Verena Ellerkamp

Pancreatoblastoma: A report from the European cooperative study group for paediatric rare tumours (EXPeRT)

BACKGROUND Pancreatoblastoma is a very rare malignant tumour typically occurring in the early years of life. Due to its rarity, standardised diagnostic and therapeutic guidelines are not available for pancreatoblastoma. METHODS The newborn cooperative group denominated EXPeRT - European cooperative study group for paediatric rare tumours - combined in a joint analysis of all cases registered between 2000 and 2009 by the national groups of Italy, France, United Kingdom, Poland and Germany. RESULTS Twenty patients <18years old (median age 4years) were analysed: nine had distant metastases at diagnosis. Seventeen patients had tumour resection, at initial or delayed surgery. Eighteen received chemotherapy (response rate 73%), seven received radiotherapy. For the whole series, 5-year event-free survival and overall survival were 58.8% and 79.4%, respectively. Outcome did not correlate with tumour site and size, but was strongly influenced by the feasibility of tumour complete resection. CONCLUSIONS This international study confirms the rarity of the disease, the critical role of surgical resection both as therapy and as a prognostic variable, and the potential efficacy of chemotherapy. The adoption of an intensive multidisciplinary approach is required, as well as the referral to highly experienced centres. Further international cooperation is needed to collect larger series and stimulate biological studies to improve our understanding of the biology and the natural history of PBL.

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.

Exocrine Pancreatic Tumors in Childhood in Germany

Pancreatic tumors (PT) in childhood are rare. Standard therapeutic approaches are lacking. Our aim was to analyze treatment modalities and outcome in children with PT.

Effects of curcumin in pediatric epithelial liver tumors: inhibition of tumor growth and alpha-fetoprotein in vitro and in vivo involving the NFkappaB- and the beta-catenin pathways.

In children with hepatocellular carcinoma (pHCC) the 5-year overall survival rate is poor. Effects of cytostatic therapies such as cisplatin and doxorubicin are limited due to chemoresistance and tumor relapse. In adult HCC, several antitumor properties are described for the use of curcumin. Curcumin is one of the best-investigated phytochemicals in complementary oncology without relevant side effects. Its use is limited by low bioavailability. Little is known about the influence of curcumin on pediatric epithelial hepatic malignancies. We investigated the effects of curcumin in combination with cisplatin on two pediatric epithelial liver tumor cell lines. As mechanisms of action inhibition of NFkappaB, beta-catenin, and decrease of cyclin D were identified. Using a mouse xenograft model we could show a significant decrease of alpha-fetoprotein after combination therapy of oral micellar curcumin and cisplatin. Significant concentrations of curcuminoids were found in blood samples, organ lysates, and tumor tissue after oral micellar curcumin administration. Micellar curcumin in combination with cisplatin can be a promising strategy for treatment of pediatric HCC.

The timing of surgery for undescended testis - a retrospective multicenter analysis.

BACKGROUND n Germany, it is recommended that the surgical treatment of an undescended testis should be carried out between the ages of 6 months and 1 year to lower the risks of subfertility and testicular carcinoma. Although this recommendation has appeared in the German guidelines from 2007 onward, orchidopexy is still frequently performed at later ages. METHOD We retrospectively analyzed data from seven pediatric surgical services in the German state of Baden-Württemberg on all boys who underwent orchidopexy from 2009 to 2012. We classified the timing of surgery as Age Group I (before the first birthday), Age Group II (between the first and second birthdays), and Age Group III (after the second birthday). We determined whether preoperative hormonal treatment was given and distinguished primary from secondary undescended testis. RESULTS Among 2213 boys who underwent orchidopexy, 1850 had primary and 363 had secondary undescended testis. Of those with primary undescended testis, the percentages of boys who underwent surgery in Age Groups I, II, and III were (respectively, with 95% confidence intervals): 18.7% (17-20.6%), 24.4% (22.5-26.5%), and 57% (54.6-59.2%). A small percentage of boys in each group also received preoperative hormonal treatment. From 2009 to 2012, there was a secular trend favoring earlier orchidopexy. In 2012, 28 boys (14.2% [9.7-20.0%]) had orchidopexy in outpatient pediatric surgery practices before their first birthday, while 68 did on hospital inpatient services (40.7% [33.2-48.6%]). CONCLUSION Most of the patients studied had surgery at a later age than recommended. Adherence to the guidelines in this respect is nonetheless relatively good in Germany compared to other countries, as studies from abroad have yielded findings that are just as bad or worse.

Successful Establishment of an Orthotopic Hepatoblastoma In Vivo Model in NOD/LtSz-scid IL2Rγnull Mice

Investigation of hepatoblastoma in experimental conditions contributes relevantly to a detailed understanding of tumor biology and the investigation of new treatment approaches. Most systematical analyses currently use subcutaneous xenografts. We established a reproducible intrahepatic model with the hepatoblastoma-cell lines HuH6 and HepT1. The cells were stably transfected with a plasmid vector encoding for Gaussia luciferase. HuH6 and HepT1 were injected intrasplenically in NOD/LtSz-scid IL2Rγnull mice. Mice were splenectomized in order to avoid intrasplenical tumor growth. Multifocal intrahepatic tumor growth was observed in 85% (11/13) of HuH6 tumors and 55% (5/9) of HepT1 tumors. Serum Alpha-fetoprotein and Gaussia luciferase increased 5 weeks after tumor-cell inoculation. Tumors were detected by MRI at this time point. Immunhistochemical analysis such as vascularity (CD31), proliferation index (Ki-67), cytokeratin 7 and distribution of β -catenin in intrahepatic tumors were different to subcutaneous tumors. We established a reproducible xenograft model for intrahepatic hepatoblastoma growth with a high tumor incidence. Monitoring of tumor cell viability was optimized by measuring GLuc. This model enables further experimental investigations of HB in a more physiological milieu as emphasized by the β-catenin distribution.

