Guido Seitz

Treatment efficiency, outcome and surgical treatment problems in patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma: a report from the Cooperative Soft Tissue Sarcoma trial CWS-96.

To analyze the clinical course, treatment modalities, complications and outcome of patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma (BPRMS) treated on the CWS‐96 trial.

Transperineal Sonography for Determination of the Type of Imperforate Anus

OBJECTIVE The purpose of this study was to assess whether transperineal sonography is valid and accurate for discriminating the low (translevator) type of imperforate anus from the intermediate and high (supralevator) types. The distinction is critical in determination of the surgical approach. MATERIALS AND METHODS Fifty-six consecutively enrolled infants (0-90 days old) with imperforate anus underwent transperineal gray-scale sonography with a 12-MHz linear array transducer. The distance between the distal rectal pouch and the perineum was measured, and a cutoff distance for differentiating types of imperforate anus was identified. The sonographic findings were compared with the final diagnosis reached with radiographic and surgical findings. RESULTS Transperineal sonography was feasible in all children without specific preparation. The mean distance between the distal rectal pouch and the perineum in the 22 infants with low imperforate anus was 10 +/- 4 (SD) mm compared with a mean of 24 +/- 6 mm in the 34 infants with intermediate or high anomalies (p < 0.001). The sensitivity of transperineal sonography was 100%; all 34 cases of intermediate or high imperforate anus were identified with a cutoff distance between the distal rectal pouch and the perineum of 15 mm. The specificity of sonography was 86% and the accuracy, 95%. CONCLUSION Transperineal sonography is a valid and accurate noninvasive imaging technique for differentiating low and intermediate or high imperforate anus.

Comprehensive Oncologic Imaging in Infants and Preschool Children With Substantially Reduced Radiation Exposure Using Combined Simultaneous ¹⁸F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Imaging: A Direct Comparison to ¹⁸F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

ObjectiveThe aim of this study was to evaluate the clinical applicability and technical feasibility of fluorodeoxyglucose (FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) compared with FDG PET/computed tomography (CT) in young children focusing on lesion detection, PET quantification, and potential savings in radiation exposure. MethodsTwenty examinations (10 PET/CT and 10 PET/MRI examinations) were performed prospectively in 9 patients with solid tumors (3 female, 6 male; mean age, 4.8 [1–6] years). Fluorodeoxyglucose PET/CT and FDG PET/MRI were performed sequentially after a single tracer injection. Lesion detection and analysis were performed independently in PET/CT and PET/MRI. Potential changes in diagnostic or therapeutic patient management were recorded. Positron emission tomography quantification in PET/MRI was evaluated by comparing standardized uptake values resulting from MRI-based and CT-based attenuation correction. Effective radiation doses of PET and CT were estimated. ResultsTwenty-one PET-positive lesions were found congruently in PET/CT and PET/MRI. Magnetic resonance imaging enabled significantly better detection of morphologic PET correlates compared with CT. Eight suspicious PET-negative lesions were identified by MRI, of which one was missed in CT. Sensitivity, specificity, and accuracy for correct lesion classification were not significantly different (90%, 47%, and 62% in PET/CT; 100%, 68%, and 79% in PET/MRI, respectively). In 4 patients, the use of PET/MRI resulted in a potential change in diagnostic management compared with PET/CT, as local and whole-body staging could be performed within 1 single examination. In 1 patient, PET/MRI initiated a change in therapeutic management. Positron emission tomography quantification using MRI-based attenuation correction was accurate compared with CT-based attenuation correction. Higher standardized uptake value deviations of about 18% were observed in the lungs due to misclassification in MRI-based attenuation maps. Potential reduction in radiation dose was 48% in PET/MRI compared with PET/CT (P < 0.05). ConclusionsFDG PET/MRI is at least equivalent to FDG PET/CT for oncologic imaging in young children. Specifically, superior soft tissue contrast of MRI results in higher confidence in lesion interpretation. Substantial savings in radiation exposure can be achieved, and the number of necessary imaging examinations can be reduced using PET/MRI compared with PET/CT.

Inhibition of Bcl-2 and Bcl-X enhances chemotherapy sensitivity in hepatoblastoma cells†

An increased expression of anti‐apoptotic proteins is regularly found in malignant cells, contributing to their clonal expansion by conferring an improved survival ability. In Hepatoblastoma (HB) apoptosis regulation contributes to resistance and therapy failure, therefore we modulated apoptosis sensitivity of HB cells for an improved cytotoxic activity of commonly used drugs.

