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  • DKFZ Publication Database  (993)
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  • 1
    Keywords: GENE-EXPRESSION ; DIFFERENTIATION ; TUMORS ; BIOLOGY ; PROGRESSION ; PHENOTYPE ; P-TEFB ; RISK STRATIFICATION ; SUBGROUPS ; MIRNA EXPRESSION
    Abstract: Neuroblastoma, a childhood cancer that originates from neural crest-derived cells, is the most common deadly solid tumor of infancy. Amplification of the MYCN oncogene, which occurs in approximately 20-25% of human neuroblastomas, is the most prominent genetic marker of high-stage disease. The availability of valid preclinical in vivo models is a prerequisite to develop novel targeted therapies. We here report on the generation of transgenic mice with Cre-conditional induction of MYCN in dopamine beta-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of 〉75%, regardless of strain background. Molecular profiling of tumors revealed upregulation of the MYCN-dependent miR-17-92 cluster as well as expression of neuroblastoma marker genes, including tyrosine hydroxylase and the neural cell adhesion molecule 1. Gene set enrichment analyses demonstrated significant correlation with MYC-associated expression patterns. Array comparative genome hybridization showed that chromosomal aberrations in LSL-MYCN;Dbh-iCre tumors were syntenic to those observed in human neuroblastomas. Treatment of a cell line established from a tumor derived from a LSL-MYCN;Dbh-iCre mouse with JQ1 or MLN8237 reduced cell viability and demonstrated oncogene addiction to MYCN. Here we report establishment of the first Cre-conditional human MYCN-driven mouse model for neuroblastoma that closely recapitulates the human disease with respect to tumor localization, histology, marker expression and genomic make up. This mouse model is a valuable tool for further functional studies and to assess the effect of targeted therapies.Oncogene advance online publication, 1 September 2014; doi:10.1038/onc.2014.269.
    Type of Publication: Journal article published
    PubMed ID: 25174395
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  • 2
    Keywords: CANCER ; EXPRESSION ; TUMORS ; NERVOUS-SYSTEM ; GLIOMA ; temozolomide ; TELOMERASE ACTIVITY ; GENOME-WIDE ASSOCIATION ; SECONDARY GLIOBLASTOMAS ; PHASE-3 TRIAL
    Abstract: Background. Activating somatic mutations in the promoter region of the telomerase reverse transcriptase gene (TERT) have been detected in several cancers. In this study we investigated the TERT promoter mutations and their impact on patient survival in World Health Organization grade IV glioblastoma multiforme (GBM). Methods. The TERT core promoter region containing the previously described mutations and a common functional polymorphism (rs2853669) was sequenced in tumors and blood samples from 192 GBM patients. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was assessed by pyrosequencing in 177 (92.2%) cases. Relevant clinical data were obtained from a prospectively maintained electronic database. Results. We detected specific (-124 C〉T and -146 C〉T) TERT promoter mutations in 143/178 (80.3%) primary GBM and 4/14 (28.6%) secondary GBM (P〈 .001). The presence of TERT mutations was associated with poor overall survival, and the effect was confined to the patients who did not carry the variant G-allele for the rs2853669 polymorphism. An exploratory analysis suggested that TERT mutations might be prognostic only in patients who had incomplete resections and no temozolomide chemotherapy. Conclusions. In this study, specific TERT promoter mutations were markers of primary GBM and predicted patient survival in conjunction with a common functional polymorphism. The prognostic impact of TERT mutations was absent in patients with complete resections and temozolomide chemotherapy. If confirmed in additional studies, these findings may have clinical implications, that is, TERT mutations appear to characterize tumors that require aggressive treatment.
    Type of Publication: Journal article published
    PubMed ID: 25140036
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  • 3
    Keywords: DISEASE ; TUMORS ; SUSCEPTIBILITY ; VARIANTS ; DNA-REPAIR ; MALIGNANT-MELANOMA ; beta-catenin ; CUTANEOUS MELANOMA ; SKIN PIGMENTATION ; SPORADIC MELANOMA
    Abstract: Multifactorial predisposition to melanoma includes genes involved in pigmentation, immunity and DNA repair. Nonetheless, missing heritability in melanoma is still important. We studied the role of 335 candidate SNPs in melanoma susceptibility by using a dedicated chip and investigating 110 genes involved in different pathways. A discovery set was comprised of 1069 melanoma patients and 925 controls from France. Data were replicated using validation phases II (1085 cases and 801 controls from Spain) and III (1808 cases and 1894 controls from Germany and a second set of Spanish samples). In addition, an exome sequencing study was performed in three high-risk French melanoma families. Nineteen SNPs in 17 genes were initially associated with melanoma in the French population. Six SNPs were replicated in phase II, including two new SNPs in the WNT3 (rs199524) and VPS41 (rs11773094) genes. The role of VPS41 and WNT3 was confirmed in a meta-analysis (3940 melanoma cases and 3620 controls) with two-side p values of 0.002, (OR=0.86) and 4.07x10(-10) (OR=0.80), respectively. Exome sequencing revealed a non-synonymous VPS41 variant in one family that was shown to be strongly associated with familial melanoma (OR=4.46, p=0.001) in an independent sample of 178 melanoma families. WNT3 belongs to WNT pathway known to play a crucial role in melanoma, whereas VPS41 regulates vesicular trafficking and is thought to play a role in pigmentation. Our work identified two new pathways involved in melanoma predisposition. These results may be useful in the future for identifying individuals highly predisposed to melanoma. What's New? While our understanding of the molecular pathways that lead to malignant melanoma has increased over the past few years, it is still incomplete. In this study, the authors identified two new pathways: one that involves WNT signaling (involved in melanoblast development), and another that involves vesicular trafficking (involved in changes in pigmentation phenotype). These results may be useful in developing screening tests for people who are genetically susceptible to melanoma. In addition, the whole-exome sequencing techniques used in this study may aid researchers in identifying mutations in unknown disease-candidate genes.
    Type of Publication: Journal article published
    PubMed ID: 25303718
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  • 4
    Keywords: APOPTOSIS ; GENES ; TUMORS ; ACTIVATION ; PROMOTER ; SUBTYPES ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CYCLIN D1 EXPRESSION ; FUNCTIONAL VARIANTS
    Abstract: Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER-: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, p(trend) = 5.7 3 10(-44)) and estrogen-receptor-negative (ER-: OR = 1.10, 95% CI = 1.05-1.15, p(trend) = 3.0 x 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [p(cond) = 1.61 x 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER-: OR = 0.90, 95% CI = 0.87-0.93, p(cond) = 1.4 x 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
    Type of Publication: Journal article published
    PubMed ID: 25529635
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  • 5
    Keywords: TUMORS ; STABILITY ; ARCHITECTURE ; mammographic density ; GENOME-WIDE ASSOCIATION ; AUTOPHAGY ; COMMON VARIANTS ; BRCA2 MUTATION CARRIERS ; GENOTYPE IMPUTATION ; ZNF365
    Abstract: Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 10.82-0.881) and ER-negative (OR = 0.87 [0.82-0.911) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:0) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 10.91-0.951 and OR = 1.06 [1.03-1.091) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.131) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.961). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 26073781
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  • 6
    Keywords: CANCER ; SURVIVAL ; TUMORS ; TRIAL ; MUTATIONS ; SAFETY ; IMMUNOTHERAPY ; LYMPHOCYTE ; INTRAVENOUS FOTEMUSTINE ; CONJUNCTIVAL
    Abstract: PURPOSE: Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM. PATIENTS AND METHODS: We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naive) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. RESULTS: Forty five pretreated (85%) and eight treatment-naive (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7-8.1), median progression-free survival 2.8 months (95% CI 2.5-2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3-4 events (36%). One drug-related death due to pancytopenia was observed. CONCLUSIONS: Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT01355120.
