Comparative analysis of resource utilization in integrative anthroposophic and all German pediatric inpatient departments.

BACKGROUND: Integrative Medicine (IM) combines conventional and complementary therapies. It aims to address biological, psychological, social, spiritual and environmental aspects of patients' health. During the past 20 years, the use and request of IM in children and adults has grown. Anthroposophic Medicine (AM) is an IM approach frequently used in children in Germany. From both public health and health economic perspectives, it is relevant to investigate whether there are differences in the resource utilization between integrative pediatric departments (IPD) and the entirety of all pediatric departments. METHODS: Standard ward documentation data from all German integrative anthroposophic pediatric departments (2005-2016; N = 29,956) is investigated and systematically compared to data of the entirety of all pediatric departments in Germany derived from the Institute for the Hospital Reimbursement System (2005-2016, N = 8,645,173). The analyses focus on: length of stay, Diagnosis Related Groups (DRG), Major Diagnosis Categories (MDC), and effective Case Mix Index (CMI). RESULTS: The length of stay in the IPD (M = 5.38 ± 7.31) was significantly shorter than the DRG defined length of stay (M = 5.8 ± 4.71; p < .001; d = - 0.07) and did not exceed or undercut the DRG covered length of stay. Compared to the entirety of all pediatric departments (M = 4.74 ± 6.23) the length of stay was significantly longer in the in the IPD (p <. 001; d = 0.12). The effective CMI in IPD and all pediatric departments were identical (M = 0.76). The frequencies of DRG and MDC differed between IPD and all pediatric departments, with higher frequencies of DRGs and MDCs associated with chronic and severe illnesses in the IPD. CONCLUSIONS: Treatment within integrative anthroposophic pediatric departments fits well in terms of the DRG defined conditions concerning length of stay, even though integrative pediatric patients has an increased length of stay of averagely 1 day, which is most likely associated to time consuming, complex integrative treatment approaches and to a certain extend to higher amount of chronic and severe diseases.

Preclinical Evaluation of Antitumoral and Cytotoxic Properties of Viscum album Fraxini Extract on Pediatric Tumor Cells.

In Europe, especially in German-speaking countries, administration of mistletoe extracts is the most common and popular complementary and alternative therapy approach reported in oncology. Mistletoe therapy is applied to children with cancer for curative and palliative therapeutic regimes with increasing frequency, but at the same time, there are only a few studies on the effectiveness of this therapy. Therefore, we have investigated the response of various pediatric cell lines (acute myeloid leukemia, Ewing's sarcoma, hepatocellular carcinoma, medulloblastoma, neuroblastoma, and osteosarcoma) to mistletoe extract, abnobaVISCUM Fraxini. Effects on cell proliferation, cell cycle distribution as well as on mitochondrial integrity and caspase-mediated apoptosis were investigated in neuroblastoma cell lines, SH-SY5Y and Kelly. Additionally, in vitro tumor cell migration and invasion were studied. In vivo effects of the mistletoe extract were investigated in a syngeneic neuroblastoma mouse model. We could show that tumor cell lines were from 5- to 640-fold more sensitive to abnobaVISCUM Fraxini treatment than non-tumorigenic fibroblasts, whereby neuroblastoma cell lines were the most sensitive. For two neuroblastoma cell lines, SH-SY5Y and Kelly, induction of caspase-9-mediated apoptosis, a decrease of mitochondrial integrity as well as attenuation of migration and invasion were observed. In vivo experiments revealed a reduction of tumor growth and a prolonged survival of tumor-bearing animals. In summary, we can state that these results provide the first preclinical data for cytotoxic activities of abnobaVISCUM Fraxini for a broad panel of pediatric tumor cell lines, in particular, neuroblastoma cells. Thus, it might be a potential remedy for the supportive treatment of neuroblastoma.

Do patients of integrative anthroposophic pediatric inpatient departments differ? Comparative analysis to all pediatric inpatients in Germany considering demographic and clinical characteristics.

