TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants.

Wilms tumors (WTs) are histologically diverse childhood cancers with variable contributions of blastema, stroma, and epithelia. A variety of cancer genes operate in WTs, including the tripartite-motif-containing-28 gene (TRIM28). Case reports and small case series suggest that TRIM28 mutations are associated with epithelial morphology and WT predisposition. Here, we systematically investigated the prevalence of TRIM28 inactivation and predisposing mutations in a cohort of 126 WTs with >2/3 epithelial cells, spanning 20 years of biobanking in the German SIOP93-01/GPOH and SIOP2001/GPOH studies. Overall, 44.4% (56/126) cases exhibited loss of TRIM28 by immunohistochemical staining. Of these, 48 could be further analyzed molecularly, revealing TRIM28 sequence variants in each case - either homozygous (~2/3) or heterozygous with epigenetic silencing of the second allele (~1/3). The majority (80%) of the mutations resulted in premature stops and frameshifts. In addition, we detected missense mutations and small deletions predicted to destabilize the protein through interference with folding of key structural elements such as the zinc-binding clusters of the RING, B-box-2, and PHD domains or the central coiled-coil region. TRIM28-mutant tumors otherwise lacked WT-typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency. Expression profiling identified TRIM28-mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease. There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested. Importantly, 46% of the TRIM28 mutations were present in blood cells or normal kidney tissue, suggesting germline events or somatic mosaicism, partly supported by family history. Given the high prevalence of predisposing variants in TRIM28-driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

How to improve initial diagnostic accuracy of kidney tumours in childhood?-A non-invasive approach.

Non-invasive differentiation of paediatric kidney tumours is particularly important in the SIOP-RTSG protocols, which recommend pre-operative chemotherapy without histological confirmation. The identification of clinical and tumour-related parameters may enhance diagnostic accuracy. Age, metastases, and tumour volume (TV) were retrospectively analysed in 3306 patients enrolled in SIOP/GPOH 9, 93-01, and 2001 including Wilms tumour (WT), congenital mesoblastic nephroma (CMN), clear cell sarcoma (CCSK), malignant rhabdoid tumour of the kidney (MRTK), and renal cell carcinoma (RCC). WT was diagnosed in 2927 (88.5%) patients followed by CMN 138 (4.2%), CCSK 126 (3.8%), MRTK 58 (1.8%) and RCC 57 (1.7%). CMN, the most common localized tumour (71.6%) in patients younger than 3 months of age, was diagnosed earliest and RCC the latest (median age [months]: 0 and 154, respectively) both associated with significantly smaller TV (median TV [mL]: 67.2 and 45.0, respectively). RCC occurred in >14% of patients older than 120 months or older than 84 months with TV <100 mL. Receiver operating characteristic analyses discriminated WT from CMN, RCC and MRTK regarding age (AUC = 0.976, 0.929 and 0.791) and TV (AUC = 0.768, 0.813 and 0.622). MRTK had the highest risk of metastasis (37.9%) despite young age, whereas the risk of metastasis increased significantly with age in WT. Age and TV at diagnosis can differentiate WT from CMN and RCC. MRTK must be considered for metastatic tumours at young age. Identification of CCSK without histology remains challenging. Combined with MRI-characteristics, including diffusion-weighted imaging, and radiomics and liquid biopsies in the future, our approach allows optimization of biopsy recommendations and prevention of misdiagnosis-based neoadjuvant treatment.

Can Lymph Node Involvement in Unilateral Wilms Tumor be Predicted by Preoperatively known Data in Combination with Intraoperative Findings?

OBJECTIVE: This study aimed to identify parameters that allow the estimation of tumor-infiltrated lymph nodes (LN) after pretreatment for unilateral Wilms tumor (WT). SUMMARY BACKGROUND DATA: Complete tumor resection with removal of regional LN is always necessary. Positive LNs require local irradiation influencing benefits in case of NSS in long-term follow-up. Clinical and tumor-related data available at the time of surgery in combination with intraoperative findings (IAF) were used to estimate the LN status during surgery. METHODS: Altogether, 2115 patients with unilateral WT were prospectively enrolled in SIOP-93-01 / GPOH and SIOP-2001 / GPOH over a period of 30 years (1993-2023). LN infiltration by tumor was calculated for age, sex, metastases at diagnosis, tumor volume (TV), TV shrinkage, and intraoperative findings (IAF) using logistic regression models. RESULTS: Age ≥48 months (P<0.001, OR 2.17, CI 1.57 - 3.00), TV at diagnosis ≥300 (P<0.001, OR 3.72, CI 2.37 - 5.85), metastasis at diagnosis (P<0.001, OR 6.21, CI 4.47 - 8.62) and IAF (>1: P<0.001, OR 3.54, CI 2.13 - 5.88) correlated with positive LNs. TV shrinkage was not predictive of positive LN. Three flow charts were developed based on age, TV at diagnosis, metastasis, and IAF. These flowcharts defined risks between 0% and 41.5% for LN infiltration by tumor. CONCLUSIONS: The combination of age, TV at diagnosis, and metastasis with IAF allows the estimation of the frequency of positive LNs, which may help surgeons deciding about NSS.

