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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.

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.

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.

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.

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

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.

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 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.

Introduction Neuroblastoma is the most common extracranial solid tumor in infancy. It is responsible for around 15% of all oncological deaths during childhood. Due to its retroperitoneal location, neuroblastoma is invasively growing directly in and around the lymphatic duct. Consecutively, lymphatic leakage (LL) after surgery for neuroblastoma is a known complication. The purpose of this study is the investigation of frequency and impact of this complication. Material and Methods Between February 2003 and December 2016, 204 patients with neuroblastoma received surgical treatment in our department. A retrospective analysis for macroscopical extent of resection, duration of drainage postsurgery, maximum amount of fluid drained in 24 hours, MYCN amplification status, therapeutic options for LL, follow-up status, and overall survival was performed. Results A total of 40% of patients (82/204) showed LL to some extent. In patients with MYCN amplification, LL was seen significantly more often than in patients without MYCN amplification status (p = 0.019). LL was also significantly correlated with extent of surgery (p = 0.005). Follow-up status and overall survival were significantly inversely associated with LL (p = 0.004 and p = 0.0001). LL was self-limiting in all cases. There was a trend toward shorter duration of LL if either no special therapy was chosen or total parenteral nutrition (TPN) was administered (p = 0.0603). Conclusion We show that LL in neuroblastoma is a common complication of tumor resection and occurring more often than anticipated. Since, in our study cohort, all cases of LL were self-limiting, we question the indication for invasive therapy besides supporting measures.

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 &lt, 0.001, OS 32% 95%-CI 25–39%, p &lt, 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 &lt, 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 &lt, 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.

Background Although several studies have been conducted on the role of surgery in localized neuroblastoma, the impact of surgical timing and extent of primary tumor resection on outcome in high-risk patients remains controversial. Methods Patients from the German neuroblastoma trial NB97 with localized neuroblastoma INSS stage 1–3 age > 18 months were included for retrospective analysis. Imaging reports were reviewed by two independent physicians for Image Defined Risk Factors (IDRF). Operation notes and corresponding imaging reports were analyzed for surgical radicality. The extent of tumor resection was classified as complete resection (95–100%), gross total resection (90–95%), incomplete resection (50–90%), and biopsy (

The clinical course of neuroblastoma is more heterogeneous than any other malignant disease. Most low-risk patients experience regression after limited or even no chemotherapy. However, more than half of high-risk patients die from disease despite intensive multimodal treatment. Precise patient characterization at diagnosis is key for risk-adapted treatment. The guidelines presented here incorporate results from national and international clinical trials to produce recommendations for diagnosing and treating neuroblastoma patients in German hospitals outside of clinical trials.

Summary Background Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the four major trial groups. To address this challenge, we formed a global coalition, the Children's Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer. Methods The CHIC steering committee—consisting of leadership from the four major cooperative trial groups (the International Childhood Liver Tumours Strategy Group, Children's Oncology Group, the German Society for Paediatric Oncology and Haematology, and the Japanese Study Group for Paediatric Liver Tumours)—created a shared international database that includes comprehensive data from 1605 children treated in eight multicentre hepatoblastoma trials over 25 years. Diagnostic factors found to be most prognostic on initial analysis were PRETreatment EXTent of disease (PRETEXT) group; age younger than 3 years, 3–7 years, and 8 years or older; α fetoprotein (AFP) concentration of 100 ng/mL or lower and 101–1000 ng/mL; and the PRETEXT annotation factors metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal bifurcation (P), contiguous extrahepatic tumour (E), multifocal tumour (F), and spontaneous rupture (R). We defined five clinically relevant backbone groups on the basis of established prognostic factors: PRETEXT I/II, PRETEXT III, PRETEXT IV, metastatic disease, and AFP concentration of 100 ng/mL or lower at diagnosis. We then carried the additional factors into a hierarchical backwards elimination multivariable analysis and used the results to create a new international staging system. Results Within each backbone group, we identified constellations of factors that were most predictive of outcome in that group. The robustness of candidate models was then interrogated using the bootstrapping procedure. Using the clinically established PRETEXT groups I, II, III, and IV as our stems, we created risk stratification trees based on 5 year event-free survival and clinical applicability. We defined and adopted four risk groups: very low, low, intermediate, and high. Interpretation We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare paediatric tumour. This achievement provides the structural framework for further collaboration and prospective international cooperative study, such as the Paediatric Hepatic International Tumour Trial (PHITT). Funding European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission (grant number 261474); Children's Oncology Group CureSearch grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research; and Swiss Cancer Research grant.

We report a case of a 9-year-old female who required surgical treatment and resuscitation after severe transoesophageal bleeding of a right aberrant subclavian artery (RASA). Bleeding of this RASA was caused by a mechanical irritation due to an oesophageal stent. The stent was placed weeks before to dilate the oesophagus after accidental ingestion of a caustic agent. Although conservative management of benign oesophageal stenosis in children is highly recommended, there are still some major complications to be considered. To avoid erosion of aberrant subclavian artery vascular rings and slings, as described in several case reports, these vessels should be excluded by computed tomography (CT) or magnetic resonance imaging (MRI) scans before placement of oesophageal stents. This case suggests that management of caustic ingestion in children is still a major challenge in paediatric surgical departments. Keywords: Paediatric surgery, Chemical Burn, Oesophageal stenosis, Oesophageal stenting, Vascular abnormalities, Right aberrant subclavian artery

Purpose: Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification.Methods: We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors.Results: Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture.Conclusion: Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.

