M. Grotzer - Academia.edu (original) (raw)

Papers by M. Grotzer

BackgroundImprovement of paediatric healthcare is hampered by inefficient processes of generating... more BackgroundImprovement of paediatric healthcare is hampered by inefficient processes of generating new evidence. Clinical research often requires extra encounters with patients, is costly, takes place in an artificial situation with a biased selection of patients, and entails long delays until new evidence is implemented into health care. Electronic health records (EHR) contain detailed information on real patients and cover the entirety of patients. However, the use of EHR for research is limited because they are not standardized between hospitals. This leads to disproportionate amounts of work for extracting data of interest and frequently data are incomplete and of poor quality.AimsSwissPedData aims to lay the foundation for a paediatric learning health system in Switzerland by facilitating EHR-based research. In this project, we aimed to assess the way routine clinical data are currently recorded in large paediatric clinics in Switzerland and to develop a national EHR-based commo...

Quality of Life Research, 2018

Hearing loss, a complication of cancer treatment, may reduce health-related quality of life (HRQo... more Hearing loss, a complication of cancer treatment, may reduce health-related quality of life (HRQoL), especially in childhood cancer survivors of central nervous system (CNS) tumours who often have multiple late effects. We examined the effect of hearing loss on HRQoL in young survivors of CNS and other childhood cancers. Methods: Within the Swiss Childhood Cancer Survivor Study, we sent questionnaires about hearing loss and HRQoL (KIDSCREEN-27) to parents of survivors aged 8-15 years. We stratified the effect of hearing loss on HRQoL by cancer diagnosis, using multivariable logistic regression and adjusting for sociodemographic and clinical factors. Results: Hearing loss was associated with impaired physical well-being [unadjusted estimated differences-4.6 (CI-9.2;-0.1); adjusted-4.0 (CI-7.6;-0.3)] and peers & social support [unadjusted-6.7 (CI-13.0;-0.3); adjusted-5.0 (CI-10.5; 0.9)] scores in survivors of CNS tumours (n=123), but not in children diagnosed with other tumours (all p-values > 0.20, n=577). Conclusion: Clinicians should be alert to signs of reduced physical well-being and impaired relationships with peers. Especially survivors of CNS tumours may benefit most from strict audiological monitoring and timely intervention to mitigate secondary consequences of hearing loss on HRQoL.

Background: The aetiology of most childhood cancers is largely unknown. Spatially varying environ... more Background: The aetiology of most childhood cancers is largely unknown. Spatially varying environmental factors such as traffic-related air pollution, background radiation and agricultural pesticides might contribute to the development of childhood cancer. We investigated the spatial variation of childhood cancers in Switzerland using exact geocodes of place of residence. Methods: We included 5,947 children diagnosed with cancer during 1985-2015 at age 0-15 from the Swiss Childhood Cancer Registry. We modelled cancer risk using log-Gaussian Cox processes and indirect standardization to adjust for age and year of diagnosis. We examined whether the modelled spatial variation of risk can be explained by ambient air concentration of NO2, natural background radiation, area-based socio-economic position (SEP), linguistic region, years of existing general cancer registration in the canton or degree of urbanization. Results: For all childhood cancers combined, the posterior median relative ...

Cancer Causes & Control, 2018

The work of the Swiss Childhood Cancer Registry is supported by the Swiss Paediatric Oncology Gro... more The work of the Swiss Childhood Cancer Registry is supported by the Swiss Paediatric Oncology Group (www.spog.ch), Schweizerische Konferenz der kantonalen Gesundheitsdirektorinnen unddirektoren (www.gdk-cds.ch), Swiss Cancer Research (www.krebsforschung.ch), Kinderkrebshilfe Schweiz (www.kinderkrebshilfe.ch), Ernst-Göhner Stiftung, Stiftung Domarena and National Institute of Cancer Epidemiology and Registration (www.nicer.org).