Impact of COVID-19 on paediatric chronic intestinal failure: A tertiary care children's hospital experience.

OBJECTIVES: Paediatric patients with intestinal failure (IF) are at risk for both gastrointestinal (GI) and systemic complications, thus depending on a functioning network of multidisciplinary care. Data on the clinical impact of coronavirus disease 2019 (COVID-19) or the pandemic-related restrictions are limited. We aimed to analyse the clinical course of COVID-19 in children with IF, and to evaluate the perceived impact of the COVID-19 pandemic on IF patients and their caregivers by analysing quality of life (QoL), health-related QoL (HRQoL) and health care. METHODS: Children with IF presenting at our intestinal rehabilitation centre were enrolled and interviewed about test-proven COVID-19 infection. A standardised questionnaire was offered to all caregivers of IF patients and to two control groups (children with inflammatory bowel disease and gastrointestinal healthy children). RESULTS: Between December 2020 and November 2022, 25 out of 127 patients with IF contracted COVID-19. Forty-eight per cent had GI symptoms, 32% required additional intravenous fluids and 20% were hospitalized. Only 25% of vaccinated children showed signs of GI dysfunction, compared to 52% of unvaccinated children. Analysis of 93 questionnaires showed a negative impact on QoL and HRQoL (>66.7% and >27.8%, respectively). IF patients frequently experienced restrictions in health care, including appointments, services and supply of parenteral nutrition or medications. Caregiver burden increased significantly more often in caregivers of children with IF (p = 0.007). CONCLUSIONS: Paediatric patients with IF contracting COVID-19 have an increased risk for GI dysfunction which may be alleviated by vaccination. Children and their caregivers were highly burdened by pandemic-related restrictions and reductions in health care provision.

Image-defined risk factors in localized thoracic neuroblastoma and ganglioneuroma.

BACKGROUND: The pretreatment International Neuroblastoma Risk Group Staging System (INRGSS) discriminates localized tumors L1/L2 depending on the absence/presence of image-defined risk factors (IDRFs) at diagnosis. Referring to this new staging system, we assessed initial imaging of localized thoracic neuroblastoma (NB) and ganglioneuroma (GN) and the extent of initial tumor resection. METHODS: Patients with localized thoracic NB/GN from the German clinical trials NB97 and NB2004 were included. Imaging at diagnosis and operative reports were reviewed retrospectively. IDRFs were assessed centrally and correlated to International Neuroblastoma Staging System (INSS) stage and extent of tumor resection. Additionally, we analyzed data on surgery-related complications. RESULTS: Imaging series of 88 patients were available for central review. In 18 children, no IDRF was present, 28 exhibited one IDRF, 42 two or more IDRFs, resulting in 70 patients with L2 disease. The most frequently observed IDRF was encasement of any vessel (n = 38). Initial surgical resection was aimed for in 45 patients (L1: n = 11; L2: n = 34). Complete and gross total resection rates were higher children with L2 NB (n = 8/25 L1, n = 17/25 L2 vs. n = 2/15 L1, n = 13/15 L2, respectively). The proportion of surgical complications was very similar between INRGSS L1 and L2 (n = 4/11 vs. n = 17/34). All complications were manageable, and no surgery-related deaths were observed. CONCLUSION: In this retrospective cohort, the extent of resection and the rate of surgical complications did not differ substantially between patients classified as L1/L2, indicating that INRGSS L2 does not equate unresectability. It appeared that individual IDRFs differ in value. Larger studies are needed to assess the significance and therapeutic/prognostic impact of such findings.

Nephron sparing surgery and surgical management of intravascular extension of Wilms tumor.

