Centralization of pediatric surgical care in the Netherlands:Lessons learned

Centralization of care is a difficult process, as there are several stakeholders that are involved and should be heard. What can be the best option for a small group of patients may be detrimental to a larger group of patients that cannot be adequately treated close to home. The weighing of these factors is different in every environment. One universal rule however is: if you don't do it yourselves, others will do it for you. In the Netherlands, pediatric oncology, including surgery, is centralized in one center (Utrecht) with the help of several shared care centers scattered throughout the country for things that can be managed close to home. (c) 2021 Elsevier Inc. All rights reserved

Evaluation of pregnancy and delivery in 13 women who underwent resection of a sacrococcygeal teratoma during early childhood

Sacrococcygeal teratoma resection often brings changes in pelvic anatomy and physiology with possible consequences for defecation, micturition and sexual function. It is unknown, whether these changes have any gynecological and obstetric sequelae. Until now four pregnancies after sacrococcygeal teratoma resection have been described and cesarean section has been suggested to be the method of choice for delivery. We evaluated the pregnancy course and mode of delivery in women previously treated for a sacrococcygeal teratoma. The records of all patients who underwent sacrococcygeal teratoma resection after 1970 in one of the six pediatric surgical centers in the Netherlands were reviewed retrospectively. Women aged 18 years and older were eligible for participation. Patient characteristics, details about the performed operation and tumor histology were retrieved from the records. Consenting participants completed a questionnaire addressing fertility, pregnancy and delivery details. Eighty-nine women were eligible for participation; 20 could not be traced. Informed consent was received from 41, of whom 38 returned the completed questionnaire (92.7%). Thirteen of these 38 women conceived, all but one spontaneously. In total 20 infants were born, 17 by vaginal delivery and 3 by cesarean section, in one necessitated by previous intra-abdominal surgery as a consequence of sacrococcygeal teratoma resection. Conversion to a cesarean section was never necessary. None of the 25 women without offspring reported involuntary childlessness. There are no indications that resection of a sacrococcygeal teratoma in female patients is associated with reduced fertility: spontaneous pregnancy is possible and vaginal delivery is safe for mother and child, irrespective of the sacrococcygeal teratoma classification or tumor histolog

Virtual Resection: A New Tool for Preparing for Nephron-Sparing Surgery in Wilms Tumor Patients

Nephron-sparing surgery (NSS) in Wilms tumor (WT) patients is a surgically challenging procedure used in highly selective cases only. Virtual resections can be used for preoperative planning of NSS to estimate the remnant renal volume (RRV) and to virtually mimic radical tumor resection. In this single-center evaluation study, virtual resection for NSS planning and the user experience were evaluated. Virtual resection was performed in nine WT patient cases by two pediatric surgeons and one pediatric urologist. Pre- and postoperative MRI scans were used for 3D visualization. The virtual RRV was acquired after performing virtual resection and a questionnaire was used to assess the ease of use. The actual RRV was derived from the postoperative 3D visualization and compared with the derived virtual RRV. Virtual resection resulted in virtual RRVs that matched nearly perfectly with the actual RRVs. According to the questionnaire, virtual resection appeared to be straightforward and was not considered to be difficult. This study demonstrated the potential of virtual resection as a new planning tool to estimate the RRV after NSS in WT patients. Future research should further evaluate the clinical relevance of virtual resection by relating it to surgical outcome

Sentinel Lymph Node Procedure in Pediatric Patients with Melanoma, Squamous Cell Carcinoma, or Sarcoma Using Near-Infrared Fluorescence Imaging with Indocyanine Green: A Feasibility Trial