BACKGROUND: Integrative medicine (IM) is a patient-centered, evidence-based, therapeutic paradigm which combines conventional and complementary approaches. The use of IM in pediatrics has increased in the past two decades and parents' demand for it is growing. An IM whole systems approach is anthroposophic medicine. Considering the growing demand for integrative approaches in children, it is relevant from a public health perspective to find out which kind of children use IM in Germany and whether they differ from the entirety of pediatric inpatients in Germany. Moreover, it would be interesting to known, whether these patients are willing to travel a longer distance to gain integrative treatment. METHODS: The present study investigates the standard ward documentation datasets of 29,956 patients of all German integrative anthroposophic pediatric inpatient wards from 2005 to 2016 and compares them systematically to collect data of the entirety of all pediatric inpatient wards in Germany. Apart from patients' age and gender, and the ICD-10 admission diagnoses, the geographical catchment area of the hospitals were analyzed. RESULTS: Sociodemographic characteristics of pediatric inpatients in the integrative anthroposophic departments (IAH) did not differ from the entirety of all pediatric inpatients. Regarding clinical characteristics, higher frequencies were found for endocrine, nutritional and metabolic diseases (IAH: 7.24% vs. 2.98%); mental, behavioral, and neurodevelopmental disorders (IAH: 9.83% vs. 3.78%) and nervous diseases (IAH: 8.82% vs. 5.16%) and lower frequencies for general pediatric diseases such as respiratory diseases (IAH: 17.06% vs. 19.83%), digestive diseases (IAH: 3.90% vs. 6.25%), and infectious and parasitic diseases (IAH: 12.88% vs. 14.82%) in comparison to the entirety of all pediatric inpatients in Germany. The IAH showed a broad catchment area, with most patients being from former, Western federal republic of Germany. Large catchment areas (> 100 km) for the IAH are merely covered by severe and chronic diseases. CONCLUSION: Pediatric inpatients of IAH do not differ from the entirety of pediatric inpatients in Germany regarding sociodemographic characteristics but show differences regarding clinical characteristics. Parents are willing to travel further distance to get specialized integrative anthroposophic medical care for children with severe and chronic diseases.

Pharmaceutically inhibiting polo-like kinase 1 exerts a broad anti-tumour activity in retinoblastoma cell lines.

BACKGROUND: Retinoblastoma is the most common malignant cancer of the eye in children. Although metastatic retinoblastoma is rare, cure rates for this advanced disease remain below 50%. High-level polo-like kinase 1 expression in retinoblastomas has previously been shown to be correlated with adverse outcome parameters. Polo-like kinase 1 is a serine/threonine kinase involved in cell cycle regulation at the G2/M transition. Polo-like kinase 1 inhibition has been demonstrated to have anti-tumour effects in preclinical models of several paediatric tumours. Here, we assessed its efficacy against retinoblastoma cell lines. METHODS: Expression of polo-like kinase 1 was determined in a panel of retinoblastoma cell lines by polymerase chain reaction and western blot analysis. We analysed viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT assay), proliferation (5-bromo-2'-deoxyuridine enzyme-linked immunosorbent assay), cell cycle progression (propidium iodid staining) and apoptosis (cell death enzyme-linked immunosorbent assay) in three retinoblastoma cell lines after treatment with two adenosine triphosphate-competitive polo-like kinase 1 inhibitors, BI6727 or GSK461364. Activation of polo-like kinase 1 downstream signalling components including TP53 were assessed. RESULTS: Treatment of retinoblastoma cells with either BI6727 or GSK461364 reduced cell viability and proliferative capacity and induced both cell cycle arrest and apoptosis. Polo-like kinase 1 inhibition also induced the p53 signalling pathway. Analysis of key players in cell cycle control revealed that low nanomolar concentrations of either polo-like kinase 1 inhibitor upregulated cyclin B1 and increased activated cyclin-dependent kinase 1 (phosphorylated at Y15) in retinoblastoma cell lines. CONCLUSIONS: These preclinical data indicate that polo-like kinase 1 inhibitors could be useful as components in rationally designed chemotherapy protocols to treat patients with metastasized retinoblastoma in early phase clinical trials.