Background/aim Hepatic hemangiomas (HH) can show an aggressive course with significant complications. Prognostic markers that identify an aggressive course are entirely absent. Since we have showed that Hedgehog signaling is overexpressed in aggressive hemangiomas of the skin. Here, we hypothesize that it is also altered in aggressive HH. Materials and methods Immunohistological staining for GLUT1 and quantitative PCR was performed in seven specimens with aggressive HH. For comparison, we included specimens of kaposiform hemangioendothelioma (KHE), skin hemangioma and normal liver tissue. Results Overexpression of the Hedgehog signaling components SHH and GLI2 and its target gene FOXA2 in HH were similar to those found in aggressive skin hemangioma and KHE, their expression being significantly higher than in mild skin hemangioma. High expression levels of SHH and FOXA2 positively correlated with HH, but not with normal liver tissue. Conclusion Hedgehog signaling is up-regulated in aggressive HH. This finding may lead to a biomarker allowing early intervention.

Introduction: Both a Hickman catheter (HC) and port catheter (Port) can be inserted either percutaneously by the Seldinger technique or by surgical venous cut-down. Catheters are inserted with a vessel-sparing technique when they are placed in the internal jugular vein (IJV) by venous cut-down. Although this technique is common, data are sparse regarding the vessel's state at long-term follow-up. This study was aimed at determining the flow pattern and constitution of the IJV after vessel-sparing implantation of an HC or Port and comparing the outcomes to those of implantation with the Seldinger technique. Methods: One hundred children (58 boys, 42 girls) between 33 days and 18 years of age who underwent a vessel-sparing implantation of an HC or Port in the IJV were prospectively included. All patients underwent surgical venous cut-down at a single institution. Patency and shape of the IJV were determined by ultrasound and categorized according to 2 possible outcomes: relevant alteration (including occlusion of the IJV) and no relevant alteration, with relevant alteration defined as changes that caused an altered flow pattern. Results: Median age was 6 years at the time of operation, and the median indwelling time of catheters was 271 days. Twenty-two of our patients (22%) showed relevant alterations. These changes included high-grade stenosis or lesion in 13 patients (13%) and occlusion in 9 patients (9%). There were no operation-associated complications, such as pneumothorax, hematopericardium, or accidental puncture of the carotid artery. Statistical analysis did not reveal any specific parameter as a risk factor for relevant structural abnormalities. Discussion: In a comparison of our data to the literature, venous cut-down showed an alteration rate of 26% and a patency rate of 85%, whereas the Seldinger technique was found to cause alteration in 15%, with a patency rate of 97% but a successful placement rate of only 90.3-91.6%. Conclusion: The indication for long-term catheter placement may determine which method is preferable. A child who is likely to need more catheters in the future might benefit from the Seldinger technique, since there is a higher chance of long-term patency of the vessel. A patient undergoing chemotherapy might benefit more from the surgical venous cut-down with less placement-associated complications.

Introduction: Ethiopia is a rapidly developing country in Eastern Africa. In total, 43.2% of the population are 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 children who require surgery. JimmaChild was established to set up a pediatric surgery in Jimma. Material and 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: The 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 independently of external funding and trains its own fellows.

Wilms tumor (WT) is the most common pediatric renal malignancy. A recent ontogenic model suggests that undifferentiated tumor state, and hence poor prognosis, in WT is determined by stabilization of β-catenin in the nucleus. Forkhead box M1 (FOXM1) is a downstream component of the Wnt pathway and promotes nuclear localization of β-catenin. As elevation of FOXM1 gene expression is prognostic in various types of malignancy, we hypothesized that high FOXM1 expression in WT is associated with undifferentiated histology and thus poor prognosis. In the current study, the expression of FOXM1 mRNA was determined in 46 WT specimens and 11 renal tissue controls from patients undergoing tumor nephrectomy, and these data were assessed with regard to clinicopathological parameters. The results demonstrated an upregulation of FOXM1 in WT by 10-fold compared to normal tissue. Expression differed significantly between controls and tumors of intermediate- and high-risk histopathology (P

We report on four female adolescents, who presented with inflammatory symptoms. Extensive diagnostic workup revealed tumors on different locations. After surgical removal, clinical and laboratory signs of inflammation disappeared rapidly. On histology, the tumors showed a mixture of inflammatory cells characteristic of inflammatory pseudotumors in three of the patients.In patients with unclear inflammatory symptoms, inflammatory pseudotumor should be added to the differential diagnosis.• The inflammatory pseudotumor (IPT) is a mostly benign myofibroblastic tumor of the soft tissue and causes inflammatory symptoms. What is new: • IPTs have may wider than hitherto defined histologic features. Removal of IPT is curative.