BACKGROUND: Standard sentinel lymph node procedure (SNP) in pediatric cancer consists of a preoperative injection with 99mtechnetium nanocolloid in combination with an optional intraoperative injection with blue dye. However, blue dye has disadvantages, and the detection rate is low, with only 60% of sentinel lymph nodes (SLNs) staining blue. In adult oncology, fluorescence imaging using indocyanine green (ICG) has been shown to be a safe and accurate method for visual detection of SLNs, with a higher sensitivity (up to 97%) compared with blue dye. Therefore, our aim is to determine the feasibility of the addition of ICG to 99mtechnetium nanocolloid (ICG-TC) for visual detection of SLN in pediatric patients. METHODS: A total of 15 pediatric patients with melanoma, squamous cell carcinoma, and sarcoma were prospectively included. Preoperatively, patients were injected with ICG-TC and imaging with lymphoscintigraphy and single-photon emission computed tomography- computed tomography was performed. Intraoperatively, SLN was detected with fluorescence and the gamma probe. Postoperatively, fluorescence was quantified by tumor-to-background ratio (TBR) and surgeons evaluated the use of ICG using a standardized questionnaire. RESULTS: In 10/15 (67%) patients, SLNs were visible transcutaneously. Of all intraoperatively detected SLNs, 35/37 (95%) were fluorescent and 37/37 (100%) were radioactive. Furthermore, ICG-TC led to the identification of six additional SLNs as compared with preoperative imaging. The median TBR in vivo was 6.5 (IQR 5.3). The surgical evaluation showed that ICG assisted in SLN detection and was easy to use. CONCLUSIONS: ICG-TC for the SNP is a feasible procedure in pediatric patients. It showed an accurate detection rate, was helpful for visual guidance, and no adverse events occurred

Treatment and Survival of Malignant Extracranial Germ Cell Tumours in the Paediatric Population: A Systematic Review and Meta-Analysis

OBJECTIVE: This systematic review and meta-analysis was performed to explore overall survival (OS) and event free survival (EFS) rates internationally over the past two decades and to define specific subgroups with inferior outcomes which may demand different treatment strategies. METHODS: The search focused on malignant extracranial germ cell tumours (GCTs) in the paediatric population. The initial database search identified 12,556 articles; 32 articles were finally included in this review, comprising a total of 5095 patients. RESULTS: The studies were heterogeneous, varying from single institution reports to large prospective trials. Older studies, describing eras where non-platinum-based chemotherapy regimens were used, showed clearly worse outcomes. Survival for stage I-II gonadal disease is excellent. On the other hand, patients with an initial alpha-fetoprotein (AFP) > 10,000 ng/mL or kU/L, age > 11 years and stage IV disease confer a survival disadvantage. For testicular disease in particular, lymphovascular invasion and certain histopathological subtypes, such as embryonal carcinoma (EC) and mixed malignant GCTs, survival is poorer. Survival data for sacrococcygeal and mediastinal GCTs show a heterogeneous distribution across studies in this review, independent of year of publication. Patients > 12 years presenting with a mediastinal GCT pose a subpopulation which fares worse than GCTs in other locations or age groups. This is independent of AFP levels, stage of disease or treatment protocol, and these patients may demand a different treatment strategy. CONCLUSIONS: This review describes the heterogeneous nature of GCTs in different anatomical locations, impacting on stage at presentation, treatment modalities used and survival data. Despite this heterogeneity, in line with the current developmental biology-based classification system, subpopulations can be defined which have an inferior EFS and OS and where future research and more individualised treatment would help to improve survival

Surgical Outcome of Children with a Malignant Liver Tumour in The Netherlands:A Retrospective Consecutive Cohort Study