Expert consensus-based clinical recommendation for an integrative anthroposophic treatment approach to acute tonsillitis in childhood.

BACKGROUND: Medical guidelines are an important basis for qualitative and cost-effective patient care. However, there is a lack of clinical recommendations in anthroposophic medicine (AM), an integrative medicine approach frequently practised in Europe. Acute tonsillitis, which includes tonsillopharyngitis, is a common childhood disease. that is mostly caused by a viral infection. Symptomatic treatment is therefore of high importance, and AM can offer several therapy options. METHODS: 53 physicians from Germany, Spain, Netherlands, Switzerland, Austria, and Hungary with at least one year of experience in anthroposophic paediatric medicine were invited to participate in an online Delphi process. The process comprises five survey rounds starting with open-ended questions and ending with final statements, which need 75% agreement of experts to reach consensus. Expert answers were evaluated by two independent reviewers using MAXQDA and Excel. RESULTS: Response rate was between 28% and 45%. The developed recommendation included 15 subtopics. These covered clinical, diagnostic, therapeutic and psychosocial aspects of acute tonsillitis. Six subtopics achieved a high consensus (>90%) and nine subtopics achieved consensus (75-90%). CONCLUSION: The clinical recommendation for acute tonsillitis in children aims to simplify everyday patient care and provide decision-making support when considering and prescribing anthroposophic therapies. Moreover, the recommendation makes AM more transparent for physicians, parents, and maybe political stakeholders as well.

Evaluation of a guideline for supportive anthroposophic therapies for hospitalised children with acute gastroenteritis - A prospective case series study.

OBJECTIVE: Even though several German children's hospitals offer integrative, anthroposophic medical therapies in addition to the standard medical care, guidelines for these anthroposophic therapies are still rare. Therefore, we investigated the feasibility of implementing a published, consensus-based guideline for the treatment of children with acute gastroenteritis (aGE) with anthroposophic therapies in the community hospital Herdecke. DESIGN: A prospective case series of paediatric patients (≤18 years) with an aGE admitted to the department of integrative paediatrics of the community hospital Herdecke was conducted. Demographic, clinical and therapeutic data was recorded at initial presentation and at follow-up visits. Physicians were surveyed with a questionnaire to evaluate feasibility of implementing the guideline. RESULTS: Sixty-two patients (0-15 years; 22 male, 40 female) were included in the case series. All patients received some form of anthroposophic therapy. The most frequently used remedies were Geum urbanum, Nux vomica and Bolus alba comp. Treating physicians showed a high adherence to the expert-based consensus guideline in their prescribed therapies. All physicians stated that they were familiar with the guideline and used the recommendation to inform their therapy decision. Suitability for daily use and effectiveness in treating the main symptoms of aGE were highly scored by the physicians. CONCLUSION: The consensus-based guideline of anthroposophic therapies for aGE in children was successfully implemented and found to be useful for physicians in clinical practice.

Next-generation RNA sequencing reveals differential expression of MYCN target genes and suggests the mTOR pathway as a promising therapy target in MYCN-amplified neuroblastoma.