European journal of cancer care, Jan 30, 2017

Parents take an important role in follow-up of young cancer survivors. We aimed to investigate (1... more Parents take an important role in follow-up of young cancer survivors. We aimed to investigate (1) parents' preferences for organisation of follow-up (including content, specialists involved and models of care), and (2) parents' and children's characteristics predicting preference for generalist vs. specialist-led follow-up. We sent a questionnaire to parents of childhood cancer survivors aged 11-17 years. We assessed on a 4-point Likert scale (1-4), parents' preferences for organisation of long-term follow-up. Proposed models were: telephone/questionnaire, general practitioner (GP) (both categorised as generalist for regression analysis); and paediatric oncologist, medical oncologist or multidisciplinary team (MDT) (categorised as specialists). Of 284 contacted parents, 189 responded (67%). Parents welcomed if visits included checking for cancer recurrence (mean = 3.89), late effects screening (mean = 3.79), taking patients seriously (mean = 3.86) and competent staf...

Clinical Nutrition, 2017

Background & aims: Poor diet may increase the risk that childhood cancer survivors (CCS) will suf... more Background & aims: Poor diet may increase the risk that childhood cancer survivors (CCS) will suffer from chronic disease. We compared adherence to national dietary recommendations between CCS, their siblings and the Swiss population, identified determinants of adherence, and assessed the association of adherence with cardiovascular disease (CVD) risk profiles. Methods: As part of the Swiss Childhood Cancer Survivor Study (SCCSS), a questionnaire was sent to all Swiss resident CCS aged <21 years at diagnosis, who survived ≥5 years and were 16-45 years old at the time of the survey. We compared dietary adherence between CCS, their siblings and participants in the Swiss Health Survey (SHS), a representative survey of the general population. A multivariable logistic regression was used to assess characteristics associated with dietary adherence. We sorted CCS into four kinds of CVD risk groups based on type of treatment (anthracyclines, chest irradiation, a combination, or neither). Results: We included 1'864 CCS, 698 siblings and 8'258 participants of the general population. Only 43% of the CCS met the recommended dietary intakes for meat, 34% for fruit, 30% for fish, 18% for dairy products, 11% for vegetables, and 7% for combined fruit and vegetables. Results were similar for both control groups. In all groups, dietary adherence was associated with gender, parental education, migration background, language region in Switzerland, smoking, alcohol consumption and sport participation. CCS with a higher CVD risk profile because of cardiotoxic treatment had no better adherence. Conclusions: CCS have similar food patterns as their siblings and the general population, and poorly adhere to current recommendations. Awareness of the importance of a healthy diet should be raised among CCS, to prevent chronic diseases like CVD.

Scientific Reports, 2015

High-throughput analysis of cancer cell dissemination and its control by extrinsic and intrinsic ... more High-throughput analysis of cancer cell dissemination and its control by extrinsic and intrinsic cellular factors is hampered by the lack of adequate and efficient analytical tools for quantifying cell motility. Oncology research would greatly benefit from such a methodology that allows to rapidly determine the motile behaviour of cancer cells under different environmental conditions, including inside three-dimensional matrices. We combined automated microscopy imaging of two- and three-dimensional cell cultures with computational image analysis into a single assay platform for studying cell dissemination in high-throughput. We have validated this new approach for medulloblastoma, a metastatic paediatric brain tumour, in combination with the activation of growth factor signalling pathways with established pro-migratory functions. The platform enabled the detection of primary tumour and patient-derived xenograft cell sensitivity to growth factor-dependent motility and dissemination a...

BMC cancer, Jan 25, 2007

With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from prog... more With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to correlate with anaplasia and unfavorable prognosis. In neuroblastoma--an embryonal tumor with biological similarities to MB--the quassinoid NBT-272 has been demonstrated to inhibit cellular proliferation and to down-regulate c-MYC protein expression. To study MB cell responses to NBT-272 and their dependence on the level of c-MYC expression, DAOY (wild-type, empty vector transfected or c-MYC transfected), D341 (c-MYC amplification) and D425 (c-MYC amplification) human MB cells were used. The cells were treated with different concentrations of NBT-272 and the impact on cell proliferation, apoptosis and c-MYC expression was analyzed. NBT-272 treatment resulted in a dose-dependent i...