Although general treatment approaches for Wilms tumor differ between Children's Oncology Group and Société Internationale d'Oncologie Pédiatrique-Renal Tumors Study Group protocols, complex tumors that may be candidates for nephron sparing surgery (NSS) and those with intravascular tumor extension represent a management challenge. In both of these scenarios, anatomic considerations are important in guiding management, making these areas of significant similarities in management between the international groups. This paper aims to explore the current approaches to NSS and intravascular tumor extension by both international groups, with attention to the evidence supporting these approaches and current knowledge gaps.

Solid pseudopapillary neoplasms of the pancreas in childhood and adolescence-an analysis of the German Registry for Rare Pediatric Tumors (STEP).

Solid pseudopapillary neoplasms (SPNs) are the most common entity among pediatric pancreatic tumors. Still, these are rare tumors with an annual incidence of 0.1-0.2/1,000,000, and little is known about their optimal treatment. This analysis aimed to increase knowledge about the occurrence and treatment strategies of SPN in childhood. Data regarding diagnostics, treatment, and outcome of children aged 0-18 years with SPN recorded in the German Registry for Rare Pediatric Tumors (STEP) were analyzed. Thirty-eight patients were identified with a median age of 14.5 years at diagnosis (range: 8-18) and a female preponderance (81.6%). The most frequent location of the tumor was the pancreatic tail. In histopathological and immunohistochemical examination, pseudopapillary, solid, and cystic lesions as well as expression of beta-catenin, progesterone receptors, and cyclin D1 were the most common findings. All patients underwent surgical resection. Most patients underwent open resection, predominantly tail resection for tumors in the tail region and pylorus-preserving pancreaticoduodenectomy for tumors in the head region. The main postoperative sequela was exogenous pancreatic insufficiency (23.7%), especially with SPN in the pancreatic head. No recurrence occurred during follow-up, although two patients underwent resection with microscopic residue. CONCLUSION: SPN of the pancreas in childhood are low-grade malignancies with usually favorable treatment outcomes. However, therapy can lead to relevant long-term sequelae. To prevent recurrence, complete surgical resection is recommended, sparing as much healthy pancreatic tissue as possible. Interdisciplinary collaboration between specialists is essential to optimize treatment. Molecular genetic analysis of these tumors could improve understanding of their genesis. WHAT IS KNOWN: • Solid pseudopapillary neoplasms (SPNs) of the pancreas are very rare tumors in childhood. • Little is known about tumorigenesis, and there are no specific guidelines for treatment and follow-up in pediatric patients. WHAT IS NEW: • Characteristics, treatment, and outcome were comprehensively assessed in a large cohort of pediatric patients with SPN. • We propose recommendations for diagnosis, treatment, and follow-up of children with SPN, based on our analysis and considering published experience.

Epitope detection in monocytes (EDIM) for liquid biopsy including identification of GD2 in childhood neuroblastoma-a pilot study.

BACKGROUND: Neuroblastoma (NB) is the most common paediatric extracranial solid malignancy. We analysed the role of the epitope detection in monocytes (EDIM) technique for liquid biopsy in NB patients. METHODS: Tumour epitopes transketolase-like 1 (TKTL1), Apo10 (DNaseX) and GD2 were assessed: expression levels in seven NB tumour samples and five NB cell lines were analysed using RT-PCR and flow cytometry. LAN-1 cells were co-cultured with blood and assessed using EDIM. Peripheral blood macrophages of patients with neuroblastoma (n = 38) and healthy individuals (control group, n = 37) were labelled (CD14+/CD16+) and assessed for TKTL1, Apo10 and GD2 using the EDIM technology. RESULTS: mRNA expression of TKTL1 and DNaseX/Apo10 was elevated in 6/7 NB samples. Spike experiments showed upregulation of TKTL1, Apo10 and GD2 in LAN-1 cells following co-culturing with blood. TKTL1 and Apo10 were present in macrophages of 36/38 patients, and GD2 in 15/19 patients. The 37 control samples were all negative. EDIM expression scores of the three epitopes allowed differentiation between NB patients and healthy individuals. CONCLUSIONS: The EDIM test might serve as a non-invasive tool for liquid biopsy in children suffering from NB. Future studies are necessary for assessing risk stratification, tumour biology, treatment monitoring, and early detection of tumour relapses.

The Relevance of Preoperative Identification of the Adamkiewicz Artery in Posterior Mediastinal Pediatric Tumors.

