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Swallowing and feeding disorders are a major concern for children with oesophageal atresia (OA) after primary or staged OA repair. Primary OA repair is associated with higher rates of short-term complications in preterm infants with very low birth weight (VLBW) or extreme low birth weight (ELBW). On the other hand, primary repair may have the benefit of early commencement of oral feedings. We hypothesize that also in the medium-term, swallowing-related quality of life is better after primary oesophageal repair. We conducted a prospective cross-sectional study on swallowing quality in a national cohort of former VLBW and ELBW children with OA, using the structured paediatric swallowing quality of life (pedSWAL-QOL) questionnaire. Results were correlated with surgical approach and baseline clinical data. Principal component analysis of pedSWAL-QOL domains was performed. In total, 44 complete data sets of 78 children were available. The mean age of children was 8.5 years (SD = 7.4), and 23 children (52%) had primary OA repair. The overall median pedSWAL-QOL score was 2 (IQR = 0–3), representing a high swallowing-related quality of life, independent of surgical technique (p = 0.086). Children with a history of intracranial haemorrhage (ICH) (p = 0.002) and those with VACTERL association (p = 0.008) had significantly decreased enjoyment with eating. In addition, children with VACTERL association had problems to find suitable foods (p = 0.04). Conclusion: In this national cohort of VLBW and ELBW preterm-born children with OA, swallowing-related quality of life is good, mostly independent of initial surgery. Children with OA and ICH or VACTERL association may require more intense support with feeding. What is Known:• Dysphagia, resembling feeding and swallowing disorders, is common in children and adults with repaired oesophageal atresia. Nevertheless, dysphagia in children with oesophageal atresia decreases with age.• Parents of younger children suffer from increased anxiety and fear regarding eating and swallowing abilities of their children. What is New:• Swallowing-related quality of life in former preterm children with oesophageal atresia is good, independent of initial surgical approach (primary vs. staged repair), even in very low birth weight or extreme low birth weight infants. • Children suffering from VACTERL association or intracranial haemorrhage show decreased enjoyment with eating.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases.Significance:The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659

Supplementary Table from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

(A) Heat map of unchanged proteins that were analyzed by RPPA. The analysis is represented similar to Fig. 1B.

Phospho/total protein ratios as evaluated by RPPA screening (Fig. 1).

Supplementary Figure from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Supplementary Figures S1-S4; Supplementary Table S1.

Purpose: Hepatoblastoma represents the most frequent malignant liver tumor in childhood. The phosphatidylinositol-3′-kinase (PI3K)/AKT pathway is crucial in downstream signaling of multiple receptor tyrosine kinases of pathogenic importance in hepatoblastoma. Increased PI3K/AKT signaling pathway activity and activating mutations of PIK3CA, encoding a PI3K catalytic subunit, have been reported in different childhood tumors. The current study was done to analyze the role of PI3K/AKT signaling in hepatoblastoma.Experimental Design: Immunohistochemical stainings of (Ser473)-phosphorylated (p)-AKT protein, its targets p-(Ser9)-GSK-3β and p-(Ser2448)-mTOR, as well as the cell cycle regulators Cyclin D1, p27KIP1, and p21CIP1 were done and the PIK3CA gene was screened for mutations. In vitro, two hepatoblastoma cell lines treated with the PI3K inhibitor LY294002 were analyzed for AKT and GSK-3β phosphorylation, cell proliferation, and apoptosis. Additionally, simultaneous treatments of hepatoblastoma with LY294002 and cytotoxic drugs were carried out.Results: Most tumors strongly expressed p-AKT, p-GSK-3β, and p-mTOR; subgroups showed significant Cyclin D1, p27KIP1, and p21CIP1 expression. One hepatoblastoma carried an E545A mutation in the PIK3CA gene. In vitro, PI3K inhibition diminished hepatoblastoma cell growth being accompanied by reduced AKT and GSK-3β phosphorylation. Flow cytometry and 4', 6-diamidino-2-phenylindole stainings showed that PI3K pathway inhibition leads to a substantial increase in apoptosis and a decrease in cellular proliferation linked to reduced Cyclin D1 and increased p27KIP1 levels. Simultaneous treatment of hepatoblastoma cell lines with LY294002 and cytotoxic drugs resulted in positive interactions.Conclusions: Our findings imply that PI3K signaling plays an essential role in growth control of hepatoblastoma and might be successfully targeted in multimodal therapeutic strategies.

