ClinOmicsTrailbc: a visual analytics tool for breast cancer treatment stratification.

MOTIVATION: Breast cancer is the second leading cause of cancer death among women. Tumors, even of the same histopathological subtype, exhibit a high genotypic diversity that impedes therapy stratification and that hence must be accounted for in the treatment decision-making process. RESULTS: Here, we present ClinOmicsTrailbc, a comprehensive visual analytics tool for breast cancer decision support that provides a holistic assessment of standard-of-care targeted drugs, candidates for drug repositioning and immunotherapeutic approaches. To this end, our tool analyzes and visualizes clinical markers and (epi-)genomics and transcriptomics datasets to identify and evaluate the tumor's main driver mutations, the tumor mutational burden, activity patterns of core cancer-relevant pathways, drug-specific biomarkers, the status of molecular drug targets and pharmacogenomic influences. In order to demonstrate ClinOmicsTrailbc's rich functionality, we present three case studies highlighting various ways in which ClinOmicsTrailbc can support breast cancer precision medicine. ClinOmicsTrailbc is a powerful integrated visual analytics tool for breast cancer research in general and for therapy stratification in particular, assisting oncologists to find the best possible treatment options for their breast cancer patients based on actionable, evidence-based results. AVAILABILITY AND IMPLEMENTATION: ClinOmicsTrailbc can be freely accessed at https://clinomicstrail.bioinf.uni-sb.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Feasibility and Results of a Mobile Haemophilia Outpatient Care Pilot Project.

INTRODUCTION: Regular visits at haemophilia treatment centres (HTCs) in rural regions are often dependent on the access to a private car due to lack of or limited availability of public means. Therefore, a mobile haemophilia outpatient care (MHOC) concept providing home visits to haemophilia patients has been developed by the Saarland HTC, which is located in a rural German region. METHODS: Haemophilia patients and their parents were home visited at least twice (baseline, follow-up) by trained medical staff. Socio-demographic and clinical data were collected and interviews were performed asking the patients and parents about their needs and expectations towards such a MHOC. RESULTS: Seventy-nine patients were enrolled (56 adults, 23 children), 62.0% severely affected, 48.1% on prophylaxis, with a mean age of 37.4 ± 16.4 years (17-78) and 9.8 ± 4.2 years (3-16), respectively. Median travel distance to the HTC was 43.5 km (3-200). Note that 92.4% considered an intense binding to the HTC and a MHOC concept as 'rather/very important' (88.6%). They expected from a MHOC to provide consulting and educating activities, support in elderhood issues and treatment. For 35.4%, a MHOC could currently provide additional support, mainly due to patient's immobility and need of consultancy. They mainly used services in terms of consultancy in social-legal affairs and support in contacting authorities. CONCLUSION: The results of this study support the hypothesis that a MHOC concept is a needful supplement in haemophilia comprehensive care and will improve the challenging haemophilia treatment, especially for those with limited access to HTCs or with disabilities.

Use of complementary and alternative medicine in healthy children and children with chronic medical conditions in Germany.

OBJECTIVES: Use of complementary and alternative medicine (CAM) in children is common and probably increasing. However little is known about differences between healthy and chronically ill children with a focus on prevalence, reasons for use/non-use, costs, adverse effects and socio-demographic factors. DESIGN: A questionnaire-based survey with 500 participants visiting the outpatient clinic of the University Children's Hospital Homburg, Germany was conducted over a 4-week period in 2004. Recruitment was stopped when 500 questionnaires were handed out in total. RESULTS: Of the 405 (81%) respondents (242 with chronic conditions, 163 healthy children incidentally visiting the hospital for minor ailments) 229 (57%) reported lifetime CAM use (59% with chronic conditions versus 53% healthy children). Among CAM users the most prevalent therapies were homeopathy (25%), herbal remedies (8%), anthroposophic medicine (7%), vitamin preparations (6%) and acupuncture (5%). The main reasons for use were to strengthen the immune system, physical stabilisation and to increase healing chances/maintain health. Socio-demographic factors associated with CAM use were tertiary education (mother: p=0.017; father: p>0.001), higher family income (p=0.001) and being Protestant (p=0.01). Expectations towards CAM were high and most parents would recommend certain CAM (94%). 79% of the users informed a physician about CAM use. Side effects were rarely reported (4%), minor and self-limiting. CONCLUSIONS: Clinical care and the physician-patient relation would benefit from an enhanced understanding of CAM and a greater candidness towards the parental needs. The safety and efficacy especially of CAM with high prevalence rates should be determined in rigorous basic and clinical researches.

Complementary and alternative treatment methods in children with cancer: A population-based retrospective survey on the prevalence of use in Germany.

