Search

ZusammenfassungKrebskranke Kinder und Jugendliche überleben heute dank Heilungsraten von über 80% viel häufiger ihre Krebserkrankung als vor 40 Jahren. Etwa 33 000 geheilte ehemalige krebskranke Kinder und Jugendliche sind in der Langzeitbeobachtung über das Deutsche Kinderkrebsregister (DKKR) bundesweit erfasst. Heißt geheilt aber auch gesund? Beim Vergleich mit der Normalbevölkerung ist festzustellen, dass die Morbidität und Mortalität bei den ehemaligen Patienten deutlich erhöht ist. Die Krebserkrankungen und deren Behandlungen können bei zwei von drei Überlebenden 30 Jahre später zu therapiebedürftigen Spätfolgen führen, bei etwa einem Drittel werden sie als schwer eingestuft. Mittels einer strukturierten Nachbeobachtung können diese frühzeitig erkannt und bei Bedarf behandelt werden. Ziel dieses Positionspapiers ist eine Aktualisierung des ersten Positionspapiers aus dem Jahre 2007. Hierbei werden die aktuellen Entwicklungen beschrieben und dargestellt, wie geeignete Nachsorgestrukturen und Nachsorgeeinrichtungen – unter Berücksichtigung der bestehenden Strukturen und dem steigenden Bedarf – geplant werden sollten.

ZusammenfassungMit dem neuen Zertifizierungsmodul wird die Entwicklung der interdisziplinären Vernetzung und eines zentralisierten Engagements für eine hohe Versorgungsqualität in der Kinderonkologie konsequent fortgeführt. Das neue Modul wurde gemeinsam durch die Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) und die Deutsche Krebsgesellschaft (DKG) 2016 initiiert. Der umfassende Anforderungskatalog, ausgehend von, aber nicht begrenzt auf die GBA-Richtlinie, konnte bisher von 7 Pilotzentren erfolgreich umgesetzt und dessen Praxistauglichkeit bestätigt werden. Interessierte Zentren können sich ab sofort für eine Zertifizierung als Kinderonkologisches Zentrum anmelden.

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.

Nowadays, childhood cancer patients survive much more often than they did 40 years ago. Therefore, the cure rates rise over 80%. Approximately 33,000 cured childhood cancer patients are documented by the German Childhood Cancer Registry (GCCR) for long-term follow-up in Germany. But does that mean, they are healthy, too? When compared to the normal population, it can be seen that morbidity and mortality are significantly higher among former childhood cancer patients. In two out of three survivors, the cancer and its treatments can lead to treatment-related late complications 30 years later; in about one-third, these late complications are classified as severe. A structured long-term follow-up is needed to detect and to treat new diseases early. The purpose of this position paper is to update the first position paper from 2007. Current developments are described, how appropriate aftercare structures and aftercare facilities should be planned, taking into account existing structures and increasing needs.Krebskranke Kinder und Jugendliche überleben heute dank Heilungsraten von über 80% viel häufiger ihre Krebserkrankung als vor 40 Jahren. Etwa 33 000 geheilte ehemalige krebskranke Kinder und Jugendliche sind in der Langzeitbeobachtung über das Deutsche Kinderkrebsregister (DKKR) bundesweit erfasst. Heißt geheilt aber auch gesund? Beim Vergleich mit der Normalbevölkerung ist festzustellen, dass die Morbidität und Mortalität bei den ehemaligen Patienten deutlich erhöht ist. Die Krebserkrankungen und deren Behandlungen können bei zwei von drei Überlebenden 30 Jahre später zu therapiebedürftigen Spätfolgen führen, bei etwa einem Drittel werden sie als schwer eingestuft. Mittels einer strukturierten Nachbeobachtung können diese frühzeitig erkannt und bei Bedarf behandelt werden. Ziel dieses Positionspapiers ist eine Aktualisierung des ersten Positionspapiers aus dem Jahre 2007. Hierbei werden die aktuellen Entwicklungen beschrieben und dargestellt, wie geeignete Nachsorgestrukturen und Nachsorgeeinrichtungen – unter Berücksichtigung der bestehenden Strukturen und dem steigenden Bedarf – geplant werden sollten.