Supplementary Data from Activation of Phosphatidylinositol-3′-kinase/AKT Signaling Is Essential in Hepatoblastoma Survival

Purpose: Searching for novel strategies to modulate apoptosis in neuroblastoma, we investigated the potential of the proteasome inhibitor bortezomib.Experimental Design: The effect of bortezomib on TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis signaling pathways was analyzed in neuroblastoma cell lines, primary neuroblastoma cultures, and in an in vivo model.Results: Bortezomib synergistically cooperates with TRAIL to induce apoptosis and to reduce colony formation of neuroblastoma cells (combination index: 0.5). Mechanistic studies reveal that bortezomib profoundly enhances TRAIL-induced cleavage of Bid into tBid, accumulation of tBid in the cytosol, and its insertion into mitochondrial membranes, pointing to a concerted effect on Bid cleavage (TRAIL) and stabilization of tBid (bortezomib), which links the death receptor to the mitochondrial pathway. In addition, bortezomib increases expression of p53 and Noxa. All these changes lead to increased activation of Bax and Bak, loss of the mitochondrial membrane potential, cytochrome c release, caspase activation, and caspase-dependent apoptosis on treatment with bortezomib and TRAIL. Knockdown of Bid, Noxa, or p53 significantly delays the kinetic of bortezomib- and TRAIL-induced apoptosis, whereas it does not confer long-term protection. By comparison, overexpression of Bcl-2, which simultaneously antagonizes tBid and p53, significantly inhibits bortezomib- and TRAIL-induced apoptosis and even rescues clonogenic survival. Importantly, bortezomib and TRAIL act in concert to trigger apoptosis and to suppress tumor growth in patient-derived primary neuroblastoma cells and in an in vivo model of neuroblastoma.Conclusions: Bortezomib represents a promising new approach to prime neuroblastoma cells toward TRAIL, which warrants further investigation. Clin Cancer Res; 17(10); 3204–18. ©2011 AACR.

ZusammenfassungInvaginationen betreffen in der Regel Kinder im ersten Lebensjahr, sie können sehr selten aber auch bereits intrauterin auftreten. Wir berichten von einem Neugeborenen mit Mekoniumverhalt, wiederholtem Erbrechen und distendiertem Abdomen in der ersten Lebenswoche. Nach radiologischer Diagnose eines gastrointestinalen Passagehindernis’ erfolgt am 7. Lebenstag die explorative Laparatomie. Hier zeigt sich ein atretisches distales Ileum und aboral davon eine Invagination. Nach Resektion dieser Darmabschnitte gelingt eine End-zu-End-Anastomose. Der postoperative Verlauf ist unkompliziert. Der Fall veranschaulicht, dass bei einem gastrointestinalen Passagehindernis in der Neonatalperiode auch an eine Invagination als Ursache gedacht werden sollte. Eine rasche Diagnostik und gute interdisziplinäre Zusammenarbeit mit den Kollegen der Kinderchirurgie sind ausschlaggebend für einen zufriedenstellenden Verlauf.

Introduction The VACTERL association is a rare malformation complex, showing at least three anomalies of the following organ systems: vertebra, anorectum, heart and vessels, trachea and esophagus, genitourinary tract, and limbs. In addition to a multifactorial event, congenital vascular disorders are also discussed as triggers for the VACTERL association. The aim of this study was to determine whether there is a genetic background for vascular disorders triggering VACTERL association. Materials and Methods We performed a functional analysis on whole exome sequencing data of 21 patients with VACTERL or VACTERL-like phenotype using the online analysis tool “Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8.” The study was approved by the institutional ethics committee (approval no. 026–13). Written informed consent was obtained from all patients or their parents. Results We identified a total of 86 genetic variants (in 75 genes) classified as damaging (including probably damaging missense, nonsense, and frameshift variants), which are associated to cardiovascular development. Each investigated patient showed at least one damaging variant in genes associated to cardiovascular development. These variants were further reduced by significance in cardiovascular development to 39 genetic variants (in 33 genes). Of note, a pair of siblings, both presenting with cardiac and renal defects, had the same damaging variant in two different genes. Conclusion Our results indicate a genetic background for congenital vascular disorders in patients with VACTERL association. In line with the literature, our data suggest that genetic mutation led to vascular diseases, which in turn may cause malformations similar to the VACTERL association.