BACKGROUND: Injury to the artery of Adamkiewicz (AKA) during surgery may lead to spinal cord ischemia and severe neurologic complications. Posterior mediastinal tumors may be adjacent to AKA, but data on preoperative visualization of AKA in children are rare. This study analyzed the importance of identifying the AKA preoperatively by spinal digital subtraction angiography (DSA) in children with posterior mediastinal tumors for therapeutic procedure. METHODS: Between 2002 and 2021, 36 children with posterior mediastinal tumors were evaluated for surgery at the authors' clinic. In 10 children with left-sided or bilateral tumor located at vertebral levels T8 to L1, spinal DSA was performed during preoperative workup to assess AKA. The patient and tumor characteristics as well as the diagnostic and therapeutic procedures were analyzed. RESULTS: The median age of the 10 children at examination was 69 months (range, 16-217 months). Three of the children were younger than 2 years. The tumor entities were neuroblastoma, ganglioneuroblastoma, ganglioneuroma, local relapse of a hepatocellular carcinoma, and neurofibroma. The AKA was identified in all cases, and proximity to the tumor was detected in four patients, three of whom had their planned surgery changed to irradiation. No complications occurred during spinal DSA or surgery. CONCLUSIONS: In posterior mediastinal pediatric tumors, spinal DSA is a safe and reliable method for preoperative visualization of the AKA. It can show proximity to the tumor and guide the local therapy, thereby avoiding critical intra- and postoperative situations.

A new variant of Abernethy malformation treated by transhepatic interventional closure: a case report.

BACKGROUND: Congenital portosystemic shunts (CPSS) are rare vascular malformations and can be classified into extrahepatic and intrahepatic shunts. Extrahepatic CPSS, also termed Abernethy malformations are associated with severe long-term complications including portopulmonary hypertension, liver atrophy, hyperammoniemia and hepatic encephalopathy. We report a hitherto undescribed variant of Abernethy malformation requiring an innovative approach for interventional treatment. CASE PRESENTATION: We describe a 31-year-old patient following surgical repair of atrioventricular septal defect at the age of 6 years. In the long-term follow-up he showed persistent pulmonary hypertension which deteriorated despite dual pulmonary vasodilative treatment. When he developed arterial desaturation and symptomatic hyperammoniemia detailed reassessment revealed as underlying cause a hitherto undescribed variant of Abernethy malformation connecting the portal vein with the right lower pulmonary vein. Following interdisciplinary discussions we opted for an interventional approach. Since the malformation was un-accessible to interventional closure via antegrade venous or retrograde arterial access, a transhepatic percutaneous puncture of the portal vein was performed. Temporary balloon occlusion of the malformation revealed only a slight increase in portal venous pressure. Interventional occlusion of the large vascular connection was achieved via this transhepatic approach by successive implantation of two large vascular occluding devices. The postinterventional course was unremarkable and both ammonia levels and arterial saturation normalized at follow-up of 12 months. CONCLUSIONS: Portal vein anomalies should be included in the differential diagnoses of pulmonary hypertension or pulmonary arterio-venous malformations. Based on careful assessment of the anatomy and testing of portal vein hemodynamics interventional therapy of complex Abernethy malformations can be performed successfully in specialized centers.

Interventional closure of a bronchopleural fistula in a 2 year old child with detachable coils.

BACKGROUND: Bronchopleural fistula (BPF) is a severe complication following pneumonia or pulmonary surgery, resulting in persistent air leakage (PAL) and pneumothorax. Surgical options include resection, coverage of the fistula by video-assisted thoracoscopic surgery (VATS), or pleurodesis. Interventional bronchoscopy is preferred in complex cases and involves the use of sclerosants, sealants and occlusive valve devices. CASE PRESENTATION: A 2.5-year-old girl was admitted to our hospital with persistent fever, cough and dyspnoea. Clinical and radiological examination revealed right-sided pneumonia and pleural effusion. The child was started on antibiotics, and the effusion was drained by pleural drainage. Following removal of the chest tube, the child developed tension pneumothorax. Despite insertion of a new drain, the air leak persisted. Thoracoscopic debridement with placement of another new drain was performed after 4 weeks, without abolishment of the air leak. Bronchoscopy with bronchography revealed a BPF in right lung segment 3 (right upper-lobe anterior bronchus). We opted for an interventional approach that was performed under general anaesthesia during repeat bronchoscopy. Following bronchographic visualisation of the fistula, a 2.7 French microcatheter was placed in right lung segment 3 (upper lobe), allowing occlusion of the fistula by successive implantation of 4 detachable high-density packing volume coils, which were placed into the fistula. Subsequent bronchography revealed no evidence of residual leakage, and the chest tube was removed 2 days later. The chest X-ray findings normalized, and follow-up over 4 years was uneventful. CONCLUSIONS: Bronchoscopic superselective occlusion of BPF using detachable high-density packing large-volume coils was a successful minimally invasive therapeutic intervention performed with minimal trauma in this child and has not been reported thus far. In our small patient, the short interventional time, localized intervention and minimal damage in the lung seemed superior to the corresponding outcomes of surgical lobectomy or pleurodesis in a young growing lung, enabling normal development of the surrounding tissue. Follow-up over 4 years did not show any side effects and was uneventful, with normal lung-function test results to date.