The 'Effects of Transfusion Thresholds on Neurocognitive Outcome of Extremely Low Birth-Weight Infants (ETTNO)' Study: Background Aims, and Study Protocol

Background: Infants with extremely low birth weight uniformly develop anemia of prematurity and frequently require red blood cell transfusions (RBCTs). Although RBCT is widely practiced, the indications remain controversial in the absence of conclusive data on the long-term effects of RBCT. Objectives: To summarize the current equipoise and to outline the study protocol of the ‘Effects of Transfusion Thresholds on Neurocognitive Outcome of extremely low birth-weight infants (ETTNO)’ study. Methods: Review of the literature and design of a large pragmatic randomized controlled trial of restrictive versus liberal RBCT guidelines enrolling 920 infants with birth weights of 400–999 g with long-term neurodevelopmental follow-up. Results and Conclusions: The results of ETTNO will provide definite data about the efficacy and safety of restrictive versus liberal RBCT guidelines in very preterm infants.

Nephron Sparing Surgery for Synchronous Bilateral Nephroblastoma Involving the Renal Hilus

PURPOSE Bilateral nephroblastoma involving the renal hilus represents a significant surgical challenge. Different operative strategies have been proposed for this condition. We analyzed the outcome of simultaneous bilateral partial nephrectomy for complex stage V nephroblastoma. MATERIALS AND METHODS We retrospectively analyzed patients with bilateral nephroblastoma involving the renal hilus operated on at our institution between 2002 and 2008. We assessed patient data and surgical and oncologic outcomes. RESULTS We analyzed data from 5 patients with a median age of 27 months at surgery (range 13 to 58). Two children had additional pulmonary metastases. Patients were treated according to the International Society of Pediatric Oncology 2001/German Society of Pediatric Oncology and Hematology protocol. All children underwent synchronous bilateral nephron sparing surgery (longitudinal partial nephrectomy or enucleation) of the central tumors. Median operating time was 182 minutes (range 129 to 291), with vascular exclusion performed in 4 patients (7 to 25 minutes). Complications consisted of urinary leakage in 2 cases. Postoperative renal function was unimpaired in 4 patients and 1 patient had Wilms tumor/aniridia/genitourinary malformations/retardation syndrome with glomerulopathy. One patient with pulmonary metastases and blastemal histology had multiple pulmonary relapses and died due to pulmonary progressive disease. Four patients are alive without evidence of disease at a median followup of 45 months (range 44 to 73). CONCLUSIONS Surgery for central stage V nephroblastoma is possible with good functional and oncologic outcomes. The single stage approach is safe, provided that operating and treating physicians have sufficient expertise with such conditions. The ultimate goal is to avoid tumor nephrectomy.

Analysis of sternotomy as treatment option for the resection of bilateral pulmonary metastases in pediatric solid tumors

BACKGROUND Radical surgical resection of metastases is an important prognostic factor for survival of patients suffering from solid pediatric tumors. The aim of this study is to evaluate the efficacy of median sternotomy as treatment option for the resection of multiple bilateral lung metastases in children with different tumor entities. Furthermore, the sensitivity of preoperative imaging (CT) was assessed by intraoperative findings. PATIENTS AND METHODS Between 2002 and 2007, 13 children (4 with sarcoma, 4 with nephroblastoma, 5 with hepatoblastoma) underwent median sternotomy for resection of bilateral lung metastases after R0-resection of the primary tumor. In 6/13 cases, the sternotomy was combined with the primary tumor resection. RESULTS Median patient age at the first operation was 5 years (range: 11 months to 17 years). The median total number of resected metastases per operation was 9 and ranged from 0 to 65. In 13/16 operations, the intraoperative number of metastases did not agree with the preoperative radiological work-up. Median hospital stay was 14 days (range from 9 to 36 days). Ten out of 13 children are alive after a median follow-up of 13 months (range from 6 to 66 months). CONCLUSION Median sternotomy is an adequate treatment modality for the resection of bilateral pulmonary metastases as a one-stage procedure. The combination of primary tumor resection with sternotomy should be considered as a treatment option. Complete resection of metastases of solid pediatric tumors should be aimed for in order to increase the survival of these patients.

Surgical management of extremely low birth weight infants with neonatal bowel perforation: a single-center experience and a review of the literature.