INTRODUCTION: Six to eight children are diagnosed with a malignant liver tumour yearly in the Netherlands. The majority of these tumours are hepatoblastoma (HB) and hepatocellular carcinoma (HCC), for which radical resection, often in combination with chemotherapy, is the only curative treatment option. We investigated the surgical outcome of children with a malignant liver tumour in a consecutive cohort in the Netherlands. METHODS: In this nationwide, retrospective observational study, all patients (age < 18 years) diagnosed with a malignant liver tumour, who underwent partial liver resection or orthotopic liver transplantation (OLT) between January 2014 and April 2021, were included. Children with a malignant liver tumour who were not eligible for surgery were excluded from the analysis. Data regarding tumour characteristics, diagnostics, treatment, complications and survival were collected. Outcomes included major complications (Clavien-Dindo ≥ 3a) within 90 days and disease-free survival. The results of the HB group were compared to those of a historical HB cohort. RESULTS: Twenty-six children were analysed, of whom fourteen (54%) with HB (median age 21.5 months), ten (38%) with HCC (median age 140 months) and one with sarcoma and a CNSET. Thirteen children with HB (93%) and three children with HCC (30%) received neoadjuvant chemotherapy. Partial hepatic resection was possible in 19 patients (12 HB, 6 HCC, and 1 sarcoma), whilst 7 children required OLT (2 HB, 4 HCC, and 1 CNSET). Radical resection (R0, margin ≥ 1.0 mm) was obtained in 24 out of 26 patients, with recurrence only in the patient with CNSET. The mean follow-up was 39.7 months (HB 40 months, HCC 40 months). Major complications occurred in 9 out of 26 patients (35% in all, 4 of 14, 29% for HB). There was no 30- or 90-day mortality, with disease-free survival after surgery of 100% for HB and 80% for HCC, respectively. Results showed a tendency towards a better outcome compared to the historic cohort, but numbers were too small to reach significance. CONCLUSION: Survival after surgical treatment for malignant liver tumours in the Netherlands is excellent. Severe surgical complications arise in one-third of patients, but most resolve without long-term sequelae and have no impact on long-term survival

Radiologic versus Segmentation Measurements to Quantify Wilms Tumor Volume on MRI in Pediatric Patients

Wilms tumor is a common pediatric solid tumor. To evaluate tumor response to chemotherapy and decide whether nephron-sparing surgery is possible, tumor volume measurements based on magnetic resonance imaging (MRI) are important. Currently, radiological volume measurements are based on measuring tumor dimensions in three directions. Manual segmentation-based volume measurements might be more accurate, but this process is time-consuming and user-dependent. The aim of this study was to investigate whether manual segmentation-based volume measurements are more accurate and to explore whether these segmentations can be automated using deep learning. We included the MRI images of 45 Wilms tumor patients (age 0-18 years). First, we compared radiological tumor volumes with manual segmentation-based tumor volume measurements. Next, we created an automated segmentation method by training a nnU-Net in a five-fold cross-validation. Segmentation quality was validated by comparing the automated segmentation with the manually created ground truth segmentations, using Dice scores and the 95th percentile of the Hausdorff distances (HD95). On average, manual tumor segmentations result in larger tumor volumes. For automated segmentation, the median dice was 0.90. The median HD95 was 7.2 mm. We showed that radiological volume measurements underestimated tumor volume by about 10% when compared to manual segmentation-based volume measurements. Deep learning can potentially be used to replace manual segmentation to benefit from accurate volume measurements without time and observer constraints

Osteoblasts secrete miRNA-containing extracellular vesicles that enhance expansion of human umbilical cord blood cells

Osteolineage cells represent one of the critical bone marrow niche components that support maintenance of hematopoietic stem and progenitor cells (HSPCs). Recent studies demonstrate that extracellular vesicles (EVs) regulate stem cell development via horizontal transfer of bioactive cargo, including microRNAs (miRNAs). Using next-generation sequencing we show that human osteoblast-derived EVs contain highly abundant miRNAs specifically enriched in EVs, including critical regulators of hematopoietic proliferation (e.g., miR-29a). EV treatment of human umbilical cord blood-derived CD34 + HSPCs alters the expression of candidate miRNA targets, such as HBP1, BCL2 and PTEN. Furthermore, EVs enhance proliferation of CD34 + cells and their immature subsets in growth factor-driven ex vivo expansion cultures. Importantly, EV-expanded cells retain their differentiation capacity in vitro and successfully engraft in vivo. These discoveries reveal a novel osteoblast-derived EV-mediated mechanism for regulation of HSPC proliferation and warrant consideration of EV-miRNAs for the development of expansion strategies to treat hematological disorders