    Type of Publication: Journal article published
    PubMed ID: 25761109
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  • 7
    Keywords: carcinoma ; THERAPY ; TUMORS ; RAT MODEL ; DIRECTIONS
    Abstract: PURPOSE: To validate imaging parameters from diffusion-weighted imaging and dynamic contrast-enhanced MRI with immunohistology and to non-invasively assess microstructure of experimental breast cancer bone metastases. MATERIALS AND METHODS: Animals bearing breast cancer bone metastases were imaged in a clinical 1.5 T MRI scanner. HASTE sequences were performed to calculate apparent diffusion coefficients. Saturation recovery turbo FLASH sequences were conducted while infusing 0.1 mmol/l Gd-DTPA for dynamic contrast-enhanced MRI to quantify parameters amplitude A and exchange rate constant kep. After imaging, bone metastases were analyzed immunohistologically. RESULTS: We found correlations of the apparent diffusion coefficients from diffusion-weighted imaging with tumor cellularity as assessed with cell nuclei staining. Histological vessel maturity was correlated negatively with parameters A and kep from dynamic contrast-enhanced MRI. Tumor size correlated inversely with cell density and vessel permeability as well as positively with mean vessel calibers. Parameters from the rim of bone metastases differed significantly from values of the center. CONCLUSION: In vivo diffusion-weighted imaging and dynamic contrast-enhanced MRI in experimental bone metastases provide information about tumor cellularity and vascularity and correlate well with immunohistology.
    Type of Publication: Journal article published
    PubMed ID: 25641009
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  • 8
    Keywords: radiotherapy ; SURVIVAL ; CLASSIFICATION ; TUMORS ; NERVOUS-SYSTEM ; temozolomide ; HIGH-GRADE GLIOMAS ; NEWLY-DIAGNOSED GLIOBLASTOMA ; BEVACIZUMAB ; PHASE-3 TRIAL
    Abstract: Dismal glioblastoma (GB) patient outcome calls for the elucidation of further reliable predictors of prognosis. Established "biomarkers," age and functional status, employed in today's patient stratification have limits in fingerprinting this heterogeneous tumor entity. We aimed at ascertaining additional prognostic factors that may facilitate patient stratification for surgery. A retrospective review of 233 consecutive adult patients operated on for newly diagnosed GB at a single tertiary institution over a 5-year period (2006-2011) was conducted. Modern defined outcome associating factors recorded included demographics (preoperative age, gender, signs, symptoms, comorbidity status quantified by the Charlson comorbidity index (CCI), functional status computed by the Karnofsky performance scale (KPS)), tumor characteristics (size, location, isocitrate dehydrogenase mutation, and O-6-methylguanine-DNA methyltransferase promoter methylation status), and treatment parameters (volumetrically quantified extent of resection and adjuvant therapy). Survival analysis was performed by the Kaplan-Maier method. Influence of variables was evaluated using log-rank test. Median neuroradiographic evidence of tumor progression was 6 months after surgery (range 0-72). The median overall survival was 9.5 months (range 0-72). Age 〉 65 years, KPS a parts per thousand currency sign 70, and CCI 〉 3 were significantly associated with both poor OS (each p 〈 0.0001) and PFS (p 〈 0.0001, p 〈 0.001 and p 〈 0.002), respectively. Also, patients older than 65 years significantly had a CCI 〉 3 (p 〈 0.0001). Our data evidence that aside established prognostic parameters (age and KPS) for GB patient outcome, the CCI additionally significantly impacts outcome and may be employed for preoperative patient stratification.
    Type of Publication: Journal article published
    PubMed ID: 25577223
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  • 9
    Keywords: HISTORY ; TUMORS ; MALIGNANT-MELANOMA ; PREVALENCE ; CANCER DATABASE ; SKIN-CANCER ; PREDISPOSES ; MITF GERMLINE MUTATION ; MULTIPLE PRIMARY MELANOMAS ; QUEENSLAND
    Abstract: IMPORTANCE: The risk of next melanoma in patients with 2 or more previous melanomas stratified by familial and sporadic cases separately has not yet been reported, although a few population-based studies have assessed the risk of second melanoma. OBJECTIVE: To assess the risk of next melanoma in patients with multiple primary melanomas by number of previous melanomas, stratified by demographic and melanoma characteristics. DESIGN, SETTING, AND PARTICIPANTS: Prospective population-based cohort study with follow-up from 1958 to 2010 using the Swedish Family-Cancer Database with information on cancer cases retrieved from the Swedish Cancer Registry. A total of 65429 patients with invasive or in situ melanoma who received a diagnosis during 1958 through 2010 were observed for next melanoma incidence. MAIN OUTCOMES AND MEASURES: Standardized incidence ratios (SIRs) expressing risk of next melanoma by calculating the incidence of next (second, third, fourth, and fifth) melanoma in melanoma patients who had received a diagnosis of 1, 2, 3, and 4, respectively, previous melanomas, compared with the risk of first melanoma in the Swedish population. RESULTS: For patients with either familial or sporadic melanoma, we observed a stable 2- to 3-times elevated risk by increasing number of previous melanomas; for example, for 2 previous melanomas, the SIR was 2.8 (95% CI, 2.3-3.4) for patients with familial melanoma and 2.5 (95% CI, 2.3-2.7) for patients with sporadic melanoma. Overall risk of second melanoma was higher in patients with familial melanoma who received a diagnosis at younger than 40 years (SIR, 4.7 [95% CI, 3.9-5.6]), and we found a notable risk in young patients with familial melanoma during the first 5-year follow-up after first melanoma: SIR of 6.1 (95% CI, 4.0-9.0) for interval up to 1 year, 6.2 (95% CI, 3.2-11) for 2 to 3 years, and 19 (95% CI, 10-31) for 4 to 5 years. Risk was notable in young (〈40 years) patients with sporadic melanoma within the first year of follow-up (SIR, 5.3 [95% CI, 4.3-6.4]) and afterward remained steadily elevated by 2 to 3 times. CONCLUSIONS AND RELEVANCE: We found a stable 2- to 3-times elevated risk by number of previous melanomas for patients with either familial or sporadic melanoma. Notable risk in young patients with familial melanoma during first 5-year follow-up after first melanoma may suggest that it is important to refer these patients for clinical genetic testing.
    Type of Publication: Journal article published
    PubMed ID: 25671687
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  • 10
    Keywords: radiotherapy ; TUMORS ; SURVIVORS ; REGISTRIES
    Abstract: Women with a diagnosis of breast cancer are at increased risk of second primary cancers, and the identification of risk factors for the latter may have clinical implications. We have followed-up for 11 years 10,045 women with invasive breast cancer from a European cohort, and identified 492 second primary cancers, including 140 contralateral breast cancers. Expected and observed cases and Standardized Incidence Ratios (SIR) were estimated using Aalen-Johansen Markovian methods. Information on various risk factors was obtained from detailed questionnaires and anthropometric measurements. Cox proportional hazards regression models were used to estimate the role of risk factors. Women with breast cancer had a 30% excess risk for second malignancies (95% confidence interval-CI 18-42) after excluding contralateral breast cancers. Risk was particularly elevated for colorectal cancer (SIR, 1.71, 95% CI 1.43-2.00), lymphoma (SIR 1.80, 95% CI 1.31-2.40), melanoma (2.12; 1.63-2.70), endometrium (2.18; 1.75-2.70) and kidney cancers (2.40; 1.57-3.52). Risk of second malignancies was positively associated with age at first cancer, body mass index and smoking status, while it was inversely associated with education, post-menopausal status and a history of full-term pregnancy. We describe in a large cohort of women with breast cancer a 30% excess of second primaries. Among risk factors for breast cancer, a history of full-term pregnancy was inversely associated with the risk of second primary cancer.