Neuro-Oncology, 2014

between the implicated miRNA genes and molecular functional ontologies. Expression of miRNA subse... more between the implicated miRNA genes and molecular functional ontologies. Expression of miRNA subsets were further validated using quantitative Real-Time PCR (qRT-PCR). In total, 40 significantly differentially expressed miRNAs were identified. Among them, lower expression levels of miR-2355-5 and miR-130a were obtained in all tumors irrespective of histological grade, as opposed to control samples. On correlations between miRNA expression and the course or outcome of malignancy, more reduced expression levels of miR-2355-5 were observed in relapsed and deceased cases, respectively. MiR-130a and miR-155 were observed to compete with Ki-67, appearing to have tumor suppressor activity, whereas miR-218-1* probably acted synergistically with Ki-67; as an oncogene. The current study highlighted: A) as tumor suppressor diagnostic molecules; miR-2355-5 and miR-130a, B) as indicators of favorable prognosis; miR-2355-5 when overexpressed and C) miR-130a and miR-155 as personalized therapeutic targets in tumors with high Ki-67 proliferative index. Collectively, our findings modulated novel molecular biomarkers which might have a promising potential in the parthogenesis of pediatric brain malignancies. IKY Fellowships of Excellence for postgraduate studies in Greece-Siemens Program.

Methods of Cancer Diagnosis, Therapy, and Prognosis, 2010

Central nervous system (CNS) atypical teratoid/rhabdoid tumors (AT/RT) are among the pediatric ma... more Central nervous system (CNS) atypical teratoid/rhabdoid tumors (AT/RT) are among the pediatric malignant tumors with the worst prognosis. Insulin-like growth factor I receptor (IGF-IR) protects cancer cells from apoptosis induced by a variety of anticancer drugs and radiation. IGF-IR is expressed in primary CNS AT/RT as detected by immunohistochemistry. Moreover, there is evidence for the potential presence of an autocrine/paracrine IGF-I/II/IGF-IR loop in CNS AT/RT. IGF-IR antisense oligonucleotide treatment of human CNS AT/RT cells results in significant down-regulation of IGF-IR mRNA and protein expression, induction of apoptosis, and chemosensitization to doxorubicin and cisplatin. These studies provide evidence for the influence of IGF-IR on cellular responses to chemotherapy and raise the possibility that curability of selected CNS AT/RT may be improved by pharmaceutical strategies directed toward the IGF-IR.

Purpose: This study investigates physical performance limitations for sports and daily activities... more Purpose: This study investigates physical performance limitations for sports and daily activities in recently diagnosed childhood cancer survivors and siblings. Methods: The Swiss Childhood Cancer Survivor Study sent a questionnaire to all survivors ($16 years) registered in the Swiss Childhood Cancer Registry, who survived .5 years and were diagnosed 1976-2003 aged ,16 years. Siblings received similar questionnaires. We assessed two types of physical performance limitations: 1) limitations in sports; 2) limitations in daily activities (using SF-36 physical function score). We compared results between survivors diagnosed before and after 1990 and determined predictors for both types of limitations by multivariable logistic regression. Results: The sample included 1038 survivors and 534 siblings. Overall, 96 survivors (9.5%) and 7 siblings (1.1%) reported a limitation in sports (Odds ratio 5.5, 95%CI 2.9-10.4, p,0.001), mainly caused by musculoskeletal and neurological problems. Findings were even more pronounced for children diagnosed more recently (OR 4.8, CI 2.4-9.6 and 8.3, CI 3.7-18.8 for those diagnosed ,1990 and $1990, respectively; p = 0.025). Mean physical function score for limitations in daily activities was 49.6 (CI 48.9-50.4) in survivors and 53.1 (CI 52.5-53.7) in siblings (p,0.001). Again, differences tended to be larger in children diagnosed more recently. Survivors of bone tumors, CNS tumors and retinoblastoma and children treated with radiotherapy were most strongly affected. Conclusion: Survivors of childhood cancer, even those diagnosed recently and treated with modern protocols, remain at high risk for physical performance limitations. Treatment and follow-up care should include tailored interventions to mitigate these late effects in high-risk patients.