This study aims to identify factors associated with the occurrence of local relapse (LR) after treatment for unilateral nephroblastoma.Despite the fact that LR is rare (~5%) its adverse impact on the need for relapse treatment and outcome (40-80% OS) cannot be neglected. Identifying the causative factors may improve initial treatment to achieve better local control.Altogether 2386 patients with unilateral nephroblastoma prospectively enrolled over a period of 32 years (1989 - 2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH) were retrospectively analyzed. Hazard ratios (HR) of LR were calculated for sex, age, size, local staging, histology, type of removal, rupture, lymph node removal using univariate and multivariate Cox models.Age48 months, tumor volume500 mL, histology and lymph node (LN) extent of removal were identified as significant risk factors for LR (HR 1.68, P=0.018, CI 1.09 - 2.58; HR 1.84, P=0.015, CI 1.13 - 3.00; HR 3.19, P0.001, CI 2.03 - 5.00; HR 2.26, P=0.002, CI 1.36 - 3.576). LR occur significantly more often in Stage I and II, even if no LN are removed. The risk of metastases is significantly increased after local recurrence (HR 11.5, P0.001, CI 7.11 - 18.60). LR is associated with a subsequent 18.79-fold increased risk of death (HR 18.79, P0.001, CI 2.07 - 5.28).Several factors are responsible for the occurrence of LR. Surgical ones, like LN sampling allow further reduction of LR and consequently a better outcome of patients with unilateral nephroblastoma.

Simple Summary Hepatoblastoma patients with tumors that do not respond to preoperative chemotherapy often experience incomplete surgical resection and thus poor outcomes. By analyzing the gene expression data of chemoresistant and responsive tumors using sophisticated drug prediction software we identified mebendazole, a medication usually used to treat parasitic worm infestations, as a putative drug to circumvent chemoresistance. We evaluated the efficacy of this drug in cell culture models of hepatoblastoma and found that both short- and long-term tumor cell growth were significantly inhibited upon treatment. Moreover, we identified the cellular and molecular consequences of mebendazole treatment to be the arrest of cell division and the induction of programmed cell death by the deregulation of genes involved in the unwindosome. Most importantly, mebendazole also proved effective when tested in a mouse model carrying a patient-derived tumor. Our results demonstrate the successful repurposing of mebendazole as a new treatment option for chemoresistant hepatoblastoma. Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin, the current treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony and tumor spheroid formation capabilities, cell cycle arrest, and induction of apoptosis of hepatoblastoma cells. Mechanistically, mebendazole causes blockage of microtubule formation and transcriptional downregulation of genes encoding the unwindosome, which are highly expressed in chemoresistant tumors. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model without side effects. In conclusion, our results strongly support the clinical use of mebendazole in the treatment of chemoresistant hepatoblastoma and highlight the potential theranostic value of unwindosome-associated genes.

Aim: Stratification of hepatoblastoma (HB) patients is based on clinical and imaging characteristics obtained at the time of diagnosis. We aim to integrate biomarkers into a tool that accurately predicts survival of HB patients. Methods: We retrospectively analysed 174 HB patients for the presence of four biomarkers and explored their prognostic potential by correlating with overall survival (OS) and event-free survival (EFS). Results: Mutations of CTNNB1, NFE2L2 and TERT were found in 135 (78%), 10 (6%) and 10 (6%) patients, respectively, and the adverse C2 subtype of the 16-gene signature in 63 (36%) patients. C2-patients had more frequent metastatic disease, higher alpha-fetoprotein levels, non-fetal histology and significantly worse 3-year OS (68% versus 95%) and EFS (63% versus 87%) than C1-patients. Patients carrying a NFE2L2 mutation had a significantly worse 3-year OS (57% versus 88%) than NFE2L2 wild-type patients and were more likely to have vessel invasive growth and non-fetal histology. TERT mutations were almost exclusively found in older patients, whereas CTNNB1 mutations showed no association with any clinical feature or outcome. In a multivariable analysis, the C2 subtype remained a significant predictor of poor outcome with hazard ratios of 6.202 and 3.611 for OS and EFS, respectively. When added to the Children's Hepatic tumors International Collaboration risk stratification, the presence of the C2 subtype identified a group of high-risk patients with a very poor outcome. Conclusion: We propose a new stratification system based on the combination of clinical factors and the 16-gene signature, which may facilitate a risk-adapted management of HB patients. (C) 2020 The Author(s). Published by Elsevier Ltd.