Contemporary state-of-the-art management of cancer is increasingly defined by individualized treatment strategies. For very rare tumors, like hepatoblastoma, the development of biologic markers, and the identification of reliable prognostic risk factors for tailoring treatment, remains very challenging. The Children's Hepatic tumors International Collaboration (CHIC) is a novel international response to this challenge.Four multicenter trial groups in the world, who have performed prospective controlled studies of hepatoblastoma over the past two decades (COG; SIOPEL; GPOH; and JPLT), joined forces to form the CHIC consortium. With the support of the data management group CINECA, CHIC developed a centralized online platform where data from eight completed hepatoblastoma trials were merged to form a database of 1605 hepatoblastoma cases treated between 1988 and 2008. The resulting dataset is described and the relationships between selected patient and tumor characteristics, and risk for adverse disease outcome (event-free survival; EFS) are examined.Significantly increased risk for EFS-event was noted for advanced PRETEXT group, macrovascular venous or portal involvement, contiguous extrahepatic disease, primary tumor multifocality and tumor rupture at enrollment. Higher age (≥ 8 years), low AFP (100 ng/ml) and metastatic disease were associated with the worst outcome.We have identified novel prognostic factors for hepatoblastoma, as well as confirmed established factors, that will be used to develop a future common global risk stratification system. The mechanics of developing the globally accessible web-based portal, building and refining the database, and performing this first statistical analysis has laid the foundation for future collaborative efforts. This is an important step for refining of the risk based grouping and approach to future treatment stratification, thus we think our collaboration offers a template for others to follow in the study of rare tumors and diseases.

Despite tremendous progress in therapy, about 30 % of patients with hepatoblastoma still succumb to the disease. Thus, the development of improved therapies as well as the identification of prognostic factors are urgently needed. In the present study, expression and promoter methylation of the N-myc downstream-regulated gene (NDRG2), a tumor suppressor gene contributing to the regulation of the Wnt signalling pathway, was analysed in 38 hepatoblastoma samples by real-time reverse transcription-PCR and pyrosequencing, respectively. The NDRG2 gene was highly expressed in normal pediatric liver tissue, but was significantly downregulated in heptoblastoma primary tumors. Detailed methylation analysis of CpG sites in the NDRG2 promoter region revealed a general high degree of DNA methylation in hepatoblastoma, which correlated with the suppression of NDRG2. By analyzing clinicopathological features we could demonstrate a strong association between low NDRG2 expression and tumor metastasis. Importantly, the overall survival analysis by Kaplan–Meier revealed that high NDRG2 expression was correlated with a higher survival rate in hepatoblastoma patients. Our data show that downregulation of NDRG2 may play an important role in advanced hepatoblastomas.

The purpose of this study was to develop a user-friendly presentation of surface-EMG data in near-time for intraoperative nerve-monitoring. We have built a novel surface-EMG probe as a diagnostic device to investigate innervation patterns of sphincter muscles in further clinical diagnostic studies. S-EMG data were recorded from 20 healthy volunteers from the orbicularis oris muscles. We developed an automated analysis based on correlation in order to find phase inversions and thus innervation zones automatically. We compared our automated analysis with manual, visual analysis. Both techniques were reviewed for variance and showed reproducible results. Data from automated analysis were compared to visually analyzed data showing high consistency. Based on our automated analysis, we created an intuitive visualization of all measurements per person. We displayed the quality and quantity of the phase inversions found in a subject thus allowing for simple identification of innervation zones. We conclude that our set-up showed sufficient reliability for detection of motoric endplate activity and can be used for further clinical neurophysiological studies.

Neuroblastoma is the most common solid extracranial malignant tumor in children. Despite recent advances in the treatment of this heterogenous tumor with surgery and chemotherapy, the prognosis in advanced stages remains poor. Interestingly, neuroblastoma is one of the few solid tumors, to date, in which an effect for targeted immunotherapy has been proven in controlled clinical trials, giving hope for further advances in the treatment of this and other tumors by targeted therapy. A large array of novel therapeutic options for targeted therapy of neuroblastoma is on the horizon. To this repεrtoirε, the neurokinin-1 receptor (NK1R) system was recently added. The present article explores the most recent developments in targeting neuroblastoma cells via the NK1R and how this new knowledge could be helpful to create new anticancer therapies agains neuroblastoma and other cancers.