PLoS ONE, 2012

The receptor tyrosine kinase (RTK)/phosphoinositide 3-kinase (PI3K) pathway is fundamental for ca... more The receptor tyrosine kinase (RTK)/phosphoinositide 3-kinase (PI3K) pathway is fundamental for cancer cell proliferation and is known to be frequently altered and activated in neoplasia, including embryonal tumors. Based on the high frequency of alterations, targeting components of the PI3K signaling pathway is considered to be a promising therapeutic approach for cancer treatment. Here, we have investigated the potential of targeting the axis of the insulin-like growth factor-1 receptor (IGF-1R) and PI3K signaling in two common cancers of childhood: neuroblastoma, the most common extracranial tumor in children and medulloblastoma, the most frequent malignant childhood brain tumor. By treating neuroblastoma and medulloblastoma cells with R1507, a specific humanized monoclonal antibody against the IGF-1R, we could observe cell line-specific responses and in some cases a strong decrease in cell proliferation. In contrast, targeting the PI3K p110a with the specific inhibitor PIK75 resulted in broad anti-proliferative effects in a panel of neuro-and medulloblastoma cell lines. Additionally, sensitization to commonly used chemotherapeutic agents occurred in neuroblastoma cells upon treatment with R1507 or PIK75. Furthermore, by studying the expression and phosphorylation state of IGF-1R/PI3K downstream signaling targets we found down-regulated signaling pathway activation. In addition, apoptosis occurred in embryonal tumor cells after treatment with PIK75 or R1507. Together, our studies demonstrate the potential of targeting the IGF-1R/ PI3K signaling axis in embryonal tumors. Hopefully, this knowledge will contribute to the development of urgently required new targeted therapies for embryonal tumors.

Neuro-Oncology, 2012

INTRODUCTION: Pediatric CNS embryonal neoplasms represent a unique group of poorly differentiated... more INTRODUCTION: Pediatric CNS embryonal neoplasms represent a unique group of poorly differentiated malignant tumors with propensity to disseminate throughout the neuraxis and exhibit aggressive clinical behavior. They are typically classified as medulloblastoma, other CNS site PNET (e.g., pineoblastoma) and AT/RT. A novel PNET variant, ETANTR, has been reported in approximately 30 children worldwide. ETANTR appears to afflict young children, have a female predominance and occurs primarily in the cerebrum. The prognosis is dismal. We report atypical neuroimaging characteristics of two young children with ETANTR. REPORTS: A 5-year-old girl presented with headaches, ataxia and photophobia. MRI revealed a 5.1 x 7.4 x 6 cm mass seeming to arise from the right lateral ventricle. The mass showed T1 hypointensity, T2 hyperintensity and was isointense to gray matter on FLAIR sequences. DWI and ADC images showed patchy reduced diffusion. T1 post-contrast images showed enhancement of large vessels, but little parenchymal tumor enhancement. Gross total resection (GTR) was achieved, ETANTR was diagnosed and there was no evidence of neuraxis metastases. A 2-year-old boy presented with seizures. MRI revealed a 2.2 x 2.9 x 2.2 cm mass in the right frontal lobe parenchyma, showing the same characteristics as the first case, except for a thin, partial FLAIR-hyperintense rim, partial reduced diffusion, and post-contrast enhancement only of a few small vessels. GTR was achieved, ETANTR was diagnosed and there was no evidence of neuraxis metastases. CONCLUSIONS: ETANTR is now recognized as a distinct type of CNS embryonal tumor/PNET. It occurs in young children and carries a poor prognosis. The neuroimaging characteristics in the two reported cases here, namely FLAIR isointensity to gray matter and paucity of parenchymal tumor enhancement, are atypical of malignant embryonal tumors and should be considered as a factor in the neurodiagnostic differential diagnosis of children with newly discovered CNS tumors.