Background: Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are major causes of morbidity in infants with extremely low birth weight (ELBW). Objective: To evaluate the surgical procedures applied, and the survival and long-term outcome of ELBW infants with NEC and FIP in a single-center study. Methods: Inborn and outborn ELBW infants (<1000 g) with NEC and FIP were analyzed retrospectively from 2002 to 2007. Data collected include surgical procedures, survival as well as complications, length of partial parenteral nutrition and hospital stay. The short-term and long-term outcomes after 2–7 years were assessed and compared with a matched control group. Results: Out of 280 ELBW infants, 28 underwent surgery, 19 because of FIP and 9 for NEC. Fourteen infants in the FIP group were treated with primary laparotomy and 5 with peritoneal drainage (PD). In the NEC group, only 1 infant was treated with PD. PD was used for unstable patients and was always followed by secondary laparotomy after stabilization. Five of 28 (18%) surgically treated ELBW infants and 4 (14%) matched controls died. The following complications occurred in the surgical group: complete (n = 1) or minor wound dehiscence (n = 4), stoma prolapse (n = 5), parastomal hernia (n = 2), stoma fistula (n = 1), and wound infection (n = 2). Dependency on parenteral nutrition was significantly shorter in infants with FIP, while there were no differences in time to stoma closure and length of hospital stay between those with FIP and those with NEC. Eleven of 23 (47.8%) surviving patients with FIP or NEC showed developmental delay, compared with 9 of 24 (37.5%) in the controls. Conclusions: The management of EBLW infants with NEC and FIP remains challenging. Our treatment approach was associated with low mortality. Developmental delay seems to be caused by extreme prematurity rather than NEC- or FIP-related bowel perforation.

Differential expression of miRNAs in rhabdomyosarcoma and malignant rhabdoid tumor.

Alveolar rhabdomyosarcoma (RMA) and malignant rhabdoid tumor (MRT) have a frequent metastatic spread and a poor prognosis. Aberrant miRNA expression is often found in metastatic tumors. The aim of this study was to identify specific miRNA expression patterns in these tumors. We analyzed the expression of miRNAs in RMA and MRT in tissue samples and in the rhabdomyosarcoma (RMS) cell lines (Rh30 and RD). Selected target miRNAs were modulated with mimic or inhibitor oligonucleotides. Functional analysis was monitored by flow cytometry and migration assays. A set of 107 differentially expressed miRNAs showed tissue-specific clustering of RMA and MRT. Comparison with the Sarcoma microRNA Expression Database revealed RMA- and MRT-specific miRNAs. Metastatic invasion associated miRNA miR-9 was overexpressed in RMA. miR-200c-inhibiting migration-was lower expressed in RMA than in MRT. Transient transfection of RMS cells with a miR-200c mimic and miR-9( inhibitor did neither increase the expression of the known target E-cadherin nor decrease migration. Expression of E-cadherin could be induced in RD cells using decitabine, but demethylation did not influence cell migration. Despite a comparable high rate of metastatic invasion pediatric RMA and MRT show a different pattern of miRNA expression possibly allowing risk stratification.

Differential expression of glutamine synthetase and cytochrome P450 isoforms in human hepatoblastoma.

Carcinogenesis is often linked to aberrant activation of Wnt/β-catenin signalling, in many cases caused by activating CTNNB1 mutations (encoding β-catenin). Recently, β-catenin was established as a decisive regulator of hepatic glutamine synthetase (GS) and cytochrome P450 (CYP) expression in mouse hepatocarcinogenesis. This study was aimed to analyse the connection of β-catenin signalling and GS/CYP expression in human paediatric tumours. Samples from 23 paediatric tumours were analysed for activating mutations in CTNNB1. Protein expression of the model β-catenin target GS and of various CYP isoforms was analysed and correlated with CTNNB1 mutational status and histological findings. Activating CTNNB1 mutations were frequent in hepatoblastoma (80%) and nephroblastoma (31%). In CTNNB1-mutated hepatoblastoma, expression of GS was only detected in tumour areas with epithelial, not with mesenchymal differentiation. Particularly high expression of glutamine synthetase was found in hepatoblastoma cells directly neighbouring a mesenchymal-type tumour area or stroma cells, associated with above-average cell proliferation. GS expression was not observed in CTNNB1-mutated nephroblastoma. Hepatoblastoma with activated β-catenin expressed different CYPs relevant for the metabolism of cytostatic drugs, but with high interindividual variance and heterogeneity within a single tumour. GS and different CYPs are co-expressed in hepatoblastoma with activated β-catenin. Moreover, other factors like histological subtype of tumour cells and cell-cell-interactions at the borders between different areas of the tumours affect expression of these β-catenin target genes. Analysis of CYP expression in resected tumour tissue might be useful for the selection of appropriate cytostatics for post-operative chemotherapy.