The option of nephron sparing surgery for unilateral Wilms tumor has been debated in the recent literature. This procedure is being used increasingly to preserve kidney tissue and function. However, nephron sparing surgery is feasible only for selected cases, and a higher local relapse rate has been observed. Moreover, a significant reduction of nephrons is associated with development of renal hypertension and progressive renal failure. We analyzed outcomes after bilateral partial nephrectomy and unilateral partial plus contralateral total nephrectomy in patients with bilateral Wilms tumor.We analyzed data from the Society of Pediatric Oncology and Hematology database on 22 patients with bilateral Wilms tumor. Kidney size was measured using volumetric analysis of magnetic resonance imaging. Patients were matched with children who had undergone magnetic resonance imaging of the abdomen for other malignancies.Mean kidney volumes after unilateral partial plus total contralateral nephrectomy (66.9 cm(3)) were significantly greater than the reference kidneys (p = 0.028), whereas controls were equal to the bilateral partial nephrectomy group (49.7 cm(3), p = 0.959). Total kidney volume was significantly larger after bilateral partial nephrectomy (102.1 cm(3)) vs unilateral partial plus total contralateral nephrectomy (66.9 cm(3), p = 0.0338). Eight patients (66.7%) had renal hypertension after unilateral partial plus total contralateral nephrectomy but only 2 (20%) after bilateral partial nephrectomy (p = 0.043). Overall survival and relapse rates were equal between the groups and did not correlate with unfavorable histology.Our findings suggest that patients with bilateral Wilms tumor benefit from bilateral nephron sparing surgery. Hypertension is less common after bilateral partial nephrectomy, and rates of local relapse or disease associated death are distributed equally between the groups.

Infantile hemangioma is a vascular neoplasm and is one of the most common tumors diagnosed in young children. Although most hemangiomas are harmless and involute spontaneously, some show severe progression, leading to serious complications, such as high-output cardiac failure, ulcerations, compression of the trachea or deprivation amblyopia, depending on their size and localization. However, the pathogenesis and cause of hemangioma are largely unknown to date. The goal of this study was to identify markers that could predict hemangiomas with aggressive growth and severe progression that would benefit from early intervention. By using a PCR-based screening approach, we first confirmed that previously known markers of hemangioma, namely FGF2 and GLUT1, are highly expressed in hemangioma. Nevertheless, these genes did not show any differential expression between severely progressing tumors and mild tumors. However, transcriptional upregulation of several Hedgehog signalling components, comprising the ligand Sonic Hedgehog (SHH), the transcription factor GLI2 and its target gene FOXA2 were detected in extremely aggressive hemangioma specimens during the proliferation phase. Notably, GLI2 was even overexpressed in involuting hemangiomas if they showed an aggressive growth pattern. In conclusion, our data suggest that overexpression of the Hedgehog components SHH, GLI2 and FOXA2 might be used as markers of an aggressive hemangioma that would benefit from too early intervention, while FGF2 and GLUT1 are more general markers of hemangiomas.

Background Complete resection of hepatoblastoma (HB) is a demanding procedure in advanced tumors. Perioperative complications are still common. The influence of complication rates on course of disease and survival of patients with HB has not been analyzed yet. Procedures Patients with high risk (HR) HB and standard-risk (SR) HB registered from 1999 to 2008 to the German prospective multicenter study HB99 were evaluated regarding perioperative complications, reasons (e.g., tumor size and vessel involvement) and impact on further treatment and overall survival (OS). Results Surgical data from 126 patients were available (47 HR–HB, 79 SR–HB). Postoperative complications occurred in 26 (21%) patients consisting of biliary leakage (n = 9), cholestasis (n = 5), deficit of liver perfusion (n = 5) and others (n = 7). Twenty of these 26 patients (77%) required a second operation. The rate of postoperative complications was higher in the HR-group (26%) compared to the SR-group (17%). Patients with vessel involvement had significantly more complications (17% vs. 54%, P = 0.01). Patients with PRETEXT I/II-tumors had the same rate of postoperative complications (19% vs. 20%) as patients with PRETEXT III/IV. Patients of HR-group with postoperative complications showed delayed start in adjuvant chemotherapy (>21d) (75% vs. 25%, n.s.) combined with significant lower 5-year-OS (75% vs. 50%, P = 0.02). In multivariate analysis postoperative complications were an independent negative prognostic factor for HR-patients (HR 3.1, P = 0.04). Conclusions Postoperative complications after HB resection are frequent and associated with worsened OS of patients with HR–HB. One possible reason is delay in postoperative chemotherapy. The approach to precarious liver resection should be carefully planned and executed by specialists. Pediatr Blood Cancer 2015;62:24–28. © 2014 Wiley Periodicals, Inc.

Treatment of stage V nephroblastoma is less established and more complex than in unilateral nephroblastoma.Retrospective analysis of 121 consecutive patients with stage V nephroblastoma registered from January 1989 to May 2005. Registration, prospective data collection and treatment were carried out within the framework of 3 consecutive SIOP/GPOH-nephroblastoma-trials.19 patients had metastasis and 29 syndromes at diagnosis. 13 patients had been pretreated for bilateral nephroblastomatosis. 1 patient was not treated and 17 patients had upfront surgery. Preoperative treatment duration ranged from 1-12 weeks (n=103). 1-3 preoperative treatment-cycles resulted in average tumor-volume-reduction of 45%. 1 patient underwent bilateral nephrectomy. 52% of the patients had 2 functioning kidneys after the end of treatment. 20 patients had died after mean follow-up of 8.6 years. 5y-Progression-Free (PFS) and Overall-Survival (OS) were excellent for patients having a localized disease without pretreatment for nephroblastomatosis (5yPFS/OS: 80±4%/93±3%). Metastasis at diagnosis (51±12%/56±12%; p=0.003) and pretreatment for nephroblastomatosis (37±14%/67±13%; p0.001) were associated with significantly poorer outcome. Cox-regression analysis revealed an independent influence of pretreatment for nephroblastomatosis, metastasis and syndromes on PFS. The latter 2 as well as anaplasia and age (2 years or3 years) had an independent influence on OS.Pretreatment for nephroblastomatosis, metastasis and syndromes are independent risk factors. 1-3 preoperative treatment-cycles are sufficient to achieve save nephron-sparing-surgery in most patients.