Molecular Cancer Therapeutics, 2010

We investigated here the effects of S2T1-6OTD, a novel telomestatin derivative that is synthesize... more We investigated here the effects of S2T1-6OTD, a novel telomestatin derivative that is synthesized to target G-quadruplex–forming DNA sequences, on a representative panel of human medulloblastoma (MB) and atypical teratoid/rhabdoid (AT/RT) childhood brain cancer cell lines. S2T1-6OTD proved to be a potent c-Myc inhibitor through its high-affinity physical interaction with the G-quadruplex structure in the c-Myc promoter. Treatment with S2T1-6OTD reduced the mRNA and protein expressions of c-Myc and hTERT, which is transcriptionally regulated by c-Myc, and decreased the activities of both genes. In remarkable contrast to control cells, short-term (72-hour) treatment with S2T1-6OTD resulted in a dose- and time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC50, 0.25–0.39 μmol/L). Under conditions where inhibition of both proliferation and c-Myc activity was observed, S2T1-6OTD treatment decreased the protein expression of the cell cycle activato...

JNCI Journal of the National Cancer Institute, 2011

BACKGROUND: It has been hypothesized that children and adolescents might be more vulnerable to po... more BACKGROUND: It has been hypothesized that children and adolescents might be more vulnerable to possible health effects from mobile phone exposure than adults. We investigated whether mobile phone use is associated with brain tumor risk among children and adolescents. METHODS: CE-FALO is a multicenter case-control study conducted in Denmark, Sweden, Norway, and Switzerland that includes all children and adolescents aged 7-19 years who were diagnosed with a brain tumor between 2004 and 2008. We conducted interviews, in person, with 352 case patients (participation rate: 83%) and 646 control subjects (participation rate: 71%) and their parents. Control subjects were randomly selected from population registries and matched by age, sex, and geographical region. We asked about mobile phone use and included mobile phone operator records when available. Odds ratios (ORs) for brain tumor risk and 95% confidence intervals (CIs) were calculated using conditional logistic regression models. RESULTS: Regular users of mobile phones were not statistically significantly more likely to have been diagnosed with brain tumors compared with nonusers (OR = 1.36; 95% CI = 0.92 to 2.02). Children who started to use mobile phones at least 5 years ago were not at increased risk compared with those who had never regularly used mobile phones (OR = 1.26, 95% CI = 0.70 to 2.28). In a subset of study participants for whom operator recorded data were available, brain tumor risk was related to the time elapsed since the mobile phone subscription was started but not to amount of use. No increased risk of brain tumors was observed for brain areas receiving the highest amount of exposure. CONCLUSION: The absence of an exposure-response relationship either in terms of the amount of mobile phone use or by localization of the brain tumor argues against a causal association.