    Type of Publication: Journal article published
    PubMed ID: 25650288
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  • 11
    Keywords: CELLS ; TUMORS ; VARIANTS ; SURVEILLANCE ; METAANALYSIS ; 8Q24 ; susceptibility loci ; SCAN ; ER STRESS ; SOCIETY-TASK-FORCE
    Abstract: Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 x 10(-10); odds ratio estimated by re-including all controls (OR) = 0.87, 95 % confidence interval (CI) 0.83-0.91; minor allele frequency (MAF) = 13 %]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95 % CI 0.77-0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 x 10(-8)).
    Type of Publication: Journal article published
    PubMed ID: 26404086
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  • 12
    Keywords: INHIBITION ; TUMORS ; INFECTION ; H-1 ; virus ; NEWBORN ; FETAL ; HAMSTERS ; COLONIES ; RV
    Abstract: The autonomous parvovirus H1 (H1PV) is transmitted in rodent populations. The natural host is the rat, in which H1PV infection is pathogenic only in fetuses and newborns. H1PV infection of human cancer cells leads to strong oncolytic effects in preclinical models. In preparation for a clinical trial of H1PV injection in patients with malignant brain tumors, H1PV had to be prepared to Good Manufacturing Practice standards, including extensive toxicology testing in rats. Because the trial involves direct intracerebral injection of H1PV into the tumor and around the resection cavity, possible toxicity to CNS tissue had to be investigated. In addition, quantitative blood levels and the tissue distribution of H1PV after single intracerebral or intravenous injection were measured. Direct injection of H1PV into rat brain at 3 dose levels (maximum, 7.96 x 107 pfu) did not cause any macroscopic or histologic pathology. Furthermore, H1PV infection of the brain did not alter central or autonomous nervous system function. H1PV DNA was detected in almost all organs at 6 h, 48 h, and 14 d after intravenous and intracerebral injection, with the highest levels in liver and spleen. H1PV concentrations in most organs were similar after intravenous and intracerebral injection, indicating high permeability of the blood-brain barrier for this small virus. The current results demonstrate wide organ distribution of H1PV after intravenous or intracerebral injection, confirm that H1PV is nonpathogenic in adult rats even after direct injection into the brain, and form the basis for the ongoing ParvOryx01 clinical trial.
    Type of Publication: Journal article published
    PubMed ID: 25730755
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  • 13
    Keywords: RECEPTOR ; CANCER ; PROTEIN ; DIFFERENTIATION ; TUMORS ; SKIN ; MUTATIONS ; beta-catenin ; LESSONS
    Abstract: Pilomatricoma is a tumour derived from hair matrix cells, which shows progressive keratin expression. Tumorigenesis is frequently associated with activating mutations in beta-catenin gene inducing nuclear expression of beta-catenin protein. The present study analysed the role of transforming growth factor-beta1 (TGF-beta1) and four-and-a-half LIM domain protein 2 (FHL2) in pilomatricoma in synopsis with their expression patterns in human anagen hair. Human anagen hair showed TGF-beta1 and nuclear FHL2 expression in the outer root sheath layer separated from nuclear beta-catenin staining, which was observed in cells of matrix and inner root sheath layers. Correspondingly, 41 out of 50 pilomatricomas showed co-labelling of TGF-beta1 and nuclear FHL2 in tumour cells, which mostly lacked nuclear beta-catenin expression. Tumoural proliferation (ki67) was associated with nuclear beta-catenin staining but not with expression of nuclear FHL2. In early pilomatricomas, TGF-beta1 expression was observed in few peripheral tumour cells showing absent or faint nuclear FHL2 co-staining. TGF-beta1 expression extended in growing tumours going along with strong nuclear FHL2 co-labelling as well as progressive keratin 14 and keratin 1 expression. In vitro, cultured human keratinocytes showed weak to marked autocrine TGF-beta1 expression; in case of enhanced TGF-beta1 expression associated with keratin 10 staining. TGF-beta1-treatment of cultured human keratinocytes induced nuclear and cytoplasmatic FHL2 staining as well as keratin 14 staining. Accordingly, siRNA-mediated FHL2 knockdown of TGF-beta1-stimulated keratinocytes reduced keratin 14 staining. In conclusion, tumoural TGF-beta1 secretion seems to induce nuclear translocation of co-factor FHL2 mediating progressive keratin expression in pilomatricoma.
    Type of Publication: Journal article published
    PubMed ID: 25477051
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  • 14
    Keywords: CELL LUNG-CANCER ; GENE ; TUMORS ; BREAST-CANCER ; immunohistochemistry ; IN-SITU HYBRIDIZATION ; PHASE-II ; RECOMMENDATIONS ; PATHOLOGISTS ; KINASE MUTATIONS
    Abstract: OBJECTIVES: Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined. To this end we prospectively studied HER2 expression, gene amplification, and mutation in relation to outcome of patients with advanced or metastatic ADC. MATERIALS AND METHODS: Diagnostic tumor biopsies from 193 sequential patients with stage III/IV ADC were prospectively studied for HER2 expression by immunohistochemistry (IHC). Cases with IHC scores 2+ or 3+ were analyzed by HER2 chromogenic in situ hybridization (CISH), and sequencing of HER2 exons 20 and 23. Additional prospectively determined biomarkers included PTEN, cMET, pAKT, and pERK expression, KRAS, EGFR, BRAF and PIK3CA mutations, and ALK fluorescence ISH (FISH). RESULTS AND CONCLUSION: HER2-IHC was feasible in 176 (91.2%) cases. Of 53 (30%) cases with IHC scores 2+/3+, 45 (85%) could be studied by CISH and 34 (64%) by sequencing. The lower number of HER2-mutational analyses resulted from exhaustion of tumor tissue and DNA following mutational analysis of KRAS, EGFR, BRAF and PIK3CA. HER2 amplification was detected in 4 cases (2.3%), while no mutation was found. HER2 expression correlated with expression of pAKT and cMET. Expression of HER2 and pAKT was associated with favorable overall survival in stage IV disease. HER2-expressing ADC more frequently harbored KRAS mutations, while HER2 expression was absent in all 4 cases with BRAF mutation. HER2-IHC was not predictive of HER2 gene amplification or mutation, which both were rare events in prospectively studied patients with advanced or metastatic ADC. Expression of HER2 and pAKT define a population of patients with stage IV ADC with a distinct disease course, who could benefit from specifically tailored pharmacotherapies.