Introduction Minor surgical interventions in children are often at times challenging due to the lack of cooperation by the child. Procedural sedation and analgesia is often appropriate, but unpleasant or painful applications of medication add additional discomfort to the child. A mixture of nitrous oxide (N2O)/oxygen (O2) in a ratio of 50:50, functioning as an inhalational sedative analgesic, may be a viable alternative, in particular in an emergency care setting because such mixtures require no fasting period and are self-administered. Therefore, in this study we investigated the feasibility and the effectiveness of N2O/O2 (50:50) as a sedative analgesic when performing minor surgical procedures. Patients and Methods Procedural sedation and analgesia with an N2O/O2 (50:50) mixture applied during minor surgical procedures were prospectively evaluated over 2.5 years in a major pediatric hospital in Germany. Indications for sedation were either minor painful interventions, the injection of a local anesthetic, or a digital block in an emergency care setting. Diagnosis, type of surgery, inhalation time, complications, side effects, pain scores, and the child's behavioral reaction were assessed. Results A N2O/O2 (50:50) mixture was administered in 210 children, ages 2.7 to 16.5 years (mean 9.0 years). Three treatments were terminated because of lack of compliance, nausea, or dizziness. No other side effects were encountered. During the intervention, 80.5% of all patients were pain free, and 81.9% were relaxed and calm. A higher rate of insufficient pain control was observed when the indication was an injection of a digital block or a reposition of fractures and dislocations. Conclusions The use of self-administered N2O/O2 (50:50) mixture for minor painful procedures in children is safe and adequate pain control can be achieved in most cases. The benefits of this approach for the child and its parents are its good acceptance and adequate pain control. The benefit for the health care provider is the lack of a fasting period before administration, good anxiolysis at minimum sedation, and a cooperative patient. Limitations are unsatisfying analgesia in some cases. Though not found in our study, potentially serious adverse events are a possibility and standard safety guidelines for minimal sedation should always be applied.

Background The German Childhood Cancer Registry (GCCR) annually registers approximately 2,000 children diagnosed with a malignant disease (completeness of registration >95%). While most pediatric cancer patients are diagnosed and treated according to standardized cooperative protocols of the German Society for Pediatric Oncology and Hematology (GPOH), patients with rare tumors are at risk of not being integrated in the network including trials and reference centers. Procedure A retrospective analysis of all rare extracranial solid tumors reported to the GCCR 2001–2010 (age

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.

Purpose Scintigraphy using 123I-metaiodobenzylguanidine (123I-MIBG) is widely used for the detection of neuroblastic tumours. The aim of this study was to identify a possible correlation between the uptake intensity on 123I-MIBG SPECT and histopathology of neuroblastic tumours.

Background Congenital hepatoblastoma, diagnosed in the first month of life, has been reported to have a poor prognosis; however, a comprehensive evaluation of this entity is lacking. Procedure We retrospectively reviewed two patients from the senior authors' personal series and 25 cases identified in the databases of several multicenter group studies (INT-0098, P9645, 881, P9346, HB 89, HB94, and HB 99). We compared this series with cases of congenital hepatoblastoma previously published in the literature. Results The 3-year survival in our case series was 86% (18/21) with a follow-up of 44–230 months (median 85.5 months). Presentation and treatment were not substantially different from hepatoblastoma cohorts unselected for age. Survival was comparable to the reported disease free survival for a similar cohort of hepatoblastoma patients unselected for age between 1986 and 2002 (82.5%) [von Schweinitz et al., Eur J Cancer 1997; 33:1243–1249]. The 2-year survival of cases reported in the literature was 0% (0/9) and 42% (10/24) for patients reported before and after 1990, respectively. Conclusions Congenital hepatoblastoma does not appear to confer a worse prognosis. The improved survival of our current series of patients, collected from the past 20 years of German and American multicenter trials and personal series, suggests that the outcome of hepatoblastoma at this young age is much better than has been historically reported. More rigorous analysis should be conducted in future multicenter trials. It is possible that congenital hepatoblastoma should be treated like all other patients with hepatoblastoma provided that the child is stable enough to proceed with surgery and chemotherapy. Pediatr Blood Cancer 2013;60:1817–1825. © 2013 Wiley Periodicals, Inc.

