM) and transgender women (TGW). This study characterizes HCV and HBV infections longitudinally among 2,496 MSM/TGW aged 18-50 years and at risk for HIV acquisition enrolled in an HIV-1 vaccine trial in 18 U.S. cities between 2009-2013. Methods: Participants completed behavioral surveys, HIV testing, and blood collection over 24 months. Of the 2,397 participants who consented for future testing, 1,792 (74.8%) had available paired stored blood samples at baseline and a later timepoint (Month 24 [N = 999]; if unavailable, M12 [N = 775] or M15 [N = 18]). Results: Among 1,792 participants, 98.1% were MSM, 0.8% were TGW, and the median age was 30 years (IQR 24, 40). Participants reported a median number of 3 male sex partners (IQR 1,5) within the past 3 months. Condomless insertive anal sex was reported by 55.8% and condomless receptive anal sex by 46.7%.1.3% reported injection drug use. During follow-up, 1.4% reported pre-exposure prophylaxis (PrEP) use. At baseline 11/1792 (0.61%) participants had HCV infection (HCV AB positive, RNA detectable), with all having persistent detectable RNA and chronic HCV infection at follow-up. Phylogenetic analysis showed no clusters of HCV infection. 8 participants had HCV AB positive, RNA undetectable at baseline and follow-up, representing past HCV infection with clearance; only 2 acquired HCV, which cleared over 12-24 months. At baseline, 2 participants (2/1792 = 0.11%) had positive HBsAg, indicating chronic HBV infection. Over 12-24 months, 4 (4/1790, 0.22%) developed HBsAg positivity; these participants had HBcAB positivity at baseline, thereby likely representing reactivation. There were no new HBV infections during follow-up. Conclusion: Among 1,792 men who have sex with men and transgender women aged 18-50 years and at risk for HIV acquisition enrolled in a U.S. HIV-1 vaccine trial, incident hepatitis C infection rates were extremely low, with no cases of incident hepatitis B infection. These rates of incident HCV infection and HBSAg positivity are lower than previously reported among MSM/TGW.

Current surgical practice for central venous access to deliver chemotherapy and enteral access for nutritional support in pediatric patients with an oncological diagnosis.

Central venous access through tunneled central venous catheters (CVCs) are one of the cornerstones of modern oncologic practice in pediatric patients since CVCs provide a reliable access route for the administration of chemotherapy. Establishing best practices for CVC management in children with cancer is essential to optimize care. This article reviews current best practices, including types of devices, their placement, complications, and long-term outcomes. Additionally, nutrition status and nutritional support are also very important determinants of outcomes and care in pediatric surgical oncology patients. We review current nutritional assessment, support, access for enteral and parenteral nutrition delivery, and their complications, mainly from a surgical perspective. Overall, access surgery, whether for CVCs, or for enteral access can be challenging, and best practice guidelines supported by current though limited evidence are necessary to minimize complications and optimize outcomes.

Retrospective Data Analysis Reveals Unusual Metabolism Pattern of Ethanol in Pediatrics as Compared to Adult and Geriatric Populations.

BACKGROUND: About 95% of consumed ethanol is metabolized by oxidative pathways. Less than 1% is metabolized via nonoxidative pathways: glucuronidation, sulfation, and the formation of fatty acid esters of ethanol. In neonates, the glucuronidation pathway has been reported to be underdeveloped but matures with age. This work compared the test results of patients' random urine samples submitted to our facility for ethyl glucuronide (EtG) and ethyl sulfate (EtS) measurements across pediatric and adult populations. METHODS: Test results (n = 63 498) from urine samples tested for EtG and EtS by quantitative liquid chromatography-tandem mass spectrometry at our facility were utilized for this study. EtG and EtS concentrations were compared across the age partitions 0 to 17 years (pediatric), 18 to 80 years (adult), and 81 to 100 years (geriatric). Eight pediatric patients from a tertiary academic hospital contributed clinical context via abstracted clinical information. RESULTS: Across the individual age partitions, 60% to 65% of patients had both EtG and EtS present in urine. Approximately 5% to 10% of patients had only EtG, and 25% to 35% had neither metabolite present. The lowest percentages (<1.5%) had EtS present in the absence of EtG. Markedly, no pediatric patients had only EtS present; compared to the adult population, this was statistically significant (Fisher exact test, P = 0.025). CONCLUSIONS: From the data presented in this work, EtG is more prevalent relative to EtS in urine samples of patients assessed for ethanol exposure.

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

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

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.

Mapping single-cell developmental potential in health and disease with interpretable deep learning.