The Role of Reconstructive Surgery and Brachytherapy in Pediatric Bladder/Prostate Rhabdomyosarcoma.

PURPOSE: The surgical approach to localized bladder/prostate rhabdomyosarcoma in children may change due to a new radiotherapeutic modality. We assessed the impact of brachytherapy following surgery for local tumor control, and report surgical techniques and outcomes. MATERIALS AND METHODS: We retrospectively analyzed the records of all children who underwent surgery for bladder/prostate rhabdomyosarcoma, including tumor relapse, at our institution from 2009 onward. RESULTS: A total of 38 patients with a median age of 29 months (range 10 to 134) met inclusion criteria. Five-year overall survival was 92.8% (95% CI 72.9 to 98.1), and event-free survival at a median followup of 12 months (range 3 to 111) was 73.7% (95% CI 53.4 to 86.2). Three treatment groups were defined, ie bladder preserving surgery combined with brachytherapy, bladder preserving surgery alone and cystectomy. Five-year event-free survival rates for the 3 groups were 85.6% (95% CI 61.2 to 95.2), 66.7% (95% CI 27.2 to 88.2) and 50% (95% CI 5.8 to 84.5), respectively. Bladder preserving surgery was performed in 33 patients (87%), of whom 23 (70%) also underwent brachytherapy, while cystectomy was performed in 5 (13%). Reconstructive procedures varied depending on tumor location and spread. CONCLUSIONS: Combining brachytherapy with surgery results in a high bladder preservation rate and improves event-free survival compared to surgery alone in children with bladder/prostate rhabdomyosarcoma. The combination is also effective in treating local tumor relapse, and is associated with less extensive reconstructive procedures due to exclusion of tumors of unfavorable size and location for brachytherapy.

Retrospective accuracy analysis of MRI based lesion size measurement in neuroblastic tumors: which sequence should we choose?

BACKGROUND: MR imaging of neuroblastic tumors is widely used for assessing the effect of chemotherapy on tumor size. However, there are some concerns that MRI might falsely estimate lesion diameters due to calcification and fibrosis. Therefore, the aim of our study was to compare neuroblastic tumor size based on MRI measurements to histopathology measurements of the resected specimens as standard of reference. METHODS: Inclusion criteria were diagnosis of a neuroblastic tumor, MR imaging within 100 days to surgery and gross total resection without fragmentation of the tumor between 2008 and 2019. Lesion diameters were measured by two radiologists according to RECIST 1.1 in axial plane in T2w turbo spin echo (TSE), diffusion-weighted imaging (DWI), and in T1w pre- and postcontrast sequences. Furthermore, the largest lesion size in three-dimensions was noted. The largest diameter of histopathology measurements of each specimen was used for comparison with MRI. RESULTS: Thirty-seven patients (mean age: 5 ± 4 years) with 38 lesions (neuroblastoma: n = 17; ganglioneuroblastoma: n = 11; ganglioneuroma: n = 10) were included in this retrospective study. There was excellent intra-class correlation coefficient between both readers for all sequences (> 0.9) Tumor dimensions of reader 1 based on axial MRI measurements were significantly smaller with the following median differences (cm): T1w precontrast - 1.4 (interquartile range (IQR): 1.8), T1w postcontrast - 1.0 (IQR: 1.9), T2w TSE: -1.0 (IQR: 1.6), and DWI -1.3 (IQR: 2.2) (p < 0.001 for all sequences). However, the evaluation revealed no significant differences between the three-dimensional measurements and histopathology measurements of the resected specimens regardless of the applied MRI sequence. CONCLUSIONS: Axial MRI based lesion size measurements are significantly smaller than histopathological measurements. However, there was no significant difference between three-dimensional measurements and histopathology measurements of the resected specimens. T2w TSE and T1w postcontrast images provided the lowest deviation and might consequently be preferred for measurements.