In many cancer types, MYC proteins are known to be master regulators of the RNA-producing machinery. Neuroblastoma is a tumor of early childhood characterized by heterogeneous clinical courses. Amplification of the MYCN oncogene is a marker of poor patient outcome in this disease. Here, we investigated the MYCN-driven transcriptome of 20 primary neuroblastomas with and without MYCN amplification using next-generation RNA sequencing and compared the results to those from an in vitro cell model for inducible MYCN (SH-EP MYCN-ER). Transcriptome sequencing produced 30-90 million mappable reads for each dataset. The most abundant RNA species was mRNA, but snoRNAs, pseudogenes and processed transcripts were also recovered. A total of 223 genes were significantly differentially expressed between MYCN-amplified and single-copy tumors. Of those genes associated with MYCN both in vitro and in vivo, 32% of MYCN upregulated and 37% of MYCN downregulated genes were verified either as previously identified MYCN targets or as having MYCN-binding motifs. Pathway analyses suggested transcriptomal upregulation of mTOR-related genes by MYCN. MYCN-driven neuroblastomas in mice displayed activation of the mTOR pathway on the protein level and activation of MYCN in SH-EP MYCN-ER cells resulted in high sensitivity toward mTOR inhibition in vitro. We conclude that next-generation RNA sequencing allows for the identification of MYCN regulated transcripts in neuroblastoma. As our results suggest MYCN involvement in mTOR pathway activation on the transcriptional level, mTOR inhibitors should be further evaluated for the treatment of MYCN-amplified neuroblastoma.

Complementary and alternative medicine in the (symptomatic) treatment of acute tonsillitis in children: A systematic review.

BACKGROUND: Acute tonsillitis (including tonsillopharyngitis) in childhood is a common disease with a peak of illness in school-age. Most of these cases have a viral origin and antibiotic therapy is not indicated, therefore, effective symptomatic therapy is required. For this reason, complementary, alternative and integrative medicine therapies might be a solution. OBJECTIVE: The aim of this review is to demonstrate study status of such therapies. METHODS: The databases PubMed, Cochrane Library, OVID, CAMbase, CAM-QUEST® and Anthromedics were systematically screened for studies investigating complementary, alternative and integrative therapy approaches in paediatric cohorts. Studies were analyzed by therapy approach, study design, cohort and outcome, using the PRISMA 2020 checklist. RESULTS: The systematic literature search resulted in 321 articles. Five publications corresponded to the search criteria and were assigned to the following specific therapeutic categories: herbal medicine (3), homeopathy (1) and ayurvedic medicine (1). Clinical trials were found for the herbal compounds BNO 1030 (Impupret®) and EPs® 7630 (Umckaloabo), the homeopathic complex Tonzolyt® and the ayurvedic medicine Kanchnara-Guggulu and Pratisarana of Tankana­Madhu. Antimicrobial effects of essential oils and carvacrol as single agents as well as in combination with erythromycin were analysed in an in vitro study. CONCLUSION: Clinical studies indicate an improvement of symptoms and a good tolerability of all investigated remedies of complementary, alternative and integrative medicine in the treatment of tonsillitis in childhood. Nevertheless, quality and quantity of the studies were insufficient to make a reliable conclusion regarding effectiveness. Therefore, more clinical trials are urgently needed to achieve a meaningful result.

Zebrafish as an Orthotopic Tumor Model for Retinoblastoma Mimicking Routes of Human Metastasis.

BACKGROUND: Retinoblastoma (RB) is the most common eye cancer in children that has a high mortality rate when left untreated. Mouse models for retinoblastoma have been established but are time- and cost-intensive. The aim of this work was to evaluate an orthotopic transplantation model of retinoblastoma in zebrafish that also allows for tracking migratory routes and to explore advantages and disadvantages with respect to drug testing. METHODS: Three fluorescence-labeled retinoblastoma cell lines (RB355, WERI-RB-1, Y79) were injected into the left eye of two-day-old zebrafish, while the un-injected right eye served as control. The migratory trajectories of injected retinoblastoma cells were observed until 8 days post injection (dpi), both in lateral and dorsal view, and measuring fluorescence intensity of injected cells was done for RB355 cells. RESULTS: Time until the onset of migration and routes for all three retinoblastoma cell lines were comparable and resulted in migration into the brain and ventricles of the forebrain, midbrain and hindbrain. Involvement of the optic nerve was observed in 10% of injections with the RB355 cell line, 15% with Y79 cells and 5% with WERI-RB-1 cells. Fluorescence intensity of injected RB355 cells showed an initial increase until five dpi, but then decreased with high variability until the end of observation. CONCLUSION: The zebrafish eye is well suited for the analysis of migratory routes in retinoblastoma and closely mirrors patterns of retinoblastoma metastases in humans.