International Journal of Cancer, 2006

The potential of the novel insulin-like growth factor receptor (IGF-IR) inhibitor NVP-AEW541 as a... more The potential of the novel insulin-like growth factor receptor (IGF-IR) inhibitor NVP-AEW541 as an antiproliferative agent in human neuroblastoma was investigated. Proliferation of a panel of neuroblastoma cell lines was inhibited by NVP-AEW541 with IC 50 values ranging from 0.15 to 5 lM. Experiments using an IGF-IR neutralizing antibody confirmed that the IGF-IR was essential to support growth of neuroblastoma cell lines. The expression levels of the IGF-IR in individual neuroblastoma cell lines did not correlate with the sensitivities to NVP-AEW541, while coexpression of the IGF-IR and the insulin receptor (IR) correlated with lower sensitivity to the inhibitor in some cell lines. Intriguingly, high levels of activation of Akt/protein kinase B (PKB) and phosphorylation of the ribosomal S6 protein were observed in neuroblastoma cell lines with decreased sensitivities to NVP-AEW541. Inhibition of Akt/PKB activity restored the sensitivity of neuroblastoma cells to the IGF-IR inhibitor. Transfection of neuroblastoma cells with activated Akt or ribosomal protein S6 kinase (S6K) decreased the sensitivity of the cells to NVP-AEW541. IGF-I-stimulated proliferation of neuroblastoma cell lines was completely blocked by NVP-AEW541, or by a combination of an inhibitor of phosphoinositide 3-kinase and rapamycin. In addition to its antiproliferative effects, NVP-AEW541 sensitized neuroblastoma cells to cisplatin-induced apoptosis. Together, our data demonstrate that NVP-AEW541 in combination with Akt/PKB inhibitors or chemotherapeutic agents may represent a novel approach to target human neuroblastoma cell proliferation.

European Journal of Cancer, 2011

Medulloblastoma (MB), the most common malignant brain tumour in children, is characterised by a h... more Medulloblastoma (MB), the most common malignant brain tumour in children, is characterised by a high risk of leptomeningeal dissemination. But little is known about the molecular mechanisms that promote cancer cell migration in MB. Aberrant expression of miR-21 is recognised to be causatively linked to metastasis in a variety of human neoplasms including brain tumours; however its function in MB is still unknown. In this study we investigated the expression level and the role of miR-21 in MB cell migration. miR-21 was found to be up-regulated, compared to normal cerebellum, in 29/29 MB primary samples and 6/6 MB-derived cell lines. Inverse correlation was observed between miR-21 expression and the metastasis suppressor PDCD4, while miR-21 repression increased the release of PDCD4 protein, suggesting negative regulation of PDCD4 by miR-21 in MB cells. Anti-miR-21 decreased protein expression of the tumour cell invasion mediators MAP4K1 and JNK, which are also known to be negatively regulated by PDCD4, and down-regulated integrin protein that is essential for MB leptomeningeal dissemination. Moreover miR-21 knockdown in MB cells increased the expression of two eminent negative modulators of cancer cell migration, E-Cadherin and TIMP2 proteins that are known to be positively regulated by PDCD4. Finally and importantly, suppression of miR-21 decreased the motility of MB cells and reduced their migration across basement membranes in vitro. Together, these compelling data propose miR-21 pathway as a novel mechanism impacting MB cell dissemination and raises the possibility that curability of selected MB may be improved by pharmaceutical strategies directed towards microRNA-21.

European Journal of Cancer, 2007

Central nervous system (CNS) atypical teratoid/rhabdoid tumours (AT/RT) are among the paediatric ... more Central nervous system (CNS) atypical teratoid/rhabdoid tumours (AT/RT) are among the paediatric malignant tumours with the worst prognosis and fatal outcome. Insulin-like growth factor I receptor (IGF-IR) protects cancer cells from apoptosis induced by a variety of anticancer drugs and radiation. In the present study, IGF-IR was expressed in 8/8 primary AT/RT as detected by immunohistochemistry. Moreover, we found IGF-I and IGF-II mRNA in BT-16 CNS AT/RT cells and IGF-II mRNA in BT-12 CNS AT/RT cells, and autophosphorylated IGF-IR in both cell lines, indicating the potential presence of an autocrine/paracrine IGF-I/II/ IGF-IR loop in CNS AT/RT. IGF-IR antisense oligonucleotide treatment of human CNS AT/RT cells resulted in significant down-regulation of IGF-IR mRNA and protein expression, induction of apoptosis, and chemosensitisation to doxorubicin and cisplatin. These studies provide evidence for the influence of IGF-IR on cellular responses to chemotherapy and raise the possibility that curability of selected CNS AT/RT may be improved by pharmaceutical strategies directed towards the IGF-IR.