Intussusception commonly affects children in the first year of life but it may rarely also appear in utero. We report a newborn with delayed passing of meconium, repeated vomiting, and abdominal distension in the first week of life. After radiological diagnosis of a small bowel obstruction, the newborn underwent an exploratory laparotomy where an ileal atresia proximal to an intussusception was found. After resection of the affected bowel, an end-to-end anastomosis was possible. The postoperative period was uneventful. This case shows that intrauterine intussusception can be a rare cause for ileal atresia. Fast diagnosis and effective interdisciplinary team work are essential for a satisfying outcome.Invaginationen betreffen in der Regel Kinder im ersten Lebensjahr, sie können sehr selten aber auch bereits intrauterin auftreten. Wir berichten von einem Neugeborenen mit Mekoniumverhalt, wiederholtem Erbrechen und distendiertem Abdomen in der ersten Lebenswoche. Nach radiologischer Diagnose eines gastrointestinalen Passagehindernis’ erfolgt am 7. Lebenstag die explorative Laparatomie. Hier zeigt sich ein atretisches distales Ileum und aboral davon eine Invagination. Nach Resektion dieser Darmabschnitte gelingt eine End-zu-End-Anastomose. Der postoperative Verlauf ist unkompliziert. Der Fall veranschaulicht, dass bei einem gastrointestinalen Passagehindernis in der Neonatalperiode auch an eine Invagination als Ursache gedacht werden sollte. Eine rasche Diagnostik und gute interdisziplinäre Zusammenarbeit mit den Kollegen der Kinderchirurgie sind ausschlaggebend für einen zufriedenstellenden Verlauf.

Objective: To create the first structured surgical report form for NBL with international consensus, to permit standardized documentation of all NBL-related surgical procedures and their outcomes. Summary of Background Data: NBL, the most common extracranial solid malignant tumor in children, covers a wide spectrum of tumors with significant differences in anatomical localization, organ or vessel involvement, and tumor biology. Complete surgical resection of the primary tumor is an important part of NBL treatment, but maybe hazardous, prone to complications and its role in high-risk disease remains debated. Various surgical guidelines exist within the protocols of the different cooperative groups, although there is no standardized operative report form to document the surgical treatment of NBL. Methods: After analyzing the treatment protocols of the SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie – German Association of Pediatric Oncology and Haematology pediatric cooperative groups, important variables were defined to completely describe surgical biopsy and resection of NBL and their outcomes. All variables were discussed within the Surgical Committees of SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie – German Association of Pediatric Oncology and Haematology. Thereafter, joint meetings were organized to obtain intercontinental consensus. Results: The “International Neuroblastoma Surgical Report Form” provides a structured reporting tool for all NBL surgery, in every anatomical region, documenting all Image Defined Risk Factors and structures involved, with obligatory reporting of intraoperative and 30 day-postoperative complications. Conclusion: The International Neuroblastoma Surgical Report Form is the first universal form for the structured and uniform reporting of NBL-related surgical procedures and their outcomes, aiming to facilitate the postoperative communication, treatment planning and analysis of surgical treatment of NBL.

Background Long segment laryngotracheoesophageal clefts (LTECs) are very rare large‐airway malformations. Over the last 40 years mortality rates declined substantially due to improved intensive care and surgical procedures. Nevertheless, long‐term morbidity, comorbidity, and clinical outcomes have rarely been assessed systematically. Methods In this retrospective case series, the clinical presentation, comorbidities, treatment, and clinical outcomes of all children with long‐segment LTEC that were seen at our department in the last 15 years were collected and analyzed systematically. Results Nine children were diagnosed with long segment LTEC (four children with LTEC type III and five patients with LTEC type IV). All children had additional tracheobronchial, gastrointestinal, or cardiac malformations. Tracheostomy for long‐time ventilation and jejunostomy for adequate nutrition was necessary in all cases. During follow‐up one child died from multiorgan failure due to sepsis at the age of 43 days. The clinical course of the other eight children (median follow‐up time 5.2 years) was stable. Relapses of the cleft, recurrent aspirations, and respiratory tract infections led to repeated hospital admissions. Conclusions Long‐segment LTECs are consistently associated with additional malformations, which substantially influence long‐term morbidity. For optimal management, a multidisciplinary approach is essential.