The new certification module will continue to foster the development of interdisciplinary networks and a centralised commitment to high quality of care in paediatric oncology. The new module was initiated in a joint venture of the German Society of Paediatric Oncology and Haematology (GPOH) and the German Cancer Society (DKG) in 2016. The comprehensive Catalogue of Requirements is based on the directive for paediatric oncology by the Federal Joint Committee (G-BA) and has been successfully implemented into clinical practice in a pilot phase with 7 Paediatric Cancer Centres. Interested centres can register for certification as of now.Mit dem neuen Zertifizierungsmodul wird die Entwicklung der interdisziplinären Vernetzung und eines zentralisierten Engagements für eine hohe Versorgungsqualität in der Kinderonkologie konsequent fortgeführt. Das neue Modul wurde gemeinsam durch die Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) und die Deutsche Krebsgesellschaft (DKG) 2016 initiiert. Der umfassende Anforderungskatalog, ausgehend von, aber nicht begrenzt auf die GBA-Richtlinie, konnte bisher von 7 Pilotzentren erfolgreich umgesetzt und dessen Praxistauglichkeit bestätigt werden. Interessierte Zentren können sich ab sofort für eine Zertifizierung als Kinderonkologisches Zentrum anmelden.

Common complications involved in treating pediatric patients with cancer are bacterial, viral and fungal infections of the gastrointestinal tract including esophagitis, gastritis, duodenitis, colitis and hepatobiliar infections. In many cases there are multiple factors that predispose these patients to gastrointestinal infections, such as granulocytopenia, T-cell dysfunction, and mucosal damage. In addition, newer therapies have changed the spectrum of infection that is seen in these patients. The profound T-cell suppression associated with therapies such as stem cell transplantation has led to the emergence of previously rare infections including cytomegalovirus and adenovirus. This article provides the recommendations of the Infectious Diseases Working Party of the German Society for Pediatric Infectious Diseases (DGPI) and the German Society for Pediatric Hematology/Oncology (GPOH) for diagnosis, prevention, and management of local as well as invasive infections of the gastrointestinal tract.

Background: The neurotrophin-receptor TrkB plays an important role in pathogenesis, biology and prognosis of neuroblastoma. Expression of TrkB on aggressive neuroblastomas leads to proliferation and survival of the tumor cells and is associated with an unfavorable prognosis. It is now known that Trk receptors are also expressed in extraneural tissues including the kidney. Patients and Methods: To study the role of the neurotrophin-receptor TrkB in nephroblastoma/Wilms' Tumor (WT), we determined TrkB mRNA expression by semiquantitative duplex RT-PCR in 39 primary WT. Comparison of mRNA expression levels with clinical variables was performed using Cox regression analysis. Results: The 5-year overall survival was significantly worse for patients with tumors expressing high levels of a functional TrkB-receptor (TrkBfull) in comparison to patients with low levels of TrkBfull (70% versus 100%, p = 0.005). Conversely, children with tumors expressing high mRNA levels of a functionally inactive truncated TrkB receptor (TrkBtrunc) had a significantly higher 5-year overall survival rate in comparison to patients with low levels of TrkBtrunc (100% versus 68%, p=0.003). The hazard ratios for TrkBfull and TrkBtrunc remained significant after adjusting for tumor stage. All WT with high levels of TrkB also expressed the ligand brain-derived neurotrophic factor (BDNF). Conclusions: Full-length and truncated TrkB appear to be important prognostic factors in WT. Their expression should be assessed prospectively in a larger panel of WT and may have a future role in patient assignment to risk-based treatment strategies. TrkB signaling may be reduced in WT with favorable outcome due to low numbers of TrkB receptors or a competitive effect of functionally inactive TrkBtrunc.

Expression of different neurotrophin receptors of the tyrosine kinase (Trk) family plays an important role in the biology and clinical behavior of neuroblastomas (NB). Observations from several independent studies suggest that high expression of TrkA is present in NB with favorable biological features and highly correlated with patient survival, whereas TrkB is mainly expressed on unfavorable, aggressive NB with MYCN-amplification. To determine expression of Trk receptors and ligands in primary NB, we developed a reliable semiquantitative duplex RT-PCR protocol, that requires only 1 microgram RNA per tumor sample. Activation of TrkA by its ligand nerve growth factor (NGF) initiates a cascade of signaling events and promotes neuronal differentiation in vitro. Activation of TrkB by its ligand brain derived neurotrophic factor (BDNF) has been associated with proliferation and survival of NB cells. To study Trk signal transduction pathways and their biological effects in NB, we stably expressed TrkA and TrkB cDNA in the human NB cell line SH-SY5Y. Introduction of TrkA and TrkB restored responsiveness of SH-SY5Y cells to the ligands NGF and BDNF, respectively, and resulted in morphological differentiation. Expression of TrkA resulted in growth inhibition of the transfectants compared to parental cells, whereas TrkB transfectants demonstrated an increased proliferation rate. Further insight into the differences of TrkA and TrkB signaling may suggest new options for the treatment of NB. As expression of TrkA is a strong prognostic factor especially in MYCN non-amplified NB, a prospective study of Trk receptor expression using RT-PCR should be performed for German neuroblastoma patients.