The applicability of the central line-associated bloodstream infection (CLABSI) criteria for the evaluation of bacteremia episodes in pediatric oncology patients

Background: The aim of this study was to investigate the applicability of the central line-associated bloodstream infection (CLABSI) criteria of the Centers for Disease Control and Prevention in pediatric oncology patients. Methods: Bacteremia episodes from 2020 to 2022 from a prospective cohort of pediatric oncology patients with a central venous catheter were included. Episodes were classified by three medical experts following the CLABSI criteria as either a CLABSI or non-CLABSI (i.e., contamination, other infection source, or mucosal barrier injury-laboratory confirmed bloodstream infection (MBI-LCBI)). Subsequently, they were asked if and why they (dis)agreed with this diagnosis following the criteria. The primary outcome was the percentage of episodes where the experts clinically disagreed with the diagnosis given following the CLABSI criteria. Results: Overall, 84 bacteremia episodes in 71 patients were evaluated. Following the CLABSI criteria, 34 (40%) episodes were classified as CLABSIs and 50 (60%) as non-CLABSIs. In 11 (13%) cases the experts clinically disagreed with the diagnosis following the CLABSI criteria. The discrepancy between the CLABSI criteria and clinical diagnosis was significant; McNemar's test p <.01. Disagreement by the experts with the CLABSI criteria mostly occurred when the experts found an MBI-LCBI a more plausible cause of the bacteremia than a CLABSI due to the presence of a gram negative bacteremia (Pseudomonas aeruginosa n = 3) and/or mucositis. Conclusions: A discrepancy between the CLABSI criteria and the evaluation of the experts was observed. Adding Pseudomonas aeruginosa as an MBI pathogen and incorporating the presence of mucositis in the MBI-LCBI criteria, might increase the applicability

The contribution of surgical clips for optimizing highly-conformal image-guided flank irradiation in pediatric renal tumors: a single center experience

Background and aims: Two-opposing photon beams are considered standard of care for flank irradiation in pediatric patients with renal tumors. Nowadays, Image-Guided Radiotherapy (IGRT) techniques allow high-precision dose delivery to complex flank target volumes taking into account postoperative organ shifts and tumor bed motion. This study examines the contribution of a lateral and superior surgical clip on flank target volume delineation intended for IGRT. Methods: Between 01-2015 and 09-2019, 30/162 newly-diagnosed pediatric patients with renal tumors, lateral/superior surgical clips (n = 30/30) and available 4D-CT-scans (n = 27/30), underwent postoperative flank irradiation. The lateral and superior clip, as respective markers for the lateral tumor extension and intrafraction motion, were analyzed. The positive and negative values depict the lateral/dorsal/cranial or the medial/ventral/caudal direction, respectively. Planning target volumes (PTV) were generated based on lateral clips (PTV latclip), superior clips with 4D-CT technology (PTV supclip), and both clips combined (PTV combined), and compared to an approach without clips (PTV noclip). Results: Indicated by clips, the mean lateral tumor bed extension along the posterior wall was 74° (range: 50°–93°), while mean intrafraction motion was +1.2 mm (range: −1.8/+4.8 mm), +0.6 mm (range: +0.6/+4.9 mm), −0.3 mm (range: −3.8/+0.7 mm) in craniocaudal, ventrodorsal, mediolateral direction, respectively. The median PTV noclip (556 mL) was statistically different from the median PTV latclip (454 mL, p = <0.01), median PTV supclip (373 mL, p = <0.01) and median PTV combined (348 mL p = <0.01). Conclusion: In pediatric patients with renal tumors, surgical clips at the lateral and superior border of the tumor bed can optimize flank target volume delineation and, consequently, reduce the normal tissue volume receiving high-dose irradiation when IGRT techniques are applied