    Type of Publication: Journal article published
    PubMed ID: 25708529
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  • 15
    Keywords: CANCER ; TUMORS ; AMPLIFICATION ; COPY NUMBER ; LOCALIZATION ; C-MYC ; POOR-PROGNOSIS ; CELL-MIGRATION ; GROWTH-FACTOR-II ; RNA-BINDING PROTEIN
    Abstract: PURPOSE: Chromosomal 17q21-ter gain in neuroblastoma is both a common and prognostically significant event. The insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) gene is located near the proximal edge of this region. Here, its prognostic value is evaluated in neuroblastoma. METHODS: The mRNA expression of IGF2BP family members was first evaluated by microarray data sets. In addition, in a separate cohort of 69 tumors, IGF2BP1 gene copy number, mRNA, and protein abundance were determined and compared with clinical parameters. RESULTS: In two independent microarray data sets, 77% to 100% of tumors had substantial IGF2BP1 mRNA levels measured. High IGF2BP1 transcript abundance was significantly associated with stage 4 tumors (P 〈 .001) and decreased patient survival (P 〈 .001). IGF2BP1 was also associated with MYCN gene amplification and MYCN mRNA abundance. In the 69 neuroblastoma samples, IGF2BP1 DNA copy number (increased in 84% of tumors), mRNA, and protein abundance were significantly higher in stage 4 compared with stage 1 tumors. Importantly, IGF2BP1 protein levels were associated with lower overall patient survival (P = .012) and positively correlated with MYCN mRNA, even when excluding MYCN-amplified tumors. Moreover, IGF2BP1 clearly affected MYCN expression and neuroblastoma cell survival in vitro. CONCLUSION: In neuroblastoma, IGF2BP1 was expressed in the majority of neuroblastoma specimens analyzed and was associated with lower overall patient survival and MYCN abundance. These data demonstrate that IGF2BP1 is a potential oncogene and an independent negative prognostic factor in neuroblastoma.
    Type of Publication: Journal article published
    PubMed ID: 25753434
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  • 16
    Keywords: CELLS ; INHIBITION ; TUMORS ; INFECTION ; virus ; INTERFERON ; H-1 PARVOVIRUS ; FETAL ; HAMSTERS ; RV
    Abstract: Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated.
    Type of Publication: Journal article published
    PubMed ID: 25730754
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  • 17
    Keywords: CANCER ; EXPRESSION ; THERAPY ; DIFFERENTIATION ; TUMORS ; ANTITUMOR-ACTIVITY ; METASTASIS ; adoptive immunotherapy ; GLIOMA-CELLS ; ERADICATION
    Abstract: The AC133 epitope of CD133 is a cancer stem cell (CSC) marker for many tumor entities, including the highly malignant glioblastoma multiforme (GBM). We have developed an AC133-specific chimeric antigen receptor (CAR) and show that AC133-CAR T cells kill AC133+ GBM stem cells (GBM-SCs) both in vitro and in an orthotopic tumor model in vivo. Direct contact with patient-derived GBM-SCs caused rapid upregulation of CD57 on the CAR T cells, a molecule known to mark terminally or near-terminally differentiated T cells. However, other changes associated with terminal T cell differentiation could not be readily detected. CD57 is also expressed on tumor cells of neural crest origin and has been preferentially found on highly aggressive, undifferentiated, multipotent CSC-like cells. We found that CD57 was upregulated on activated T cells only upon contact with CD57+ patient-derived GBM-SCs, but not with conventional CD57-negative glioma lines. However, CD57 was not downregulated on the GBM-SCs upon their differentiation, indicating that this molecule is not a bona fide CSC marker for GBM. Differentiated GBM cells still induced CD57 on CAR T cells and other activated T cells. Therefore, CD57 can apparently be upregulated on activated human T cells by mere contact with CD57+ target cells.
    Type of Publication: Journal article published
    PubMed ID: 25426558
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  • 18
    Keywords: EXPRESSION ; INHIBITION ; DEATH ; METABOLISM ; TUMORS ; LINES ; virus ; OLIGOSACCHARIDES ; GLYCOLYSIS ; N-linked glycosylation
    Abstract: High glucose consumption due to Warburg effect is one of the metabolic hallmarks of cancer. Consequently, glucose antimetabolites, such as 2-deoxy-glucose (2DG), can induce substantial growth inhibition of cancer cells. However, the inhibition of metabolic pathways is not the sole effect of 2DG on cancer cells. As mannose-mimetic molecule, 2DG is believed to interfere with normal glycosylation of proteins in cells. Here, we address how 2DG influences protein glycosylation in cancer cells and discuss possible implications of the consequences of this influence. In detail, six colorectal cancer cell lines were examined for alterations of protein glycosylation by measuring monosaccharide incorporation into cellular glycoproteins and cell surface glycosylation by lectin FACS. A significant increase in mannose incorporation was observed on treatment with 2DG (1 mM for 48 h), which was also reflected by an increased binding of the mannose-binding lectin Concanavalin A in FACS analysis. This phenomenon, which could be reversed by external addition of mannose, was not caused by 2DG-mediated mannosidase inhibition, as shown by pulse-chase experiments, arguing in favor of the hypothesis that 2DG directly influenced the incorporation of mannose. Increased mannose content was generally observed in cellular glycoproteins, including glycoproteins isolated from the plasma membrane fraction. Our results indicate that 2DG at low doses, which have only a limited metabolism-related effect on glycosylation, induces a strong increase in mannose incorporation into cellular glycoproteins. On the other hand, higher 2DG concentrations (10 and 20 mM) led to a significant decrease of absolute mannose incorporation accompanied by a dramatically reduced protein synthesis rate. 2DG-induced alterations of glycosylation may represent a novel mechanism potentially explaining the varied effects of 2DG on cancer cells. Moreover, 2DG treatment may open a path toward novel diagnostic and cancer therapeutic approaches, which specifically target altered glycoantigen structures induced by 2DG. (c) 2015 IUBMB Life, 67(3):218-226, 2015.
    Type of Publication: Journal article published
    PubMed ID: 25854316
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  • 19
    Keywords: IN-VIVO ; TUMORS ; SUPPRESSION ; SPECTROSCOPY ; Coherence ; SEL-MQC ; SINGLE-SCAN ; RESONANCES
    Abstract: Selective detection of lactate signals in in vivo MR spectroscopy with spectral editing techniques is necessary in situations where strong lipid or signals from other molecules overlap the desired lactate resonance in the spectrum. Several pulse sequences have been proposed for this task. The double-quantum filter SSel-MQC provides very good lipid and water signal suppression in a single scan. As a major drawback, it suffers from significant signal loss due to incomplete refocussing in situations where long evolution periods are required. Here we present a refocused version of the SSel-MQC technique that uses only one additional refocussing pulse and regains the full refocused lactate signal at the end of the sequence.
    Type of Publication: Journal article published
    PubMed ID: 25909643
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  • 20
    Keywords: SURVIVAL ; CLASSIFICATION ; DIAGNOSIS ; TUMORS ; validation ; NERVOUS-SYSTEM ; MANAGEMENT ; MULTIFORME ; HIGH-GRADE GLIOMA ; PERIOPERATIVE COMPLICATIONS
    Abstract: OBJECTIVE: Thromboembolic events, seizures, neurologic symptoms and adverse effects from corticosteroids and chemotherapies are frequent clinical complications seen in Glioblastoma (GB) patients. The exact impact these have on dismal patient outcome has not been fully elucidated. We aimed at assessing treatment associated complications, evaluating the impact on survival and defining risk factors. METHODS: Two hundred and thirty three consecutive adult patients operated on for newly diagnosed GB at a single tertiary institution over a 5-year-period (2006-2011) were assessed. Demographic parameters (age, gender, comorbidity status quantified by the Charlson-comorbidity-index (CCI), functional status computed by the Karnofsky Performance Scale (KPS), tumor characteristics (size, location, IDH-1 mutation and MGMT-Promotor-methylation-status) and treatment parameters (volumetrically quantified extent of resection and adjuvant therapy) were retrospectively reviewed. Complications assessed were recorded as neurological (N), surgical (S) and medical (M). Independent risk factor analysis was performed by the univariate and multivariate logistic regression method. Survival analysis was plotted by the Kaplan-Meier-method, influence of complication occurrence was evaluated by the log-rank test. RESULTS: One hundred and fifty nine (68.2%) patients had a total of 281 complications (90 N, 174 M and 17 S). Univariate analysis identified age (P=0.003), KPS〈70 (P=0.002), CCI〉3 (P=0.03), eloquent tumor location (P=0.001) and therapy other than the standard radio-chemotherapy with temozolomide therapy (P=0.034) as risk factors for complications. Multivariate analysis extracted the eloquent tumor location (P=0.007, odds ratio 1.94) as a significant predictor for complications. Having a complication significantly decreased patient survival (P=0.015). CONCLUSIONS: Complications significantly decrease GB patient survival. Age, poor functional status, other than standard adjuvant therapy and eloquent tumor location proved as significant risk factors for encountering a therapy associated complication. Not extensive surgery or tumor size but surgery at eloquent locations impacts complication occurrence the strongest with a 2 fold increased complication occurrence risk.