Surgical management of peripheral nerve sheath tumours in children, with special consideration of neurofibromatoses.

INTRODUCTION: Peripheral nerve sheath tumours in children are a rare and heterogeneous group, consisting mostly of benign tumours as well as malignant neoplasms. Especially in the paediatric population, diagnostics and indication for therapy pose relevant challenges for neurosurgeons and paediatric neurologists alike. Most paediatric cases that need surgical intervention are associated to neurofibromatosis type 1 (NF1). METHODS: We retrospectively reviewed all paediatric cases treated at the Department of Neurosurgery in Tübingen between 2006 and 2017 for peripheral nerve sheath tumours. We analysed clinical signs, symptoms, histology, association to an underlying phacomatosis and sensory/motor function. RESULTS: Of the 82 identified patients, the majority had NF1 (76.8%). Nine children bore a sporadic tumour without underlying phacomatosis (11%), 8 had NF2 (9.8%) and 2 schwannomatosis (2.4%), A total of 168 surgical interventions were performed, and 206 tumours were removed. Indication for surgery was in most instances significant tumour growth (45.2%) followed by pain (33.9%). New deficits led to surgery in 12.5% of interventions; malignancy was suspected in 8.3%. Histopathology revealed mostly neurofibromas (82.5%), divided into cutaneous neurofibromas (10.7%), infiltrating plexiform neurofibromas (25.7%) and peripheral nerve-born neurofibromas (46.1%). 12.1% of tumours were schwannomas, 2.9% MPNST, 1.5% ganglioneuroma (n = 3) and 1 hybrid-neurofibroma and perineurinoma each. Leading symptoms, such as pain and motor and sensory deficits, improved after 125/166 interventions (74.4%), remained unchanged following 39 interventions (23.2%) and worsened in 4 occasions (2.4%). CONCLUSION: Surgery is safe and effective for (neurofibromatosis associated) peripheral nerve sheath tumours in the paediatric population; however, management needs a multidisciplinary setting. We propose early surgical resection in paediatric patients with peripheral nerve sheath tumours with significant growth, or pain, or motor deficit, or suspected malignancy.

Treatment and outcome of the patients with rhabdomyosarcoma of the biliary tree: Experience of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The management of affected patients contains unique challenges because of the rarity of this tumor entity and its critical location at the porta hepatis, which can make achievement of a radical resection very difficult. METHODS: In a retrospective chart analysis we analysed children suffering from biliary RMS who were registered in three different CWS trials (CWS-96, CWS-2002P, and SoTiSaR registry). RESULTS: Seventeen patients (12 female, 5 male) with a median age of 4.3 years were assessed. The median follow-up was 42.2 months (10.7-202.5). The 5-year overall (OS) and event free survival (EFS) rates were 58% (45-71) and 47% (34-50), respectively. Patients > 10 years of age and those with alveolar histology had the worst prognosis (OS 0%). Patients with botryoid histology had an excellent survival (OS 100%) compared to those with non-botryoid histology (OS 38%, 22-54, p = 0.047). Microscopic complete tumor resection was achieved in almost all patients who received initial tumor biopsy followed by chemotherapy and delayed surgery. CONCLUSION: Positive predictive factors for survival of children with biliary RMS are age ≤ 10 years and botryoid tumor histology. Primary surgery with intention of tumor resection should be avoided.

High-dose treatment for malignant rhabdoid tumor of the kidney: No evidence for improved survival-The Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) experience.