BH3-mimetic drugs prevent tumour onset in an orthotopic mouse model of hepatoblastoma

Drug resistance and metastasis remain major challenges in the treatment of high-risk hepatoblastoma (HB) and require the development of alternative therapeutic strategies. Modulation of apoptosis in HB cells enhances the sensitivity of these cells towards various drugs and has been discussed to enforce treatment. We investigated the impact of apoptosis sensitisers, BH3-mimetics, on the interaction between the host and HB to reduce tumour growth and dissemination while enhancing immunity. BH3-mimetics, such as obatoclax and ABT-737, enhanced the apoptosis-inducing effect of TRAIL and TNF-α resistant HB cells (HepT1 and HUH6). Tumour cell migration was inhibited by ABT-737 and more markedly by obatoclax. In an orthotopic model of HB, tumour uptake was reduced when the cells were pretreated with low concentrations of obatoclax. Only 1 of 7 mice developed HB in the liver, compared with an incidence of 0.8 in the control group. In summary, our study showed that apoptosis sensitisers had broader effects on HB cells than expected including migration and susceptibility to cytokines in addition to the known effects on drug sensitization. Sensitising HB to apoptosis may also allow resistant HB to be targeted by immune cells and prevent tumour cell dissemination.

Abstract 4337: Effect of sorafenib in combination with cytostatic agents on hepatoblastoma in vitro and in vivo

Background: Hepatoblastoma (HB) represents the most common malignant liver tumour in childhood. For patients with high risk or recurrent HB treatment results remain still poor due to a developing multidrug resistance during chemotherapy. Therefore new therapy strategies have to be evaluated. The primary objective was to investigate the combined therapy of cytotoxic agents with sorafenib. Sorafenib has been shown to reduce tumour progression and angiogenesis. In order to investigate a treatment close to a clinical setting the effect of the combined administration of cytotoxic agents with sorafenib on HB cell lines and xenotransplanted HB tumours was determined. Methods: Cell viability of two HB cell lines (HUH6 and HepT1) was evaluated in using MTT assays after treatment with sorafenib and different cytostatic agents (cisplatin (CDDP), doxorubicin, irinotecan, topotecan). ERK signalling was investigated by Western blot analysis. NMRI mice (nu/nu) bearing subcutaneous HUH6 derived tumours were treated with Sorafenib orally (30 mg/kg, on days 4-13 and 17-24) alone or in combination with CDDP i.p. (3 mg/kg, on days 1-3 and 14-16). Tumor progression and viability were monitored by tumour volume and AFP levels. Apoptosis was assessed by TUNEL assay. Angiogenesis was determined by CD31 staining and mean vascular density (MVD) was calculated. Results: In vitro the combination of sorafenib with CDDP showed a remarkable decrease in cell viability compared to the other agents tested. However with increasing concentrations of CDDP this additive effect disappeared. CDDP alone showed an enhanced phosphorylation of ERK1/2, which is a common pathway for apoptosis induction through NOXA. CDDP in combination with sorafenib led to an overall reduced phosphorylation level of ERK1/2, which also resulted in a low HB cell viability. Since CDDP and sorafenib have an opposing effect on phosphorylation of ERK1/2, we avoid the concomitant administration of both drugs in vivo. In HB xenografts both sorafenib alone or in alternating combination with CDDP reduced tumour growth compared to the control untreated group (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4337. doi:1538-7445.AM2012-4337

Guideline implementation for the treatment of undescended testes: Still room for improvement

BACKGROUND Early orchidopexy (OP) around the age of 1 year is recommended in boys with congenital undescended testis (UDT) worldwide since decades. Former retrospectives studies did not distinguish congenital from acquired UDT with a consecutive negative bias concerning the age at surgery. METHODS In a retrospective analysis, data of all boys who underwent OP in eight pediatric surgery institutions from 2009 to 2015 were analyzed. Congenital or acquired UDT were differentiated. Patients were categorized into 3 groups of age at surgery: (1) <12 months, (2) 12-24 months, (3) >24 months. Data of one institution were analyzed in detail: exact age of first referral, exact age at surgery, intraoperative findings. RESULTS Out of 4448 boys, 3270 boys had congenital UDT. In 81% (2656 cases) surgery was performed beyond the age of 1 year, in 54.4% (1780) beyond the age of 2 years. chi-Square statistics showed a higher rate of early operations in hospitals compared to outpatient services and in Germany compared to Switzerland. In 694 congenital detailed cases, median age at referral was 13 months [range 0-196], median age at surgery was 15 months [range 0-202]. CONCLUSION Delayed referral is the main reason for guideline non-conform delayed surgery in UDT. TYPE OF STUDY Clinical Research paper. LEVEL OF EVIDENCE Level III: Treatment Study.

Erkrankungen und Therapieformen des unteren Gastrointestinaltrakts

Duodenalatresien sind Hemmungsfehlbildungen und können proximal oder distal der Papilla Vateri entstehen, wobei die präpapillären Obstruktionen selten sind. Grundsätzlich kann zwischen einer Membranatresie und einer Defektatresie unterschieden werden. Die Unterscheidung beruht nicht nur auf embryologischen Gesichtspunkten, sondern hat auch eine klinische Bedeutung: Bei der Membranatresie kann die quergestellte, partiell offene oder geschlossene Membran weit in den distalen Duodenalanteil reichen („Windsackphänomen“), was zu diagnostischen und auch intraoperativen Problemen führen kann. Ein Pancreas anulare findet sich bei etwa 20 % aller Patienten mit Duodenalatresie.