[Präklinische Untersuchungen von Wechselwirkungen zwischen Mistel und Radio- oder Chemotherapie auf pädiatrische Tumorzellen]. / Preclinical Investigations of Interactions between Mistletoe and Radio- or Chemotherapy on Pediatric Tumor Cells.

Hintergrund: Mistelanwendungen werden als komplementäre Therapien häufig in der pädiatrischen Onkologie zusammen mit einer Radio- oder Chemotherapie verabreicht. Wechselwirkungen bei simultaner Applikation sind gerade in der Pädiatrie von großer Bedeutung, sie sind allerdings nach wie vor unzureichend untersucht. Material und Methoden: Zytotoxische Effekte des Mistelextraktes abnobaVISCUM Fraxini (aVF) auf LAN-1 Neuroblastomzellen und deren Etoposid- bzw. Cisplatin-resistente Subzelllinien wurden mittels Viabilitätstest untersucht, sowie mögliche Synergieeffekte zwischen aVF und den Chemotherapeutika durch die Softwareprodukte Combenefit und CompuSyn analysiert. Effekte einer Kombinationstherapie aus aVF und Bestrahlung auf SH-SY5Y Zellen wurden mittels Koloniebildungstest untersucht und Auswirkungen auf die Reparatureffizienz strahleninduzierter Doppelstrangbrüche mit Hilfe durchflusszytometrischer Quantifizierungen von γ-H2AX-Foci nach PI/FITC Doppelfärbung analysiert. Ergebnisse: Die Chemotherapie-resistenten LAN-1 Subzelllinien erwiesen sich als resistenter gegenüber der Mistelbehandlung als die Ursprungszelllinie. Auf Basis vier verschiedener Referenz-modelle konnten vor allem synergistisch/additive Effekte zwischen aVF und den Zytostatika Etoposid und Cisplatin berechnet werden. Die Kombination aus Mistelbehandlung und Bestrahlung führte zu einer Verringerung der Koloniebildung und zu einer Verzögerung der Reparaturgeschwindigkeit von strahleninduzierten Doppelstrangbrüchen. Schlussfolgerung: Die präklinischen Daten könnten darauf hinweisen, dass die Verwendung des Mistelextraktes, aVF, eine unterstützende Wirkung auf Radio- und Chemotherapien hat. BACKGROUND: Mistletoe therapies belong to the field of complementary medicines and are often administered simultaneously or successive to conventional radio- or chemotherapy. Drug-herb interactions are of great significance, especially in pediatrics, but are still insufficiently investigated. MATERIAL AND METHODS: Cytotoxic effects of the mistletoe extract, abnobaVISCUM Fraxini (aVF), on LAN-1 neuroblastoma cell line and their chemotherapy-resistant (cisplatin; etoposide) subclones were investigated by cell viability assays. Potential synergistic or antagonistic effects of the co-treatment of aVF and cisplatin or etoposide, respectively, were analyzed by Combenefit and CompuSyn software. Combinational effects of mistletoe and irradiation were assessed by colony formation assays and repair efficiency of irradiation-induced double strand breaks was investigated by flow cytometric analyses of γ-H2AX foci after PI/FITC double staining. RESULTS: Chemotherapy-resistant subclones were more resistant to mistletoe therapy than the parental cells. Based on four different reference models, primarily synergistic/additive effects between aVF and the cytostatic drugs could be calculated. Simultaneous application of mistletoe extract and irradiation led to a delay of irradiation-induced double strand break repair in neuroblastoma cells and a decreased colony formation compared to irradiation monotherapy. CONCLUSION: The preclinical data may indicate that the use of aVF has a supportive effect on radio- and chemotherapies.

Anticancer Effects of Viscum album Fraxini Extract on Medulloblastoma Cells in vitro.