In contrast to adults, neoplastic tumors of the esophagus are exceedingly rare during childhood and adolescence (Pappo and Furman 2006). As primary tumors of other parts of the gastrointestinal tract, also those of the esophagus almost never affect infants and toddlers but rather school-age children and adolescents (Ladd and Grosfeld 2006). In the SEER registry of 1992–2007, a rate of

Simple Summary Currently, patients with high-risk neuroblastoma are uniformly treated with maximum therapy. This study investigated a high-risk subgroup characterized by the presence of the amplified MYCN oncogene in the tumor regardless of the stage. In contrast to the corresponding high-risk subgroup consisting of patients with metastases and age at diagnosis over 18 months, the investigated subgroup had generally a superior survival chance. However, the detection of mutations of specific genes in the tumor tissue (RAS and p53 pathway including ALK) had a strong, negative impact. These genes should be therefore also investigated in the future. Complete surgical removal of the primary tumor proved to be beneficial for high-risk neuroblastoma patients assigned to the high-risk category solely by MYCN amplification. Abstract Background: To identify variables predicting outcome in neuroblastoma patients assigned to the high-risk group solely by the presence of MYCN oncogene amplification (MNA). Methods: Clinical characteristics, genomic information, and outcome of 190 patients solely assigned to high-risk neuroblastoma by MNA were analyzed and compared to 205 patients with stage 4 neuroblastoma aged ≥18 months with MNA (control group). Results: Event-free survival (EFS) and overall survival (OS) at 10 years were 47% (95%-CI 39–54%) and 56% (95%-CI 49–63%), respectively, which was significantly better than EFS and OS of the control group (EFS 25%, 95%-CI 18–31%, p < 0.001; OS 32% 95%-CI 25–39%, p < 0.001). The presence of RAS-/p53-pathway gene alterations was associated with impaired 10-year EFS and OS (19% vs. 55%, and 19% vs. 67%, respectively; both p < 0.001). In time-dependent multivariable analyses, alterations of RAS-/p53-pathway genes and the extent of the best primary tumor resection were the only independent prognostic variables for OS (p < 0.001 and p = 0.011, respectively). Conclusions: Neuroblastoma patients attributed to high risk solely by MYCN amplification have generally a more favorable outcome. Mutations of genes of the RAS and/or p53 pathways and incomplete resection are the main risk factors predicting poor outcome.

Purpose Neuroblastoma (NB) is the most common extracranial, solid tumor in childhood, with a peak incidence in children under 6 years of age. Due to its variable course of disease, which ranges from spontaneous regression to metastatic spread, NB still represents a significant therapeutic challenge. Strikingly, a certain number of NBs intraoperatively show vessel adhesion and/or infiltrative growth, which is often not visible in pre-operative imaging. We proposed the term unexpected vessel infiltration of NB (UVIN) to denote this phenomenon. UVIN represents a major surgical challenge. Methods In this study, we determined frequency and clinical relevance of UVIN in a cohort of 100 NB-patients with subsequent correlation to several unfavorable characteristics of disease. RNA expression levels of MYCN and its co-regulated antisense transcript MYCNOS to identify markers was measured by PCR. Results We found UVIN to be present in 34% of cases and significantly correlated with incomplete resection, MYCN amplification, complications, neoadjuvant therapy, tumor grade and MYCNOS expression levels. MYCN expression levels showed no significant results with UVIN. Conclusion Collectively, our data show that UVIN represents a frequent surgical problem associated with a poor outcome in NB patients. MYCN and MYCNOS seem to be no appropriate markers for UVIN. Type of study Prognosis study. Level of evidence Level III.