    Type of Publication: Journal article published
    PubMed ID: 25942630
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  • 21
    Keywords: carcinoma ; COMBINATION ; THERAPY ; TUMORS ; sensitivity ; CONTRAST-ENHANCED MRI ; MANAGEMENT ; ARTERIAL ; GD-EOB-DTPA ; CLINICAL-VALUE
    Abstract: PURPOSE: To compare lesion conspicuity in patients with liver metastases arising from gastroenteropancreatic neuroendocrine tumors (GEP-NETs) using MRI, PET and CT. MATERIALS AND METHODS: 16 patients with GEP-NETs were evaluated using non-contrast MRI, contrast-enhanced (CE) MRI using Gd-EOB-DTPA and CE-(68)Ga-DOTATOC PET. Quantitative analyses were performed by two blinded readers using ROI-analyses quantifying contrast ratios (CR) between normal liver-tissue and GEP-NET-metastases. Qualitative analyses were performed evaluating primary visibility and spatial detectability of all lesions. RESULTS: 103 of the same liver metastases were detected on all modalities. Qualitatively, lesion conspicuity was superior on CE-MRI imaging compared to non-contrast MR-sequences (T2, DWI, fl2D, fl3D), as well as arterial- and portal-venous phase CT. Concerning detectability of lesions, CE-MRI was superior to all other modalities. The quantitative ROI-analysis demonstrated improved CR for DWI compared to all other non-contrast MR-sequences (p〈0.001). CE-MRI presented with higher CR-values compared to CE-(68)Ga-DOTATOC PET/CT (p〈0.001). CONCLUSIONS: Anatomic imaging using non contrast MRI with fl2D-and fl3D-sequences in combination with the molecular imaging modality (68)Ga-DOTATOC PET is optimal for the assessment of liver lesions in GEP-NET-patients. Even though CE-MRI was superior to non-contrast MRI, non-contrast MRI is sufficient to detect and quantify liver metastases in daily routine, especially in combination with DW-Imaging.
    Type of Publication: Journal article published
    PubMed ID: 25999064
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  • 22
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    Nervenarzt 86 (6), 692-700 
    Keywords: CLASSIFICATION ; TUMORS ; prognosis ; TRIAL ; METHYLATION ; ASTROCYTOMAS ; temozolomide ; GLIOBLASTOMA ; ANAPLASTIC GLIOMAS
    Abstract: Current therapies for patients with malignant gliomas are starting to integrate molecular factors and age. Nonetheless, these therapies are still not sufficiently individualized. Some positive examples of transfer from basic science to clinical application are currently integrated into the standard treatment and guidelines. These are mainly genetic and other molecular factors that improve diagnosis and classification of gliomas and markers supporting prognostication. Examples for predictive biomarkers are methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter and the codeletion of chromosome arms 1p and 19q (1p/19q codel). The autoactive, truncated form of epidermal growth factor receptor (EGFRvIII) and the R132H mutation of isocitrate dehydrogenase 1 (IDH-1) are used as targets in currently running immunotherapeutic, targeted trials. Integration of functional imaging parameters into the monitoring and development of uniform assessment criteria improve the ability to evaluate therapy response and implement imaging biomarkers to guide therapies. As a result of the current efforts there are better classified prognostic groups and improved survival times with maintained functional and quality of life parameters in some glioma subgroups. Given the current dynamics, an improved, better differentiated classification of brain tumors including molecular parameters as well as more rational precise guiding of therapies with early, uniform response assessment is expected in the near future.
    Type of Publication: Journal article published
    PubMed ID: 26022855
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  • 23
    Keywords: EXPRESSION ; CELL ; LUNG-CANCER ; TUMORS ; HIGH-FREQUENCY ; UROTHELIAL CARCINOMA ; GENE PROMOTER ; THYROID-CANCER ; WHOLE-GENOME ; DISEASE RECURRENCE
    Abstract: Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR) = 4.93, 95% CI = 2.72-8.92, p 〈 0.0001]. While tumors with TERT promoter and FGFR3 mutations had shorter RTL than those without mutations (p 〈 0.0001), the TERT promoter mutations in conjunction with the common allele of the rs2853669 polymorphism defined sub-group of patients with an observed decreased overall survival (OR = 2.15, 95% CI = 1.00-4.61) and increased recurrence in patients with TaG1+TaG2 disease categories (OR = 3.68, 95%CI = 1.12-12.05). The finding of shorter telomeres in tumors with TERT promoter and/or FGFR3 mutations than without mutations implies mechanistic relevance of telomere biology in cancer progression. The observed association with recurrence and survival shows that the TERT promoter mutations can potentially be used as markers to refine selection of patients for different treatments. The overwhelming frequency of the TERT promoter mutations also represents a case for development of an eventual therapeutic target.
    Type of Publication: Journal article published
    PubMed ID: 25809917
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  • 24
    Keywords: EXPRESSION ; EPIDEMIOLOGY ; TUMORS ; DUPLICATION ; CENTRAL-NERVOUS-SYSTEM ; TRANSCRIPTS ; LOW-GRADE GLIOMAS ; RAF ; TARGETED THERAPY ; MAPK PATHWAY ACTIVATION
    Abstract: Pilocytic astrocytomas (PAs) are increasingly tested for KIAA1549-BRAF fusions. We used reverse transcription polymerase chain reaction for the 3 most common KIAA1549-BRAF fusions, together with BRAF V600E and histone H3.3 K27M analyses to identify relationships of these molecular characteristics with clinical features in a cohort of 32 PA patients. In this group, the overall BRAF fusion detection rate was 24 (75%). Ten (42%) of the 24 had the 16-9 fusion, 8 (33%) had only the 15-9 fusion, and 1 (4%) of the patients had only the 16-11 fusion. In the PAs with only the 15-9 fusion, 1 PA was in the cerebellum and 7 were centered in the midline outside of the cerebellum, that is, in the hypothalamus (n = 4), optic pathways (n = 2), and brainstem (n = 1). Tumors within the cerebellum were negatively associated with fusion 15-9. Seven (22%) of the 32 patients had tumor-related deaths and 25 of the patients (78%) were alive between 2 and 14 years after initial biopsy. Age, sex, tumor location, 16-9 fusion, and 15-9 fusion were not associated with overall survival. Thus, in this small cohort, 15-9 KIAA1549-BRAF fusion was associated with midline PAs located outside of the cerebellum; these tumors, which are generally difficult to resect, are prone to recurrence.