BACKGROUND: Mistletoe therapy is frequently administered as a supportive treatment in diverse pediatric cancer entities including brain tumors. Medulloblastoma is the most common brain tumor in childhood. Its high risk to metastasize and its long-term sequelae caused by aggressive chemo- or radiotherapies are still challenging. MATERIAL AND METHODS: Effects of a lectin-rich mistletoe extract, abnobaVISCUM Fraxini, were investigated in two medulloblastoma cell lines (Daoy and ONS-76). Responsiveness of tumor cells was assessed by cell viability assays and xCELLigence real-time analyses. Moreover, impacts on proliferation, cell cycle and apoptosis were investigated. Apoptosis was studied by staining of vital mitochondria and assessing the involvement of caspases. In addition, effects on migration and invasion were analyzed. RESULTS: Both medulloblastoma cell lines were more susceptible to treatment with the mistletoe extract than a nontumorigenic fibroblast cell line. In mistletoe-sensitive Daoy cells, reduction of proliferation and induction of caspase-mediated apoptosis were observed upon administration of 0.05 and 0.5 mg/mL abnobaVISCUM Fraxini treatment, respectively. Furthermore, mistletoe extract inhibited migration and invasion properties in Daoy and significantly impaired invasive capabilities of ONS-76 cells. CONCLUSION: AbnobaVISCUM Fraxini has cell line dependent antitumoral effects in medulloblastoma models. These results call for further investigations, to reveal mechanistic insights into antitumorigenic properties of mistletoe extracts.

Expert consensus-based clinical recommendation for an integrative anthroposophic treatment of acute bronchitis in children: A Delphi survey.

BACKGROUND: Acute bronchitis is one of the most common pediatric diseases. In addition to conventional therapies, a frequent use of complementary and alternative medicine (CAM) has been stated. Anthroposophic medicine (AM) is one of the most practiced complementary and integrative medicine (CIM) approaches in Central Europe but hitherto no consensus-based clinical recommendations or guidelines are available. Therefore, a consensus-based recommendation leading to an informed and reasonable use of AM in the treatment of acute bronchitis in pediatrics was developed. METHODS: A total of 61 physicians in Germany with expertise in the field of anthroposophic pediatrics was invited to complete an online multistep Delphi process. Two independent reviewers quantitatively and qualitatively evaluated the results. The survey was completed when >75 % consensus was achieved. RESULTS: The clinical recommendation comprises 15 subitems related to treatment as well as clinical and psychosocial aspects. All items reached strong consensus (>90 %; N = 9) or consensus (75-90 %; N = 6). CONCLUSION: The comprehensive clinical recommendation creates a scientific base for the anthroposophic integrative treatment of acute bronchitis in children in Germany. It will make the anthroposophic approach more applicable, understandable and comparable to a wider public of physicians and other health professionals in Germany.

Antitumoral Effects of Curcumin (Curcuma longa L.) and Thymoquinone (Nigella sativa L.) on Neuroblastoma Cell Lines.

INTRODUCTION: Overall survival of high-risk neuroblastoma patients is still poor, emphasizing the need for novel therapeutic options. There is evidence for anti-cancer properties of the herbal substances thymoquinone and curcumin. These substances are isolated from Nigella sativa L. and Curcuma longa L., respectively, which are used in traditional medicine. OBJECTIVE: We investigated cytotoxic effects of thymoquinone and curcumin on neuroblastoma cell lines NLF, NB69, and SK-N-BE(2), in vitro. METHODS: Cytotoxicity of compounds was investigated by MTT cell viability assays. For analyzing effects on cell proliferation BrdU assays were employed and induction of apoptosis was detected by Cell Death ELISA assays. RESULTS: Both substances showed cytotoxic effects in all three neuroblastoma cell lines, whereby primary human fibroblast cells reacted less sensitively. Overall, lower IC50 values could be calculated for curcumin (3.75-7.42 µM) than for thymoquinone (5.16-16.3 µM). Decreased proliferation and increased apoptosis rates were observed under treatment. CONCLUSIONS: Both substances showed anti-tumoral properties on neuroblastoma cell lines and should be further investigated as therapeutic agents.