The purpose of the German HB99 trial (1999-2008) for hepatoblastoma (HB), was primarily to analyse the effect of high dose (HD) chemotherapy with carboplatin/etoposide (CE) in high risk (HR) patients with extended tumors, vessel involvement, extrahepatic tumor or distant metastases. In standard risk (SR) patients the effect of treatment reduction was analysed.HR patients received 2 cycles CE at conventional dose, followed by 2 at HD with subsequent autologous stem cell transplantation before delayed surgery. SR patients received 3-4 cycles of ifosfamide, cisplatin and doxorubicin (IPA) and delayed surgery. Analysis was on an intention to treat basis including resection rate, AFP decline, event free survival (EFS) and overall survival (OS). The patients with HD therapy were additionally analysed on an "as treated" basis. The results were compared to historical/published data.Of the 142 patients, the 5-y OS was 58% for the 57 HR patients and 94% for the 85 SR patients. The AFP decline after 2 cycles CE was ≥ 50% in90% of the patients. 12/18 (67%) patients treated with HD therapy showed an AFP decline after the first cycle (as treated). Tumor resection was possible in 89% of the patients. The median FU was 7.4 years. Late deaths occurred in 4 patients.Use of HD chemotherapy for HB did not improve patient outcomes, compared to contemporaneous and more recent trials (SIOPEL 4 trial). Reduction of therapy in SR patients was possible without worsening of results compared to previous trials. The tumor response to CE was good. CE can therefore be considered for relapse patients.Die deutsche Studie HB99 für Hepatoblastome (HB) hatte das primäre Ziel den Effekt der Hochdosis (HD) Chemotherapie mit Carboplatin/Etoposid (CE) bei Hochrisiko (HR) Patienten mit ausgedehnten Tumoren, Gefäßbeteiligung, extrahepatischem Tumor oder Fernmetastasen zu analysieren. Zusätzlich wurde eine Therapiereduktion bei Standardrisiko (SR) Patienten analysiert.HR Patienten erhielten 2 Blöcke CE in konventioneller Dosis gefolgt von 2 mit HD mit anschließender Stammzelltransplantation und Resektion. SR Patienten erhielten 3–4 Blöcke Ifosfamid, Cisplatin und Doxorubicin (IPA) mit verzögerter Resektion. Die Analyse nach „intention to treat“ beinhaltete Resektionsrate, AFP Abfall, ereignisfreies Überleben (EFS) und Gesamtüberleben (OS). Die mit HD Therapie behandelten Patienten wurden zusätzlich nach „as treated“ ausgewertet. Die Ergebnisse wurden mit historischen/publizierten Daten verglichen.Von 142 Patienten war das 5-J OS der 57 HR Patienten 58% das 5-J OS der 85 SR Patienten 94%. Ein AFP Abfall ≥ 50% war nach 2 Blöcken CE bei90% der Patienten erreicht worden. 12/18 (67%) der mit HD behandelten Patienten zeigten eine AFP Abfall nach dem ersten Block (as treated). Eine Tumorresektion konnte in 89% der Patienten durchgeführt werden. Die mittlere Nachbeobachtung war 7,4 Jahre. Späte Todesfälle traten bei 4 Patienten auf.Mit der HD Chemotherapie konnte das Gesamtüberleben der Patienten mit HB nicht verbessert werden, verglichen mit zeitgleichen oder neueren Studien (SIOPEL 4). Die Therapie für SR Patienten konnte reduziert werden ohne die guten Ergebnisse früherer Studien zu verändern. Das Ansprechen des Tumors auf CE war gut, daher kann CE für Rezidivpatienten erwogen werden.

(1) Background: Vena cava thrombus (VCT) is rare in Wilms tumor (WT) (4–10%). The aim of this study is to identify factors for an outcome to improve treatment for better survival. (2) Methods: 148/3015 patients with WT (aged < 18 years) and VCT, prospectively enrolled over a period of 32 years (1989–2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH), are retrospectively analyzed to describe clinical features, response to preoperative chemotherapy (PC) (142 patients) and surgical interventions and to evaluate risk factors for overall survival (OS). (3) Results: 14 VCT regressed completely with PC and another 12 in parts. The thrombus was completely removed in 111 (85.4%), incompletely in 16 (12.3%), and not removed in 3 (2.3%). The type of removal is unknown in four patients. Patients without VCT have a significantly (p < 0.001) better OS (97.8%) than those with VCT (90.1%). OS after complete resection is (89.9%), after incomplete (93.8%) and with no resection (100%). Patients with anaplasia or stage IV without complete remission (CR) after PC had a significantly worse OS compared to the remaining patients with VCT (77.1% vs. 94.4%; p = 0.002). (4) Conclusions: As a result of our study, two risk factors for poor outcomes in WT patients with VCT emerge: diffuse anaplasia and metastatic disease, especially those with non-CR after PC.