    Type of Publication: Journal article published
    PubMed ID: 26222501
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  • 25
    Keywords: SURVIVAL ; SAMPLES ; TUMORS ; T-CELLS ; MUTATIONS ; CANCER-IMMUNOTHERAPY ; IPILIMUMAB PLUS DACARBAZINE ; UNTREATED MELANOMA ; PD-1 BLOCKADE ; NEO-ANTIGENS
    Abstract: Monoclonal antibodies directed against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, yield significant clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
    Type of Publication: Journal article published
    PubMed ID: 26359337
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  • 26
    Keywords: TUMORS ; ELECTROCHEMOTHERAPY ; Hexadecylphosphocholine
    Abstract: In this study we investigated the effect of combined treatment of HaCaT keratinocyte cells with electrical pulses (200-500V/cm) and the alkylphosholipid (ALP) miltefosine. The data show that electroporation in combination with miltefosine induces cytoskeleton disruption and increases the permeability of cell monolayers due to interruption of cell-cell junctions', as documented by fluorescent imaging of ZO-1 and actin integrity. This was accompanied with reduction of cell viability. The combination of these conditions could be considered as a method for treating several types of skin cancer or other pathological conditions affecting the skin integrity.
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  • 27
    Keywords: TUMORS ; familial risk ; TRENDS
    Abstract: Background: None of the population-based epidemiologic studies to date has had a large enough sample size to show the familial risk of testicular cancer (TC) by age at diagnosis for patients and their relatives or for rare histologic subtypes. Objective: To estimate absolute and relative risks of TC in relatives of TC patients by age at diagnosis in patients and their relatives and histological subtypes. Design, setting, and participants: In a joint population-based cohort study, 97 402 first-degree relatives of 21 254 TC patients who were diagnosed between1955 and 2010 in five European countries were followed for cancer incidence. Outcome measurements and statistical analysis: Standardized incidence ratios (SIRs) were estimated using histology-, age-, period-, and country-specific incidence rates as references. Lifetime cumulative risks were also calculated. Results and limitations: The lifetime cumulative risk of TC in brothers of a patient with TC was 2.3%, which represents a fourfold increase in risk (SIR 4.1, 95% confidence interval [CI] 3.6-4.6) compared to the general population. TC in a father increased the risk by up to twofold in his son (95% CI 1.7-2.4; lifetime risk 1.2%) and vice versa. When there were two or more TC patients diagnosed in a family, the lifetime TC risk for relatives was 10-11%. Depending on age at diagnosis, twins had a 9-74% lifetime risk of TC. Family history of most of the histologic subtypes of TC increased the risk of concordant and most discordant subtypes. There was a tendency toward concordant age at diagnosis of TC among relatives. Conclusions: This study provides clinically relevant age-specific cancer risk estimates for relatives of TC patients. Familial TC patients tended to develop TC at an age close to the age at diagnosis of TC among their relatives, which is a novel finding of this study. Patient summary: This joint European population study showed that sons and brothers of testicular cancer patients are at higher risk of developing this cancer at an age close to the age at diagnosis of their relatives.
    Type of Publication: Journal article published
    PubMed ID: 25913387
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  • 28
    Keywords: RISK ; TUMORS ; FRAMESHIFT MUTATIONS ; HEREDITARY ; microsatellite instability ; EVOLUTION ; NONPOLYPOSIS COLORECTAL-CANCER ; COLON CANCERS ; HNPCC ; GENETIC ALTERATIONS
    Abstract: Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR-DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry. The identified lesions were characterised for alterations in microsatellite-bearing genes with proven or suspected role in malignant transformation. We demonstrate that the prevalence of MMR-DCF (mean 0.84 MMR-DCF per 1 cm2 mucosa in the colorectum of Lynch syndrome patients) was significantly associated with patients' age, but not with patients' gender. No MMR-DCF were detectable in the mucosa of patients with sporadic MSI-H colorectal cancer (n = 12). Microsatellite instability of at least one tested marker was detected in 89% of the MMR-DCF examined, indicating an immediate onset of microsatellite instability after MMR gene inactivation. Coding microsatellite mutations were most frequent in the genes HT001 (ASTE1) with 33%, followed by AIM2 (17%) and BAX (10%). Though MMR deficiency alone appears to be insufficient for malignant transformation, it leads to measurable microsatellite instability even in single MMR-deficient crypts. Our data indicate for the first time that the frequency of MMR-DCF increases with patients' age. Similar patterns of coding microsatellite instability in MMR-DCF and MMR-deficient cancers suggest that certain combinations of coding microsatellite mutations, including mutations of the HT001, AIM2 and BAX gene, may contribute to the progression of MMR-deficient lesions into MMR-deficient cancers.
    Type of Publication: Journal article published
    PubMed ID: 25816162
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  • 29
    Keywords: proliferation ; DIFFERENTIATION ; TUMORS ; INDUCTION ; MUTATIONS ; STEM-CELLS ; HAIR FOLLICLE MORPHOGENESIS ; WNT/BETA-CATENIN ; BETA-CATENIN ACTIVITY ; EPIDERMAL HOMEOSTASIS
    Abstract: The mammalian skin mediates the primary interphase between the body and the external environment and provides the first line of defense against pathogens, mechanical trauma, sunlight injuries, and chemical stress. Proper physical, biochemical, and immunological composition of the skin is necessary to maintain its barrier function. Therefore, the skin reflects a complex dynamic organ with high cellular turnover during normal tissue replacement and wound repair. Stem cell reservoirs ensure constant skin renewal. Wnt signaling controls stem cell maintenance and fate decisions in various tissues and also reflects a key pathway in controlling skin development and homeostasis. Disruption of Wnt signaling in the skin causes disorders such as alopecia, chronic inflammatory skin diseases or cancer. This review summarizes the role of Wnt signaling during skin development, homeostasis, and disease.
    Type of Publication: Journal article published
    PubMed ID: 25819237
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  • 30
    Keywords: IN-VIVO ; TUMORS ; CONTRAST ; PROTON-TRANSFER ; GLIOMA ; MAGNETIZATION-TRANSFER ; 3 TESLA ; RF IRRADIATION ; EXCHANGE SATURATION-TRANSFER ; PH-WEIGHTED MRI
    Abstract: Endogenous chemical exchange saturation transfer (CEST) effects of protons resonating near to water protons are always diluted by competing effects such as direct water saturation and semi-solid magnetization transfer (MT). This leads to unwanted T2 and MT signal contributions that contaminate the observed CEST signal. Furthermore, all CEST effects appear to be scaled by the T1 relaxation time of the mediating water pool. As MT, T1 and T2 are also altered in tumor regions, a recently published correction algorithm yielding the apparent exchange-dependent relaxation AREX, is used to evaluate in vivo CEST effects. This study focuses on CEST effects of amides (3.5ppm) and Nuclear-Overhauser-mediated saturation transfer (NOE, -3.5ppm) that can be properly isolated at 7T. These were obtained in 10 glioblastoma patients, and this is the first comprehensive study where AREX is applied in human brain as well as in human glioblastoma. The correction of CEST effects alters the contrast significantly: after correction, the CEST effect of amides does not show significant contrast between contrast enhancing tumor regions and normal tissue, whereas NOE drops significantly in the tumor area. In addition, new features in the AREX contrasts are visible. This suggests that previous CEST approaches might not have shown pure CEST effects, but rather water relaxation shine-through effects. Our insights help to improve understanding of the CEST effect changes in tumors and correlations on a cellular and molecular level.