Purpose Although intensive multimodal treatment has improved the prognosis of patients with metastatic neuroblastoma, the impact of primary tumor resection on outcome is a matter of medical debate. Patients and Methods Patients from the German prospective clinical trial NB97 with stage 4 neuroblastoma and age 18 months or older at diagnosis were included. Operation notes and imaging reports were reviewed by two independent experienced physicians. Finally, the extent of tumor resections was correlated with local control rate and outcome. Results A total of 278 patients were included in this study. Image-defined risk factors present at diagnosis were found to be predictive for the extent of tumor resection at first (P < .001) and best (P < .001) operation. No patient died from surgery. Before chemotherapy, complete resection, incomplete resection, and biopsy or no surgery were performed in 6.1%, 5.0%, and 88.5% of patients, respectively. The extent of first operation had no impact on event-free survival (EFS; P = .207), local progression–free survival (LPFS; P = .195), and overall survival (OS; P = .351). After induction chemotherapy, 54.7% of patients underwent complete resection of the primary tumor, 30.6% underwent incomplete resection, and 13.3% had only biopsy or no surgery of the primary tumor. The extent of best operation also had no impact on EFS (P = .877), LPFS (P = .299), and OS (P = .778). Moreover, multivariate analyses showed that surgery did not affect EFS, LPFS, and OS. Conclusion In intensively treated patients with stage 4 neuroblastoma age 18 months or older at diagnosis, surgery of the primary tumor site has no impact on local control rate and outcome.

Aim Fundoplication is required for children with chronic recurrent gastro-oesophageal reflux disease (GERD). The aim of this study was to report parental perceptions of symptoms and overall satisfaction with the long-term course following fundoplication with special reference to patients with GERD risk factors. Methods We studied 34 patients, with a median age of 6.5 ± 4.9 years, who received fundoplication between 2001 and 2005. Clinical information and surgical complications were recorded. Parents were interviewed to evaluate post-operative symptoms, mode of nutrition and satisfaction. Results The median follow-up time was 7.3 years. Comorbidities were neurological impairment in 15 patients, other gastrointestinal disorders in seven patients and isolated GERD in 12 patients. The parents reported that fundoplication effectively treated initial reflux symptoms in 60% and improved symptoms in 37%. Vomiting and reflux-associated pain were treated most effectively. Pulmonary symptoms often remained unchanged in neurologically impaired children. Redo fundoplication was necessary in seven patients. Only two parents regretted consenting to surgery. Conclusion A high percentage of parents reported improved gastrointestinal reflux-related symptoms and a high level of satisfaction following fundoplication. Parental perceptions of GERD symptoms should be an important outcome measure when assessing the efficacy of antireflux surgery in children in routine clinical follow-up.

Background Ganglioneuroma (GN) and ganglioneuroblastoma intermixed (GNBI) are mature variants of neuroblastic tumors (NT). It is still discussed whether incomplete resection of GN/GNBI impairs the outcome of patients. Methods Clinical characteristics and outcome of localized GN/GNBI were retrospectively compared to localized neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) registered in the German neuroblastoma trials between 2000 and 2010. Results Of 808 consecutive localized NT, 162 (20 %) were classified as GN and 55 (7 %) as GNBI. GN/GNBI patients presented more often with stage 1 disease (68 % vs. 37 %, p 2 cm. No progression occurred after subtotal resection. Two patients died of treatment, none of tumor progression. Conclusions GN/GNBI account for one quarter of localized NT and differ from immature tumors in their clinical features. Chemotherapy is not effective. Subtotal resection appears to be a sufficient treatment. Trial registration ClinicalTrials.gov identifiers - NB97 (NCT00017225; registered June 6, 2001); NB2004 (NCT00410631; registered December 11, 2006) Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2513-9) contains supplementary material, which is available to authorized users.

Purpose The International Neuroblastoma Response Criteria (INRC) require serial measurements of primary tumors in three dimensions, whereas the Response Evaluation Criteria in Solid Tumors (RECIST) require measurement in one dimension. This study was conducted to identify the preferred method of primary tumor response assessment for use in revised INRC. Patients and Methods Patients younger than 20 years with high-risk neuroblastoma were eligible if they were diagnosed between 2000 and 2012 and if three primary tumor measurements (antero-posterior, width, cranio-caudal) were recorded at least twice before resection. Responses were defined as ≥ 30% reduction in longest dimension as per RECIST, ≥ 50% reduction in volume as per INRC, or ≥ 65% reduction in volume. Results Three-year event-free survival for all patients (N = 229) was 44% and overall survival was 58%. The sensitivity of both volume response measures (ability to detect responses in patients who survived) exceeded the sensitivity of the single dimension measure, but the specificity of all response measures (ability to identify lack of response in patients who later died) was low. In multivariable analyses, none of the response measures studied was predictive of outcome, and none was predictive of the extent of resection. Conclusion None of the methods of primary tumor response assessment was predictive of outcome. Measurement of three dimensions followed by calculation of resultant volume is more complex than measurement of a single dimension. Primary tumor response in children with high-risk neuroblastoma should therefore be evaluated in accordance with RECIST criteria, using the single longest dimension.