Anthroposophic medicine in the treatment of pediatric pseudocroup: A systematic review.

BACKGROUND: In Europe only few integrative pediatric wards exists and there are two German hospitals focusing on anthroposophic medicine as part of complementary and alternative medicine (CAM). Whilst the most common pediatric diseases are treated here, pseudocroup patients make up a large group in these hospitals, receiving conventional as well as anthroposophic therapies. However, effectiveness of these therapy concepts mostly based on physicians' experiences but clinical studies are hitherto missing. METHODS: A systematic literature search identifying therapy approaches for pseudocroup in children was conducted in general electronic databases (Cochrane Library, PubMed, OVID) and in CAM-specific databases (CAMbase, CAM-QUEST®, Anthromedics). Search results were screened for anthroposophic therapy options. In addition, anthroposophic guidebooks were handsearched for relevant information. RESULTS: Among 157 articles fulfilling search criteria one retrospective study, and five experience reports describing anthroposophic treatments were identified. Several medications for the treatment of pseudocroup were mentioned such as Aconitum, Apis, Bryonia, Hepar sulfuris, Lavender, Pyrit, Sambucus and Spongia. During appropriate use no adverse effects were reported. CONCLUSION: Anthroposophic medicine harbors a broad spectrum of remedies for the treatment of pseudocroup in children. In particular, Aconitum, Bryonia and Spongia are frequently recommended; however, clinical trials investigating the effectiveness are sparse. Therefore, development and validation of therapy strategies are required.

Safety of high-dose intravenous mistletoe therapy in pediatric cancer patients: A case series.

BACKGROUND: Long-term survival of children with cancer has reached rates of up to 80%. Nevertheless, continued research devoted to further improvement of survival rates especially for patients with high-risk illnesses is necessary. Recent studies have shown direct positive effects on tumor reduction through Viscum album (mistletoe) extracts in adults, mainly as a result of higher dosage treatment and intravenous or intratumoral application. PATIENTS AND METHOD: A retrospective analysis of data was carried out of all oncological, pediatric patients treated with intravenous high-dose mistletoe therapy for a period of two years (11/2013-11/2015). RESULTS: A total of ten non-coherent cases were examined, all suffering from advanced and/or relapsed forms of cancer (leukemia, neuroblastoma, nephroblastoma, osteosarcoma, lymphoma, anaplastic astrocytoma, atypical teratoid rhabdoid tumor and soft tissue sarcoma). Patients were treated for an average period of 48 days with a mean survival rate of 130 days after beginning the mistletoe therapy. Partial remission was observed in four and a slowed disease progression was monitored in two patients. However, unrestricted progression of disease was documented in two other patients. Patients showed side effects including fever as well as fatigue and in some cases systemic inflammatory reactions with transient organ impairment occurred. CONCLUSION: Our study underpinned the safety and feasibility of high-dose mistletoe infusion in children with advanced stages of cancer and showed noteworthy antineoplastic effects, which should be verified in a prospective clinical phase II/III-study. Because of possible side effects, the treatment should be implemented only in an in-patient setting in experienced pediatric oncology centers.

[Management of Acute Gastroenteritis in Children: A Systematic Review of Anthroposophic Therapies].