INTRODUCTION: Few studies have been conducted to date on the prevalence of use of complementary and alternative treatment methods (CAMs) in paediatric oncology, and those that have been conducted are often not representative. We therefore decided to study a representative sample of children with cancer in the German population. PATIENTS AND METHODS: The study took the form of a retrospective survey amongst all parents whose children were first diagnosed with a disease covered by the German Childhood Cancer Registry in 2001. The primary objectives of the survey were to establish the prevalence of use of CAM and the factors related to its use. RESULTS: Of the 1595 questionnaires sent out, 1063 (67%) could be evaluated. 35% of the responders had used CAM. The most frequently used methods were homeopathy, dietary supplements and anthroposophic medicine including mistletoe therapy. Factors which increased the probability of using CAM were the previous use of CAM, higher social status and poor prognosis of the child's disease. The most frequently named reasons for use of CAM were physical stabilisation, strengthening the immune system and improving the chance of cure. Whilst the sources of information about CAM were in most cases not doctors, 71% of users had nevertheless spoken to a doctor about using CAM. The effects of the CAM perceived by the parents were for the most part positive. 89% of the users reported that they would recommend CAM to other parents. CONCLUSIONS: CAMs are administered alongside standard therapy to 35% of children with cancer in Germany, usually by the parents. Prospective studies on the effects and side-effects of the most frequently used methods are urgently needed, and paediatric oncologists should have sufficient knowledge of CAM to enable them to advise parents professionally and competently about these treatments, too.

Laser acupuncture in children with headache: a double-blind, randomized, bicenter, placebo-controlled trial.

To investigate whether laser acupuncture is efficacious in children with headache and if active laser treatment is superior to placebo laser treatment in a prospective, randomized, double-blind, placebo-controlled trial of low level laser acupuncture in 43 children (mean age (SD) 12.3 (+/-2.6) years) with headache (either migraine (22 patients) or tension type headache (21 patients)). Patients were randomized to receive a course of 4 treatments over 4 weeks with either active or placebo laser. The treatment was highly individualised based on criteria of Traditional Chinese medicine (TCM). The primary outcome measure was a difference in numbers of headache days between baseline and the 4 months after randomization. Secondary outcome measures included a change in headache severity using a 10 cm Visual Analogue Scale (VAS) for pain and a change in monthly hours with headache. Measurements were taken during 4 weeks before randomization (baseline), at weeks 1-4, 5-8, 9-12 and 13-16 from baseline. The mean number of headaches per month decreased significantly by 6.4 days in the treated group (p<0.001) and by 1.0 days in the placebo group (p=0.22). Secondary outcome measures headache severity and monthly hours with headache decreased as well significantly at all time points compared to baseline (p<0.001) and were as well significantly lower than those of the placebo group at all time points (p<0.001). We conclude that laser acupuncture can provide a significant benefit for children with headache with active laser treatment being clearly more effective than placebo laser treatment.

The "Oncosimulator": a multilevel, clinically oriented simulation system of tumor growth and organism response to therapeutic schemes. Towards the clinical evaluation of in silico oncology.

The "Oncosimulator" is at the same time a concept of multilevel integrative cancer and (treatment affected) normal tissue biology, an algorithmic construct and a software tool which aims at supporting the clinician in the process of optimizing cancer treatment on the patient individualized basis. Additionally it is a platform for better understanding and exploring the natural phenomenon of cancer as well as training doctors and interested patients alike. In order to achieve all of these goals it has to undergo a thorough clinical optimization and validation process. This is one of the goals of the European Commission funded integrated project "ACGT: Advancing Clinicogenomic Trials on Cancer". Nephroblastoma (Wilms' tumor) and breast cancer have been selected to serve as two paradigms to clinically specify and evaluate the "Oncosimulator" as well as the emerging domain of in silico oncology.

Target genes of the WNT/beta-catenin pathway in Wilms tumors.

The WNT/beta-catenin pathway is involved in numerous human cancers. Mutations of the CTNNB1 (beta-catenin) gene have also been detected in a subset of pediatric Wilms tumors, but the target genes of the deregulated WNT/beta-catenin pathway in these tumors have yet to be identified. To compare gene expression profiles of Wilms tumors with and without mutations of CTNNB1, we used 11.5-k cDNA microarrays. Most of the tumors (86%) had received preoperative chemotherapy as mandated by the European SIOP protocol. The comparison between Wilms tumors with and without CTNNB1 mutations revealed several target genes specifically deregulated in CTNNB1-mutated Wilms tumors. Among these, PITX2, APCDD1, and two members of the endothelin axis (EDN3 and EDNRA) are directly activated downstream targets of the WNT/beta-catenin pathway that may enhance proliferation of these tumor cells. In addition, several upstream inhibitors of WNT/beta-catenin signaling like WIF1 and PRDC were also strongly up-regulated in the CTNNB1-mutated Wilms tumors. This overexpression may be a negative feedback mechanism in tumors with uncontrolled WNT signaling. Moreover, we identified deregulated genes in both the retinoic acid and the RAS pathways, such as ATX/ENPP2 and RIS1, suggesting an association between these two pathways with that of WNT. In addition, the strong representation of muscle-related genes in the expression profile of CTNNB1-mutated Wilms tumors corresponded to histologically detectable areas of myomatous cells in these tumors that displayed intense and preferential nuclear beta-catenin antibody staining. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.