BACKGROUND: Malignant rhabdoid tumor of the kidney (MRTK) is the most aggressive childhood renal tumor with overall survival (OS) rates ranging from 22% to 42%. Whether high-dose chemotherapy with autologous stem-cell transplantation (HDSCT) in an intensive first-line treatment offers additional benefit is an ongoing discussion. METHODS: A retrospective analysis of all 58 patients with MRTK from Austria, Switzerland, and Germany treated in the framework of consecutive, prospective renal/rhabdoid tumor studies SIOP9/GPO, SIOP93-01/GPOH (where SIOP is International Society of Pediatric Oncology and GPOH is German Society of Pediatric Oncology and Hematology), SIOP2001/GPOH, and European Rhabdoid Tumor Registry from 1991 to 2014. RESULTS: Median age at diagnosis was 11 months. Fifty percent of patients had metastases or multifocal disease at diagnosis (Stage IV). Local stage distribution was as follows: not done/I/II/III-1/6/11/40. Fifteen (26%) patients underwent upfront surgery. Thirty-seven (64%) patients achieved a complete remission, 17 (29%) relapsed, 34 (59%) died of disease progression, and two (3%) died of treatment-related complication. Mean time to the first event was 3.5 months. Two-year EFS/OS (where EFS is event-free survival) for the whole group was 37 ± 6%/38 ± 6%. Metastases/multifocal disease, younger age, and local stage III were associated with significantly inferior survival. Eleven (19%) patients underwent HDSCT (carboplatin + thiotepa, n = 6; carboplatin + etoposide + melphalan, n = 4; others, n = 1); 2-year OS in this group was 60 ± 15% compared to 34 ± 8% in the non-HDSCT group (P = 0.064). However, the time needed from radiologic to histologic diagnosis, stem-cell harvest, and HDSCT must also be taken into account to avoid selection bias by excluding the highest risk group with early progression (<90 days). Thus, 2-year EFS only for patients without progression until day 90 was 60 ± 16% consolidated by HDSCT compared to 62 ± 11% without (P = 0.8). CONCLUSION: Our retrospective analysis suggests comparable outcomes for patients with and without HDSCT, if adjusted for early disease progression.

Surgical treatment of children with total colonic aganglionosis: functional and metabolic long-term outcome.

BACKGROUND: Total colonic aganglionosis (TCA) is a rare variant of Hirschsprung's disease occurring in 3-10% of the cases. Only few studies reported the long-term clinical and metabolic outcomes of patients with TCA. The aim of this study was to evaluate the functional and metabolic long-term outcomes of children undergoing surgical treatment for TCA. METHODS: A 15-year retrospective study was performed. Blood chemistry tests and stool analysis performed at the last follow-up visit were recorded. Height and weight development were assessed using the corresponding percentiles for age. Faecal continence and quality of life were evaluated using a detailed questionnaire. RESULTS: Eleven patients were included in the study. The median age at surgery was 6 months (range: 3-72 months). After histological confirmation, all patients underwent a total colectomy. Ileoanal anastomosis (n = 6), ileorectal anastomosis (n = 1), J-pouch (n = 1) and Duhamel procedure (n = 3) were performed. Temporary ileostomy was closed after a median of 8 weeks in 10/11 patients. After a median follow-up of 78 months (range: 27-199 months), all evaluated patients were continent. Height and weight were appropriate for age in only 5 patients. Vitamin B12 and folic acid serum levels were normal in all examined patients. Ten patients had normal hemoglobin serum levels. Seven patients had low transferrin saturation in serum. Hemoccult tests were negative in all examined patients. Despite complex postoperative courses in some cases, patients and parents showed good overall satisfaction in terms of quality of life. CONCLUSION: The majority of patients reported a good quality of life. This can result from the adaptation of the patients to certain disease states. The failure to thrive seems to be related with the extent of aganglionosis. The inclusion of these patients in interdisciplinary long-term follow-up care, in which pediatric surgeons, gastroenterologists, and dieticians are involved, is essential.

POST-TEXT III and IV Hepatoblastoma: Extended Hepatic Resection Avoids Liver Transplantation in Selected Cases.

OBJECTIVE: To analyze the outcome of hepatoblastoma (HB) patients presenting with post treatment extent of disease (POST-TEXT) stages III and IV after neoadjuvant chemotherapy. BACKGROUND: Primary liver transplantation has been advocated as surgical treatment for children with HB involving 3 or 4 sectors at diagnosis. However, in some cases, tumors seem resectable after chemotherapy through aggressive use of nontransplant surgical procedures. METHODS: Data of 27 HB patients were reviewed, undergoing extended liver resection for POST-TEXT III or IV tumors after chemotherapy between 1992 and 2015. Median follow-up was 58 months (range 9-188). RESULTS: Median age at surgery was 18.2 months (interquartile range 10.8-32.5). Staging of the children after chemotherapy revealed POST-TEXT III in 21 and POST-TEXT IV in 6 cases. In 2 children, the hepatic resection was performed under cardiopulmonary bypass because of extended vena cava thrombosis; in 2 patients, a simultaneous sternotomy was performed for resection of bilateral lung metastases. The 5-year overall survival rate was 80.7%. CONCLUSIONS: Aggressive surgical resection is a successful approach in some patients with POST-TEXT III and IV HB who otherwise would be candidates for liver transplantation. These children should undergo central review and should be surgically managed at centers of excellence for pediatric liver surgery. Despite challenging surgical procedures and complex clinical courses, the patients benefit from avoidance of morbidities of organ transplant. However, preparation of backup liver transplantation should be considered in selected cases.