BACKGROUND: Acute gastroenteritis in children accounts for about 10% of hospital admissions and is still one of the major causes of death worldwide. As many children are treated with complementary and alternative medicine (CAM) and anthroposophic medicine, respectively, especially in Europe, the aim of this review was to descriptively present published anthroposophic therapies applied for the treatment of acute gastroenteritis in childhood. METHODS: A complex search strategy recording a broad spectrum of CAM therapies was developed to identify anthroposophic therapy options for the treatment of gastroenteritis in children. The search was conducted in 4 general scientific as well as 3 CAM-specific databases. RESULTS: In total, 3,086 articles were identified and screened for anthroposophic related content. The majority of hits deal with nutritional/dietary therapies. Articles considering anthroposophic approaches constitute only 3.1% (7/227) of all CAM-related articles. Among these articles 2 observational studies, 3 experience reports and 2 reviews were identified. In the experience reports, a variety of anthroposophic remedies was recommended but mostly unsupported by scientific evidence. However, observational studies for the anthroposophic medications, Bolus alba comp. and Gentiana comp., were detected. Additionally, studies investigating the efficacy and safety of Chamomilla, Ipecacuanha, Podophyllum or Tormentilla preparations in homeopathy and phytomedicine, respectively, were presented. CONCLUSIONS: Most CAM-associated therapies for gastroenteritis in childhood comprise dietary recommendations. Studies concerning anthroposophic approaches and medications, respectively, are deficient. The results of this study underline that effort is needed to evaluate anthroposophic therapies in a clinical setting.

Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors.

Dysregulation of the cell cycle and cyclin-dependent kinases (cdks) is a hallmark of cancer cells. Intervention with cdk function is currently evaluated as a therapeutic option in many cancer types including neuroblastoma (NB), a common solid tumor of childhood. Re-analyses of mRNA profiling data from primary NB revealed that high level mRNA expression of both cdk1 and its corresponding cyclin, CCNB1, were significantly associated with worse patient outcome independent of MYCN amplification, a strong indicator of adverse NB prognosis. Cdk1 as well as CCNB1 expression were readily detectable in all embryonal tumor cell lines investigated. Pharmacological inhibition or siRNA-mediated knockdown of cdk1/CCNB1 induced proliferation arrest independent of MYCN status in NB cells. Sensitivity to cdk1 inhibition was modulated by TP53, which was demonstrated using isogenic cells with wild-type TP53 expressing either dominant-negative p53 or a short hairpin RNA directed against TP53. Apoptosis induced by cdk1 inhibition was dependent on caspase activation and was concomitant with upregulation of transcriptional targets of TP53. Our results confirm an essential role for the cdk1/CCNB1 complex in tumor cell survival. As relapsing embryonal tumors often present with p53 pathway alterations, these findings have potential implications for therapy approaches targeting cdks.

Robust selection of cancer survival signatures from high-throughput genomic data using two-fold subsampling.

Identifying relevant signatures for clinical patient outcome is a fundamental task in high-throughput studies. Signatures, composed of features such as mRNAs, miRNAs, SNPs or other molecular variables, are often non-overlapping, even though they have been identified from similar experiments considering samples with the same type of disease. The lack of a consensus is mostly due to the fact that sample sizes are far smaller than the numbers of candidate features to be considered, and therefore signature selection suffers from large variation. We propose a robust signature selection method that enhances the selection stability of penalized regression algorithms for predicting survival risk. Our method is based on an aggregation of multiple, possibly unstable, signatures obtained with the preconditioned lasso algorithm applied to random (internal) subsamples of a given cohort data, where the aggregated signature is shrunken by a simple thresholding strategy. The resulting method, RS-PL, is conceptually simple and easy to apply, relying on parameters automatically tuned by cross validation. Robust signature selection using RS-PL operates within an (external) subsampling framework to estimate the selection probabilities of features in multiple trials of RS-PL. These probabilities are used for identifying reliable features to be included in a signature. Our method was evaluated on microarray data sets from neuroblastoma, lung adenocarcinoma, and breast cancer patients, extracting robust and relevant signatures for predicting survival risk. Signatures obtained by our method achieved high prediction performance and robustness, consistently over the three data sets. Genes with high selection probability in our robust signatures have been reported as cancer-relevant. The ordering of predictor coefficients associated with signatures was well-preserved across multiple trials of RS-PL, demonstrating the capability of our method for identifying a transferable consensus signature. The software is available as an R package rsig at CRAN (http://cran.r-project.org).