Insbesondere im Kleinkindesalter stellen die embryonalen Tumoren Neuroblastom, Nephroblastom und Hepatoblastom eine wichtige Differenzialdiagnose bei Raumforderungen im Bauchraum dar. Aufgrund einer oft nur diskreten und unspezifischen Symptomatik ist der Anteil an Zufallsdiagnosen relativ hoch. Die Diagnostik umfasst die Bestimmung spezifischer Tumormarker, definierte Staginguntersuchungen mit bildgebender Diagnostik sowie histologische und molekulare Analysen des Tumorgewebes. Diagnostik und Therapie erfolgen ausschlieslich in spezialisierten kinderonkologischen Zentren mit multidisziplinarer Expertise im Rahmen definierter Therapieoptimierungsstudien. Wahrend die Prognose bei Nephroblastomen und Hepatoblastomen auch im metastasierten Stadium noch sehr gut ist, liegt die Uberlebensrate metastasierter Neuroblastome bei

Purpose Overall survival is poor in children with primary unresectable hepatocellular carcinoma. Sorafenib has been shown to significantly improve progression-free survival in adult hepatocellular carcinoma (HCC) patients. We evaluated the experience of PLADO (cisplatin 80 mg/m2/day, doxorubicin 2 × 30 mg/m2/day) in combination with sorafenib in pediatric HCC patients. Patients and Methods Clinical data of 12 patients (7–16 years), 7 with unresectable tumor, were retrospectively assessed. Results In total 6/12 (50%) patients are in complete remission after a median follow-up of 20 months (4 with PLADO/sorafenib/resection, 2 with liver transplantation after local relapse). Of the seven patients with unresectable tumor, PLADO/sorafenib resulted in partial response (PR) in four, stable disease (SD) in two, and progression in one. Three are alive in CR after complete resection after 12 (alternative therapy after two cycles PLADO/sorafenib), 12 and 18 months (six cycles PLADO/sorafenib), respectively. All four patients with elevated alpha-fetoprotein levels had a marked drop after two cycles. Of the five patients with primary complete tumor resection one is alive disease-free at 27 months. Four had local or metastatic relapses (13, 7, 12, and 13 months), two of whom were rescued by liver transplantation (CR after 25 and 32 months). The main toxicity attributable to sorafenib was a hand–foot skin reaction (HFSR) in seven patients. Conclusion Sorafenib in combination with PLADO may be a promising approach in pediatric HCC; HFSR was the most important toxicity. Data based on prospective studies are needed to evaluate pharmacokinetics, resectability rates, and survival in pediatric HCC treated with sorafenib. Pediatr Blood Cancer 2012; 58: 539–544. © 2011 Wiley Periodicals, Inc.

To analyse different uptake patterns in 123I-MIBG scintigraphy/SPECT imaging and 18F-FDG PET in paediatric neuroblastoma patients. We compared 23 123I-MIBG scintigraphy scans and 23 18F-FDG PET scans (mean interval 10 days) in 19 patients with a suspected neuroblastic tumour (16 neuroblastoma, 1 ganglioneuroblastoma, 1 ganglioneuroma and 1 opsomyoclonus syndrome). SPECT images of the abdomen or other tumour-affected regions were available in all patients. Indications for 18F-FDG PET were a 123I-MIBG-negative tumour, a discrepancy in 123I-MIBG uptake compared to the morphological imaging or imaging results inconsistent with clinical findings. A lesion was found by 123I-MIBG scintigraphy and/or 18F-FDG PET and/or morphological imaging. A total of 58 suspicious lesions (mean lesion diameter 3.8 cm) were evaluated and 18 were confirmed by histology and 40 by clinical follow-up. The sensitivities of 123I-MIBG scintigraphy and 18F-FDG PET were 50% and 78% and the specificities were 75% and 92%, respectively. False-positive results (three 123I-MIBG scintigraphy, one 18F-FDG PET) were due to physiological uptake or posttherapy changes. False-negative results (23 123I-MIBG scintigraphy, 10 18F-FDG PET) were due to low uptake and small lesion size. Combined 123I-MIBG scintigraphy/18F-FDG PET imaging showed the highest sensitivity of 85%. In 34 lesions the 123I-MIBG scintigraphy and morphological imaging findings were discrepant. 18F-FDG PET correctly identified 32 of the discrepant findings. Two bone/bone marrow metastases were missed by 18F-FDG PET. 123I-MIBG scintigraphy and 18F-FDG PET showed noticeable differences in their uptake patterns. 18F-FDG PET was more sensitive and specific for the detection of neuroblastoma lesions. Our findings suggest that a 18F-FDG PET scan may be useful in the event of discrepant or inconclusive findings on 123I-MIBG scintigraphy/SPECT and morphological imaging.

Background Partial nephrectomy (NSS) for unilateral nephroblastoma may be beneficial, although in case of regional lymph node (LN) involvement, radiotherapy counteracts the functional benefit of NSS. The aim is to verify whether decrease of tumor volume under preoperative chemotherapy implies clearance of regional LN. Procedure SIOP 9301 (1993–2001) collected 1,450 localized nephroblastoma patients of whom 1,360 (93%) had sufficiently available data and were retrospectively reviewed. Results Histologic subtypes were classically distributed. Patients were divided in those with tumor positive LN (76, 5.5%) and those with tumor negative LN (1,284, 94.5%) at surgery. In the LN(+) group, the tumor volume changed from a median of 554 (318–772) to 192 (63–458) ml = 67% (27–88%) during preoperative ChT. In the LN(−) group—377 (200–612) to 130 (44–294) ml = 62% (28–83%) (NS). Increase of tumor volume was observed in 16% of patients with LN(+), and 11% of those with LN(−) (NS); ranges are interquartile. Initial tumor volume was significantly larger in the LN(+) patients (P = 0.00091) but not different (NS) at surgery; patients with initial tumor volume under 318 ml had the regional LN involved significantly less frequently (P = 0.00751). Conclusions Change in tumor volume under preoperative chemotherapy is not a predictor for LN status at surgery, although larger initial volume is associated with a higher risk of LN invasion. The decrease of tumor volume is not a good criterion for the safety of NSS. The low rate of LN(+) (5.5%) indicates that this risk is low. Pediatr Blood Cancer 2011; 57: 1266–1269. © 2011 Wiley Periodicals, Inc.