    Type of Publication: Journal article published
    PubMed ID: 25727379
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  • 31
    Keywords: CLASSIFICATION ; TUMORS ; GLIOMAS ; CODON 132 MUTATION ; GLIOBLASTOMAS ; II ASTROCYTOMAS
    Abstract: The WHO 2007 classification of tumors of the CNS distinguishes between diffuse astrocytoma WHO grade II (A IIWHO2007) and anaplastic astrocytoma WHO grade III (AA III WHO2007). Patients with A II WHO2007 are significantly younger and survive significantly longer than those with AA III WHO2007. So far, classification and grading relies on morphological grounds only and does not yet take into account IDH status, a molecular marker of prognostic relevance. We here demonstrate that WHO 2007 grading performs poorly in predicting prognosis when applied to astrocytoma carrying IDH mutations. Three independent series including a total of 1360 adult diffuse astrocytic gliomas with IDH mutation containing 683 A II IDHmut, 562 AA III IDHmut and 115 GBM IDHmut have been examined for age distribution and survival. In all three series patients with A II IDHmut and AA III IDHmut were of identical age at presentation of disease (36-37 years) and the difference in survival between grades was much less (10.9 years for A II IDHmut, 9.3 years for AA III IDHmut) than that reported for A II WHO2007 versus AA III WHO2007. Our analyses imply that the differences in age and survival between A II WHO2007 and AA III WHO2007 predominantly depend on the fraction of IDH-non-mutant astrocytomas in the cohort. This data poses a substantial challenge for the current practice of astrocytoma grading and risk stratification and is likely to have far-reaching consequences on the management of patients with IDH-mutant astrocytoma.
    Type of Publication: Journal article published
    PubMed ID: 25962792
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  • 32
  • 33
    Keywords: TUMORS ; chemotherapy ; MUTATIONS ; ependymoma ; SUBGROUPS ; GLIOBLASTOMA ; IDH1 ; Pilocytic astrocytoma ; ANAPLASTIC OLIGODENDROGLIOMA ; GENOMIC ANALYSIS
    Abstract: The diagnostic subdivision of gliomas is traditionally based on histological features as defined by the World Health Organization (WHO) classification of tumors of the central nervous system. In recent years molecular studies have identified a number of genetic and epigenetic markers that could contribute to an improved tumor classification and better prediction of response to therapy and prognosis in the individual patient. The most important molecular tests with differential diagnostic relevance in patients with astrocytic and oligodendroglial tumors include the detection of genetic mutations in the isocitrate dehydrogenase 1 (IDH1), IDH2, alpha thalassemia/mental retardation syndrome X-linked (ATRX), histone H3.3 (H3F3A) and v-raf murine sarcoma viral oncogene homolog B (BRAF) genes as well as the demonstration of codeletions of chromosomal arms 1p and 19q. Important predictive markers that have been linked to the response to alkylating chemotherapy are O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma patients and 1p/19q codel status in anaplastic glioma patients. Oncogenic c11orf95/RELA fusion gene formation is characteristic for a subgroup of patients with supratentorial ependymoma. In addition to diagnostic testing of individual genes, novel microarray and next generation sequencing (NGS) techniques show promising perspectives in glioma diagnostics. The assessment of DNA methylation profiles using DNA methylation arrays representing 450,000 CpG dinucleotides distributed throughout the human genome (450 k array test) now allows the robust molecular classification of gliomas into clinically relevant entities and variants. Moreover, glioma-associated gene panel NGS promises the timely parallel sequencing of relevant diagnostic and predictive marker genes in a single test. It will now be a major task to integrate these novel results and techniques into the conventional histological procedures in the up-coming revision of the WHO classification.
    Type of Publication: Journal article published
    PubMed ID: 25989737
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  • 34
    Keywords: GENES ; MOLECULAR CHARACTERIZATION ; TUMORS ; COLORECTAL-CANCER ; BREAST-CANCER RISK ; HEPATITIS-C ; CELL-TYPE ; ANALYSES REVEAL ; IDENTIFIES SUSCEPTIBILITY LOCI ; FALLOPIAN-TUBE
    Abstract: Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 x 10(-8)), rs711830 at 2q31.1 (P = 7.5 x 10(-12)) and rs688187 at 19q13.2 (P = 6.8 x 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 x 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
    Type of Publication: Journal article published
    PubMed ID: 26075790
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  • 35
    Keywords: GROWTH ; TUMORS ; MUTATIONS ; CENTRAL-NERVOUS-SYSTEM ; PYRUVATE-KINASE
    Abstract: PURPOSE: Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. EXPERIMENTAL DESIGN: Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production. RESULTS: At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1alpha. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1alpha, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. CONCLUSIONS: Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE. Clin Cancer Res; 21(16); 3750-8. (c)2015 AACR.
    Type of Publication: Journal article published
    PubMed ID: 25957288
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  • 36
    Keywords: radiotherapy ; IN-VIVO ; MODEL ; TUMORS ; RADIATION-THERAPY ; RELATIVE BIOLOGICAL EFFECTIVENESS ; cell migration ; BEAMS ; CANCER INVASION ; GROWTH DELAY
    Abstract: In a recent published study, we investigated the response of an experimental prostate carcinoma (R3327-AT1) after irradiation with 1, 2 or 6 fractions of carbon ions or photons, respectively. The original intention of this study was to measure the dose-dependent local control probability as well as the related relative biological effectiveness of carbon ions. However, we now report an increased metastatic rate when the number of fractions was increased from 2 to 6. In a total of 246 animals, the actuarial metastatic rates for 1, 2 and 6 fractions were 5.1 +/- 3.5%, 5.7 +/- 4.0% and 15.3 +/- 7.1% for photons and 9.8 +/- 7.5%, 4.0 +/- 3.9% and 20.3 +/- 6.5% for carbon ions, respectively. The increase was significant only for carbon ions (6 vs. 2 fractions, P = 0.03). Although the original experiment was not designed to investigate metastatic rates, this observation may be of general interest to researchers studying radiation-modulated metastatic activity.
    Type of Publication: Journal article published
    PubMed ID: 24844648
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  • 37
    Keywords: THERAPY ; GENE ; TUMORS ; FUSION ; MESYLATE ; GROWTH-FACTOR-B
    Abstract: PURPOSE: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor. COL1A1-PDGFB gene fusion is frequent in DFSP, rendering tumor cell proliferation and survival dependent on PDGFRB signaling. This trial investigated imatinib as neo-adjuvant treatment of DFSP including long-term follow-up. EXPERIMENTAL DESIGN: The primary endpoint of this multicenter phase-II trial was response; secondary endpoints were safety, tumor relapse, and response biomarkers. Patients with advanced primary or locally recurrent DFSP and measurable disease by RECIST were eligible and received imatinib 600 mg/d until definitive surgery with histopathological proof of tumor-free margins. RESULTS: 16 patients received imatinib; 14 patients were evaluable for all endpoints. Median treatment duration was 3.1 months; median tumor shrinkage was 31.5%. Best overall response was 7.1% CR, 50.0% PR, 35.7% SD, and 7.1% PD. Toxicity was moderate with 25.0% grade 3-4 events. During a median follow-up of 6.4 years, one patient developed secondary resistance to imatinib but responded to second-line sunitinib. This patient also presented local recurrence, distant metastasis and death from DFSP. Exploratory analysis showed that response to imatinib was associated with decreased tumor cellularity and formation of strong hyalinic fibrosis. Weak PDGFRB phosphorylation and pigmented-type DFSP were associated with non-response. Additional to PDGFRB, the kinases EGFR and insulin receptor were found activated in a high percentage of DFSPs. CONCLUSION: The neo-adjuvant use of imatinib 600 mg/d in DFSP is efficacious and well-tolerated. Long-term follow-up results do not definitely support smaller surgical margins after successful imatinib pre-treatment, and presume that secondary resistance to imatinib might promote accelerated disease progression.