Retinoblastoma affects approximately 40 children in Germany per year. Most children are diagnosed early with localized intraocular disease, and the overall survival rate exceeds 95%. However, the prognosis of metastasized retinoblastoma remains poor. In 40% of the patients, retinoblastoma occurs bilaterally and, especially for these children, the salvage of the eye and visual function is of major importance. The variety of conservative treatment options for localized retinoblastoma includes laser coagulation, thermotherapy, cryotherapy, brachytherapy and chemotherapy. While systemic chemotherapy has nearly completely replaced external beam radiotherapy in the primary treatment of intraocular retinoblastoma, intra-arterial, intravitreal and periocular application of chemotherapy was also shown to be effective in treating intraocular retinoblastoma in case series. Genetic testing is an integral part of the routine diagnostics of all patients. Available tumor material should be analyzed to detect mutational mosaicism, that affects >10% of children with unilateral retinoblastoma. Genetic testing also identifies children with heritable (50% of patients) retinoblastoma. These children have a genetic predisposition for second malignancies. For this reason, late effects are an increasing concern and the care of patients with retinoblastoma requires a multidisciplinary approach to tailor therapy and long-term follow-up. Multicenter clinical trials are being developed to evaluate evidence-based treatment concepts for localized and metastasized retinoblastoma to improve survival rates and quality of life of children with retinoblastoma.

Purpose Real-time reverse-transcriptase PCR (RT-qPCR) or conventional RT-PCR (RT-cPCR) detection of tyrosine hydroxylase (TH) is increasingly used to detect neuroblastoma (NB) cells in clinical samples. However, TH expression in normal tissues can limit its usefulness and make additional diagnostic strategies necessary. Methods We analysed TH in 857 tumour, bone marrow aspirate and peripheral blood stem cell samples from 65 NB patients using RT-cPCR, and compared results from 666 samples analysed by RT-qPCR. TH was investigated in 84 samples from patients with other diagnoses and 354 samples from healthy donors as controls, and 132 samples from the entire collection were evaluated for NB cells using 5-colour flow cytometry (FC). Results Cohen's kappa coefficient demonstrated a substantial agreement between RT-cPCR and RT-qPCR as well as RT-cPCR and FC and a moderate agreement between RT-qPCR and FC. TH expression was also detected in samples from individual patients with Ewing sarcoma, nephroblastoma and rhabdomyosarcoma, but not from healthy donors. FC panels were an effective complementary strategy, detecting as few as 0.002% NB cells, characterised as CD45negCD9+CD81+CD56+ch14:18+GD2+ cells with occasional CD57+CD138+CD166+ expression. Conclusion TH RT-qPCR alone is limited for detection of NB cells because of "false positives" in samples from patients with other diseases. Advanced FC may serve as a complementary method to detect residual NB, but needs further confirmation in larger patient cohorts.

Introduction: Viscum album (mistletoe) extract is a common complementary therapy used by cancer patients in Germany. Its safety is currently being explored in a German multicenter clinical trial in pediatric oncology, but little is known about its efficacy against pediatric tumor cells. Methods: A panel of tumor cell lines derived from several pediatric cancers (neuroblastoma, medulloblastoma, rhabdomyosarkoma, ALL, AML, lymphoma and retinoblastoma) were treated with Viscum album (abnobaVISCUM® Fraxini). Effects on apoptosis, cell cycle arrest and cell migration were investigated in vitro. Results: Viscum album significantly inhibited growth of all pediatric tumor cell lines tested, induced apoptosis in a dose-dependent manner and abrogated cell migration. Conclusion: Viscum album was cytotoxic for and reduced migration in a panel of pediatric tumor cell lines in vitro, justifying further investigation of potential use in treatment of pediatric cancers.

Neuroblastoma (NB), the most common solid tumor of childhood, is characterized by a remarkable heterogeneity of patients' courses and survival rates of older patients with metastatic disease have remained poor. Numerous prognostic factors including amplification of the MYCN oncogene have been described. However, despite advanced clinical risk stratification, current trials still fail to determine the best treatment strategy for a substantial number of patients. On the route to clinical application of improved array-based classifiers to predict the risk profile of individual patients, significant progress has been achieved over the past years. We here present data on a cohort of 138 primary NB using a novel approach including information for all human coding exons described to date (Affymetrix ExonST Array). Using a classifier trained on 100 patient samples and then used to predict the outcome of the remaining 38 patients, we were able to achieve prediction accuracies >80% in the independent test set using support vector machine (SVM) learning algorithms, which is superior to the current clinical risk stratification. Interestingly, the histone demethylase JARID1C, which had not been linked to cancer formation previously, was up-regulated in relapsing NB and found to have prognostic value independent of MYCN amplification. JARID1C was also highly expressed in all NB cell lines investigated. Down-regulation of JARID1C using siRNA inhibited cell proliferation in vitro. Taken together, exon level analysis appears to be a highly promising tool both for prediction of outcome and for providing new insights into tumor biology.