Hepatoblastoma represents the most common primary malignancy of the liver in childhood. Pathological activation of the WNT signaling pathway is characteristic for hepatoblastoma caused by mutations of CTNNB1 or other genes encoding components of the pathway. Genome-wide chromosomal analyses uncovered recurrent chromosomal alterations, in particular gain of chromosome 2q, and in some cases amplification of the region 2q24 that suggests the presence of a so far unidentified oncogene in this chromosomal region. The aim of this study was to identify and further characterize this oncogene. In the framework of the clinical hepatoblastoma study of the German Society for Pediatric Oncology and Hematology, we had the opportunity to study samples of 76 hepatoblastoma patients. Using molecular inversion probe (MIP) array technology, genome-wide, high-resolution, quantitative chromosomal copy number profiles were generated and the smallest overlapping amplified region was identified. RNA and protein expression in normal and diseased tissues as well as ascribed functions of the genes located in this area were evaluated in silico in available databases. RNA expression levels of these genes were analyzed by Nanostring method and Affymetrix arrays and compared between 2q24-amplified tumors versus non-amplified tumors and normal liver tissue. The most promising candidate gene regarding its expression pattern and described function was selected for further analysis. Its protein expression was studied in situ by immunohistochemistry in hepatoblastoma tissue microarrays. The biological function was analyzed in vitro by targeted siRNA-mediated knockdown experiments in 3 hepatoblastoma cell lines (HepT1, HepG2, HuH6) und subsequent cell growth assays (MTT) and WNT signaling pathway specific luciferase reporter assays. Gain of chromosome 2q was present in 44.7% of the cases. Amplification of the 2q24.2-24.3 region was detected in 11.8%. In the smallest overlapping amplified region of 5.6 Mbp, we could accurately map 20 protein coding genes, three genes encoding long noncoding RNAs and one gene encoding a micro-RNA. The RBMS1 gene encoding a single-stranded DNA/RNA binding protein showed significant RNA overexpression in 2q24 amplified tumors. This overexpression was validated by immunohistochemical studies at the protein level. RBMS1 knockdown by specific siRNA transfection resulted in a significantly reduced proliferation of hepatoblastoma cells. RBMS1 knockdown also resulted in a marked reduction of the WNT pathway activity in these cells. We identified RBMS1 located within the amplicon on chromosome 2q24 as a potential oncogenic driver in hepatoblastoma. Initial data suggest that RBMS1 may exert this function by interaction with the WNT signaling pathway that is pathologically activated in hepatoblastoma. Citation Format: Martin Rodemann, Verena Dreschmann, Evelyn Dörner, Dietrich von Schweinitz, Christian Vokuhl, Torsten Pietsch. Identification of RBMS1 in the amplified region 2q24 as a major driver of cellular growth in childhood hepatoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2492.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. Significance: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes. See related commentary by Eggermont et al., p. 2677 . This article is highlighted in the In This Issue feature, p. 2659

Background Children with hepatoblastoma (HB) are at risk of sarcopenia due to immobility, chemotherapy, and malnutrition. We hypothesized that children with HB have a low preoperative total psoas muscle area (tPMA), reflecting sarcopenia, which negatively impacts outcome. Procedure Retrospective study of children (1-10 years) with hepatoblastoma treated at a large university children's hospital from 2009 to 2018. tPMA was measured as the sum of the right and left psoas muscle area (PMA) at intervertebral disc levels L3-4 and L4-5. z-Scores were calculated using age- and gender-specific reference values and were compared to anthropometric measurements, clinical variables, and outcomes. Sarcopenia was defined as a tPMA z-score below -2. Results Thirty-three children were included. Mean tPMA z-score was -2.18 ± 1.08, and 52% were sarcopenic. A poor correlation between tPMA and weight was seen (r = 0.35; confidence interval [CI] 0.01, 0.62; P = .045), and most children had weights within the normal range (mean z-score -0.55 ± 1.39). All children categorized as high risk with relapse (n = 5/12) were sarcopenic before surgery. Relapse was significantly higher in the high-risk sarcopenic group compared to the nonsarcopenic group (P = .008). The change in tPMA z-score 1-4 months after surgery did not improve in patients with relapse, but did improve in 75% of children without relapse. Conclusions The majority of children with HB were sarcopenic prior to surgery. Especially in children with high-risk hepatoblastoma, sarcopenia is an additional risk factor for relapse. Large multicenter studies are needed to confirm these preliminary results.

Hepatoblastoma (HB) is the most common malignant liver tumor in childhood and it generally has a good prognosis. However, if associated with aggressive metastatic disease, outcome is still poor. The molecular mechanisms leading to metastatic spread in HB patients are still unknown. By combining RNA-sequencing and a genome-wide methylome analysis, we identified the transcription factor SP8 and the growth factor FGF8 among the most strongly upregulated genes in metastatic HB cases, with a concomitant robust demethylation of the respective promoter regions. Of note, high expression of both candidates was associated with the aggressive C2 subtype of the 16-gene signature and poor survival. Chromatin immunoprecipitation revealed a direct transcriptional regulation of FGF8 through binding of SP8 to the