Istaroxime Inhibits Motility and Down-Regulates Orai1 Expression, SOCE and FAK Phosphorylation in Prostate Cancer Cells.

BACKGROUND/AIMS: Istaroxime is a validated inotropic Na+/K+ ATPase inhibitor currently in development for the treatment of various cardiac conditions. Recent findings established that this steroidal drug exhibits potent apoptotic responses in prostate tumors in vitro and in vivo, by affecting key signaling orchestrating proliferation and apoptosis, such as c-Myc and caspase 3, Rho GTPases and actin cytoskeleton dynamics. In the present study we examined whether istaroxime is affecting cell motility and analyzed the underlying mechanism in prostate tumor cells. METHODS: Migration was assessed by transwell and wound healing assays, Orai1 and Stim1 abundance by RT-PCR and confocal immunofluorescence microscopy, Fura-2 fluorescence was utilized to determine intracellular Ca2+ and Western blotting for FAK/pFAK measurements. RESULTS: We observed strong inhibition of cell migration in istaroxime treated DU-145 prostate cancer cells. Istaroxime further decreased Orai1 and Stim1 transcript levels and downregulated Orai1 protein expression. Moreover, SOCE was significantly decreased upon istaroxime treatment. Furthermore, istaroxime strikingly diminished phosphorylated FAK levels. Interestingly, the efficacy of istaroxime on the inhibition of DU-145 cell migration was further enhanced by blocking Orai1 with 2-APB and FAK with the specific inhibitor PF-00562271. These results provide strong evidence that istaroxime prevents cell migration and motility of DU-145 prostate tumor cells, an effect at least partially attributed to Orai1 downregulation and FAK de-activation. CONCLUSION: Collectively our results indicate that this enzyme inhibitor, besides its pro-apoptotic action, affects motility of cancer cells, supporting its potential role as a strong candidate for further clinical cancer drug development.

Elevated intrathoracic CO2 pressure during thoracoscopic surgery decreases regional cerebral oxygen saturation in neonates and infants-A pilot study.

BACKGROUND: Intraoperative hypercapnia and acidosis are risk factors during thoracoscopy in neonates and infants. METHODS: In a prospective pilot study, we evaluated the effects of thoracoscopy in neonates and infants on cerebral microcirculation, oxygen saturation, and oxygen consumption. Regional cerebral oxygen saturation and blood flow were measured noninvasively using a new device combining laser Doppler flowmetry and white light spectrometry. Additionally, cerebral fractional tissue oxygen extraction and approximated oxygen consumption were calculated. Fifteen neonates and infants undergoing thoracoscopy were studied using the above-mentioned method. The chest was insufflated with carbon dioxide with a pressure of 2-6 mm Hg. Single lung ventilation was not used. As control group served 15 neonates and infants undergoing abdominal surgery. RESULTS: Data are presented as median and range. The 95% confidence intervals for differences of means (95% CI) are given for the mean difference from baseline values. We observed a correlation between intrathoracic pressure exceeding 4 mm Hg and transient decrease in regional cerebral oxygen saturation of 12.7% (95% CI: 9.7-17.2, P<.001). Peripheral oxygen saturation was normal at the same time. Intraoperative increase in arterial paCO2 (median maximum value: 48.8 mm Hg, range: [36.5-65.4]; 95% CI: -16.0 to -3.0, P=.002) and decrease in arterial pH (median minimum value: 7.3, range: [7.2-7.4]; 95% CI: 0.04-0.12, P=.008) were observed during thoracoscopy with both parameters recovering at the end of the procedure. Periods of regional cerebral oxygen saturation below 20% from baseline were significantly more frequent during thoracoscopy as compared to the control group (median maximum value: 1.3%min/h, range: [0.0-66.2] vs median maximum value: 0.0%min/h, range: [0.0-4.0]; 95% CI: -16.6 to -1.1, P=.028). CONCLUSION: We suggest that thoracoscopic surgery in neonates and infants, although generally safe, may be associated with a decrease in regional cerebral oxygen saturation correlating with the applied intrathoracic pressure. According to our data an inflation pressure >4 mm Hg should be avoided during thoracoscopic surgery.