Single-cell RNA sequencing (scRNA-seq) has transformed our understanding of cell fate in developmental systems. However, identifying the molecular hallmarks of potency - the capacity of a cell to differentiate into other cell types - has remained challenging. Here, we introduce CytoTRACE 2, an interpretable deep learning framework for characterizing potency and differentiation states on an absolute scale from scRNA-seq data. Across 31 human and mouse scRNA-seq datasets encompassing 28 tissue types, CytoTRACE 2 outperformed existing methods for recovering experimentally determined potency levels and differentiation states covering the entire range of cellular ontogeny. Moreover, it reconstructed the temporal hierarchy of mouse embryogenesis across 62 timepoints; identified pan-tissue expression programs that discriminate major potency levels; and facilitated discovery of cellular phenotypes in cancer linked to survival and immunotherapy resistance. Our results illuminate a fundamental feature of cell biology and provide a broadly applicable platform for delineating single-cell differentiation landscapes in health and disease.

Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen.

BACKGROUND: The principal barrier to an HIV cure is the presence of the latent viral reservoir (LVR), which has been understudied in African populations. From 2018 to 2019, Uganda instituted a nationwide rollout of ART consisting of Dolutegravir (DTG) with two NRTI, which replaced the previous regimen of one NNRTI and the same two NRTI. METHODS: Changes in the inducible replication-competent LVR (RC-LVR) of ART-suppressed Ugandans with HIV (n = 88) from 2015 to 2020 were examined using the quantitative viral outgrowth assay. Outgrowth viruses were examined for viral evolution. Changes in the RC-LVR were analyzed using three versions of a Bayesian model that estimated the decay rate over time as a single, linear rate (model A), or allowing for a change at time of DTG initiation (model B&C). FINDINGS: Model A estimated the slope of RC-LVR change as a non-significant positive increase, which was due to a temporary spike in the RC-LVR that occurred 0-12 months post-DTG initiation (p < 0.005). This was confirmed with models B and C; for instance, model B estimated a significant decay pre-DTG initiation with a half-life of 6.9 years, and an ∼1.7-fold increase in the size of the RC-LVR post-DTG initiation. There was no evidence of viral failure or consistent evolution in the cohort. INTERPRETATION: These data suggest that the change from NNRTI- to DTG-based ART is associated with a significant temporary increase in the circulating RC-LVR. FUNDING: Supported by the NIH (grant 1-UM1AI164565); Gilead HIV Cure Grants Program (90072171); Canadian Institutes of Health Research (PJT-155990); and Ontario Genomics-Canadian Statistical Sciences Institute.

Proliferative Effects of Mesenchymal Stromal Cells on Neuroblastoma Cell Lines: Are They Tumor Promoting or Tumor Inhibiting?

BACKGROUND: Neuroblastoma is a common pediatric malignancy with poor survival for high-risk disease. Mesenchymal stromal cells (MSCs) have innate tumor-homing properties, enabling them to serve as a cellular delivery vehicle, but MSCs have demonstrated variable effects on tumor growth. We compared how placental MSCs (PMSCs) and bone marrow-derived MSCs (BM-MSCs) affect proliferation of neuroblastoma (NB) cells in vitro. METHODS: Indirect co-culture assessed proliferative effects of 18 MSCs (early-gestation PMSCs (n = 9), term PMSCs (n = 5), BM-MSCs (n = 4) on three high-risk NB cell lines (NB1643, SH-SY5Y, and CHLA90). Controls were NB cells cultured in media alone. Proliferation was assessed using MTS assay and measured by fold change (fc) over controls. PMSCs were sub-grouped by neuroprotective effect: strong (n = 7), intermediate (n = 3), and weak (n = 4). The relationship between MSC type, PMSC neuroprotection, and PMSC gestational age on NB cell proliferation was assessed. RESULTS: NB cell proliferation varied between MSC groups. BM-MSCs demonstrated lower proliferative effects than PMSCs (fc 1.18 vs 1.44, p < 0.001). Neither gestational age nor neuroprotection significantly predicted degree of proliferation. Proliferative effects of MSCs varied among NB cell lines. BM-MSCs had less effect on CHLA90 (fc 1.01) compared to NB1643 (fc 1.33) and SH-SY5Y (fc 1.20). Only NB1643 showed a difference between early and term PMSCs (p = 0.04). CONCLUSION: Effects of MSCs on NB cell proliferation vary by MSC source and NB cell line. BM-MSCs demonstrated lower proliferative effects than most PMSCs. MSC neuroprotection was not correlated with proliferation. Improved understanding of MSC proliferation-promoting mechanisms may provide valuable insight into selection of cells best suited as drug delivery vehicles. LEVEL OF EVIDENCE: N/A. TYPE OF STUDY: Original Research.