Introduction Postoperative diaphragmatic hernia (DH) is a rare but potentially life-threatening complication following pediatric liver transplantation (LT). In the current literature, a total of 49 such hernias have been reported in 17 case series. We present eight additional cases, three of which reoccurred after surgical correction, and review the current literature with a focus on recurrence. Materials and Methods The study sample included children ( Results For the eight children with DH, the mean age at LT was 28.0 (5–132) months. All patients with a DH received left lateral segment split grafts except one, who received a full left lobe. The mean weight at time of LT was 11.8 (6.6–34) kg. Two patients had a primary abdominal muscle closure, and six had a temporary silastic mesh closure. All eight children presented with a right posterolateral DH. The small bowel was herniated in the majority of cases. Symptoms reported included nausea, vomiting, and respiratory distress. Two patients were asymptomatic, and discovery was incidental. All patients underwent prompt primary surgical repair. Three DH hernias (37.5%) recurred despite successful surgical correction. Conclusion DH following liver transplant with technical variant grafts may be underreported and is prone to recur despite surgical correction. A better understanding of the pathophysiology and more thorough reporting may help increase awareness. Early detection and prompt surgical management are the cornerstones of a successful outcome.

Introduction Pelvic neuroblastoma (NB) is a rare entity and occurs in 2 to 5% of all NBs. Surgery in the pelvic area is—even for the experienced oncological surgeon—technically challenging, as injuries of bladder and/or rectal innervation may carry lifelong consequences for the patient. Several studies have proven the impact of image-defined risk factors (IDRFs) for outcome, complications and extent of resection in NB; however, the specific role of IDRF in pelvic NB has not been investigated yet. Materials and Methods Patient charts were retrospectively evaluated for International Staging System stage, IDRF status, MYCN amplification, and outcome parameters. Results Between 2003 and 2019, 277 NBs were surgically resected in the department of pediatric surgery of Dr. von Hauner Children's Hospital. Out of these, 11 patients (3.9%) had pelvic NB. Evaluation of the preoperative imaging showed two patients without IDRF (stage L1) and eight patients in stage L2. One patient had stage M according to distant metastasis. Patients without IDRF underwent complete macroscopical resections, whereas complete tumor removal was not possible without mutilation in patients with IDRF. At time point of diagnosis, only patients with IDRF had functional neurological problems. Three patients developed perioperative complications; all of them had at least one IDRF. Three patients developed local recurrence during the course of the disease, all of them had at least one IDRF. Conclusion Our results indicate on a preliminary level the importance of IDRF as a prognostic tool for surgical removal of pelvic NB.

Background Ethiopia is a rapidly developing country in Eastern Africa. 43.2% of the population is younger than 15. In contrast, until a few years ago, pediatric surgery was only available in Addis Ababa. Now, Ethiopia is making great efforts to improve the care of surgical ill children. JimmaChild was established to set up a pediatric surgery in Jimma. Methods JimmaChild developed from a scientific collaboration between Jimma University (JU) and Ludwig-Maximilians-University. The project was developed and realized by Ethiopian and German colleagues. A curriculum was written for this purpose. The pediatric surgical training of the fellows was carried out on-site by German pediatric surgeons. Results A new pediatric surgery was established at JU with its own operating room, ward, and staff. After two and a half years, two fellows completed their final examinations as pediatric surgeons. Among others, 850 elective surgeries were performed, 82% assisted by the German colleagues. The German colleagues rated the preparation for the trip, the on-site support, and the professional progress of the fellows mostly as good to very good. Reported problems in the program flow were also recognized and solved in part. Conclusions Best possible integration of the project into existing structures was achieved by close cooperation of Ethiopian and German colleagues during the project development. Problems were identified and addressed early on by external monitoring. As the project responsibility was mainly with the Ethiopian colleagues, a department was created that now exists independent of external funding and trains its own fellows.

Background The role of microRNAs (miRs) as biomarkers to predict outcome in hepatoblastoma (HB), the most common malignant liver tumor in childhood, has still to be determined. Recently, the so-called four-miR signature has been described to efficiently stratify HB patients according to their prognosis. Objective We examined the recently described four-miR signature for its clinical relevance in an independent validation cohort of HB patients and tried to optimize its predictive value by analyzing four additional miRs involved in HB biology. Methods Expression of eight miR was determined in 29 tumor and 10 normal liver samples by TaqMan assays and association studies and Kaplan-Meier estimators determined their clinical relevance. Results Stratifying HB patients by the four-miR signature showed no difference in patients' outcome, which was also reflected by the lack of association with any clinical risk parameter. Adding miR-23b-5p and miR-23b-3p did also not increase its discriminating power. However, the integration of miR-483-5p and miR-483-3p into the four-miR signature could predict patients with poor outcome that were associated with large tumors and vessel invasive growth with high accuracy. Conclusions The expansion of the four-miR signature by miR-483 serves as a useful biomarker to predict outcome of HB patients.