BACKGROUD/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) represents a cause for significant pre- and postoperative morbidity and mortality in Hirschsprung disease (HD). Although multiple studies on HAEC have been performed and several mechanisms have been presumed, the pathogenesis of this condition remains unclear. As changes in colonic mucosal defense are key factors suggested in both Crohn's disease (CD) and HAEC pathogenesis, the aim of the current study was to investigate genetic alterations in the most important susceptibility gene for Crohn's enterocolitis (NOD2) to see whether carriers of polymorphisms within the NOD2 gene are predisposed to the development of HAEC.Genotyping for the NOD2 variants in exon 4 (p.Arg702Trp [rs2066844]), exon 8 (p.Gly908Arg [rs2066845]), and exon 11 (p.1007fs [rs2066847]) was performed in 52 white children with HD (41 boys, 11 girls), 152 healthy controls, and 152 children with CD (onset of disease17 years; mean, 11.8 years). Seventeen patients with HD (32.7%) were carriers of a RET germline mutation, 35 children (67.3%) had short segment disease, and 17 (32.7%) had long segment disease.Ten children (19.2%) with HD were heterozygous carriers of at least one NOD2 variant vs 17 (11.2%) in the healthy control group and 69 (45.4%) in the CD cohort. Hirschsprung-associated enterocolitis was observed in 7 children (13.5%), with 4 having short segment HD and 3 with long segment HD; but none of them were carriers of NOD2 variants.Our study shows that NOD2 variants described to be causatively associated with CD do not predispose to the development of HAEC. As data on the molecular basis of HAEC are limited, the distinct mechanisms involved in the pathogenesis of this complication remain unclear.

BACKGROUND/PURPOSE: Three common mutations of the NOD2/CARD15 gene have been associated with Crohn disease (CD), ileal disease location, and fibrostenotic behavior. The aim of this study was to investigate the effect of these mutations on disease manifestation and the risk of surgery in a cohort of German childhood-onset CD patients. METHODS: Genotyping for the NOD2 mutations p.Arg702Trp, p.Gly908Arg, and p.1007fs was performed in 171 CD children (onset of disease

OBJECTIVE: Studies in adults characterized the role of the pregnane X receptor (PXR) in the pathophysiology of inflammatory bowel disease (IBD) with conflicting results; pediatric studies are still lacking. PATIENTS AND METHODS: Genotyping for the -25385C/T polymorphism of the PXR gene in 187 white children with IBD and 185 controls. Determination of colonic PXR expression in selected patients with IBD. RESULTS: Minor allele frequency was seen in 35.6% patients with IBD and 40.5% controls (P = 0.174), although no significant differences were seen between the genotypes (P = 0.366). PXR was underexpressed in colonic tissue of 7 out of 11 Crohn disease and in 4 out of 5 patients with ulcerative colitis. CONCLUSIONS: We could not confirm an association of the -25385C/T polymorphism in pediatric patients with IBD.

Objectives Our aim was to improve the prediction of unfavorable histopathology (UH) in neuroblastic tumors through combined imaging and biochemical parameters. Methods I-123-MIBG SPECT and MRI was performed before surgical resection or biopsy in 47 consecutive pediatric patients with neuroblastic tumor. Semi-quantitative tumor-to-liver count-rate ratio (TLCRR),MRI tumor size and margins, urine catecholamine and NSE blood levels of neuron specific enolase (NSE) were recorded. Accuracy of single and combined variables for prediction of UH was tested by ROC analysis with Bonferroni correction. Results 34 of 47 patients had UH based on the International Neuroblastoma Pathology Classification (INPC). TLCRR and serum NSE both predicted UH with moderate accuracy. Optimal cut-off for TLCRR was 2.0, resulting in 68% sensitivity and 100% specificity (AUC-ROC 0.86, p < 0.001). Optimal cut-off for NSE was 25.8 ng/ml, resulting in 74% sensitivity and 85% specificity (AUC-ROC 0.81, p = 0.001). Combination of TLCRR/NSE criteria reduced false negative findings from 11/9 to only five, with improved sensitivity and specificity of 85% (AUC-ROC 0.85, p < 0.001). Conclusion Strong I-123-MIBG uptake and high serum level of NSE were each predictive of UH. Combined analysis of both parameters improved the prediction of UH in patients with neuroblastic tumor. MRI parameters and urine catecholamine levels did not predict UH.