    Type of Publication: Journal article published
    PubMed ID: 24173542
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    Keywords: EXPRESSION ; transcription ; TISSUE ; TUMORS ; IDENTIFICATION ; PATTERN ; SPECTRUM ; NAB2 ; STAT6 ; HEMANGIOPERICYTOMA
    Abstract: Recurrent somatic fusions of the two genes, NGFI-A-binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, have been recently identified to be presumable tumor-initiating events in solitary fibrous tumors. Herein, we evaluated a cohort of 52 solitary fibrous tumors/hemangiopericytomas by whole-exome sequencing (one case) and multiplex RT-PCR (all 52 cases), and identified 12 different NAB2-STAT6 fusion variants in 48 cases (92%). All 52 cases showed strong and diffuse nuclear positivity for STAT6 by IHC. We categorized the fusion variants according to their potential functional effects within the predicted fusion protein and found strong correlations with relevant clinicopathological features. Tumors with the most common fusion variant, NAB2ex4-STAT6ex2/3, corresponded to classic pleuropulmonary solitary fibrous tumors with diffuse fibrosis and mostly benign behavior and occurred in older patients (median age, 69 years). In contrast, tumors with the second most common fusion variant, NAB2ex6-STAT6ex16/17, were found in much younger patients (median age, 47 years) and represented typical hemangiopericytomas from deep soft tissue with a more aggressive phenotype and clinical behavior. In summary, these molecular genetic findings support the concept that classic pleuropulmonary solitary fibrous tumor and deep-seated hemangiopericytoma are separate entities that share common features but correlate to different clinical outcome.
    Type of Publication: Journal article published
    PubMed ID: 24513261
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    Keywords: TUMORS ; CENTRAL-NERVOUS-SYSTEM ; physiology ; GLIOMAS ; GRADE ; CEREBRAL BLOOD-VOLUME ; T-2-ASTERISK-DOMINANT EXTRAVASATION CORRECTION ; VASCULAR INPUT FUNCTION ; LEAKAGE CORRECTION ; CEDIRANIB
    Abstract: BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MR imaging can provide in vivo assessment of the microvasculature in intracranial tumors. The aim of the present study was to evaluate the diagnostic performance of dynamic contrast-enhanced MR imaging derived vascular permeability parameters, including the volume transfer constant, the volume of extravascular extracellular space, and the flux rate constant between the extravascular extracellular space and plasma, for the differentiation of primary CNS lymphoma and glioblastoma. MATERIALS AND METHODS: Sixty glioblastomas and 11 primary central nervous system lymphomas were included. Pretreatment T1-weighted dynamic contrast-enhanced MR imaging with a 3D T1-weighted spoiled gradient-echo sequence was performed on a 3T MR imaging scanner. Perfusion parameters (volume transfer constant, the volume of extravascular extracellular space, and the flux rate constant) were measured on the basis of the Tofts-Kernmode model. The Mann-Whitney U test and receiver operating characteristic analysis were used to compare those parameters between primary central nervous system lymphoma and glioblastoma. Histopathologic correlation of dynamic contrast-enhanced MR imaging findings was performed by using reticulin staining and CD31 immunohistochemistry. RESULTS: Median volume transfer constant and flux rate constant values were significantly higher in primary central nervous system lymphoma (0.145 +/- 0.057 and 0.396 +/- 0.088) than in glioblastoma (0.064 +/- 0.021 and 0.230 +/- 0.058) (P 〈 .001, respectively). Median volume of extravascular extracellular space values did not differ significantly between primary central nervous system lymphoma (0.434 +/- 0.165) and glioblastoma (0.319 +/- 0.107). On receiver operating characteristic analysis, volume transfer constant had the best discriminative value for differentiating primary central nervous system lymphoma and glioblastoma (threshold, 0.093; sensitivity, 90.9%; specificity, 95.0%). Histopathologic evaluation revealed intact vascular integrity in glioblastoma despite endothelial proliferation, whereas primary central nervous system lymphoma demonstrated destroyed vessel architecture, thereby promoting vascular disintegrity. CONCLUSIONS: Primary central nervous system lymphoma demonstrated significantly higher volume transfer constant and flux rate constant values compared with glioblastoma, implying a higher vascular permeability in primary central nervous system lymphoma. These findings confirm initial observations from perfusion CT and dynamic contrast-enhanced MR imaging studies, correlating with underlying histopathologic features, and may be useful in distinguishing primary central nervous system lymphoma from glioblastoma.
    Type of Publication: Journal article published
    PubMed ID: 24722313
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    Keywords: INFORMATION ; QUANTIFICATION ; TUMORS ; MULTIPLE-SCLEROSIS ; STROKE ; IMAGE-RECONSTRUCTION ; REPERFUSED MYOCARDIAL-INFARCTION ; human brain ; TISSUE SODIUM CONCENTRATION ; TO-NOISE RATIO
    Abstract: PurposeTo increase the signal-to-noise ratio (SNR) and to reduce artifacts in non-proton magnetic resonance imaging (MRI) by incorporation of a priori information from H-1 MR data in an iterative reconstruction. MethodsAn iterative reconstruction algorithm for 3D projection reconstruction (3DPR) is presented that combines prior anatomical knowledge and image sparsity under a total variation (TV) constraint. A binary mask (BM) is used as an anatomical constraint to penalize non-zero signal intensities outside the object. The BM&TV method is evaluated in simulations and in MR measurements in volunteers. ResultsIn simulated BM&TV brain data, the artifact level was reduced by 20% while structures were well preserved compared to gridding. SNR maps showed a spatially dependent SNR gain over gridding reconstruction, which was up to 100% for simulated data. Undersampled 3DPR Na-23 MRI of the human brain revealed an SNR increase of 297%. Small anatomical structures were reproduced with a mean contrast loss of 14%, whereas in TV-regularized iterative reconstructions a loss of 66% was found. ConclusionThe BM&TV algorithm allows reconstructing images with increased SNR and reduced artifact level compared to gridding and performs superior to an iterative reconstruction using an unspecific TV constraint only.
    Type of Publication: Journal article published
    PubMed ID: 23754674
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    Keywords: EXPRESSION ; CELL ; POPULATION ; TUMORS ; CYCLE ; WOMEN ; NORMAL SERUM CONCENTRATIONS ; INHIBITING SUBSTANCE ; ANTIMULLERIAN HORMONE ; TRIMESTER
    Abstract: PURPOSE: Epithelial ovarian cancers either arise directly from Mullerian-type epithelium or acquire Mullerian characteristics in the course of neoplastic transformation. The anti-Mullerian hormone (AMH) causes regression of Mullerian structures during fetal development in males and has been shown to inhibit the growth of epithelial ovarian cancer. Therefore, we hypothesized that pre-diagnostic serum concentrations of AMH are inversely associated with risk of invasive serous ovarian cancer. METHODS: A case-control study (107 cases, 208 controls) was nested within the population-based Finnish Maternity Cohort (1986-2007). The sample donated during the first trimester of the last pregnancy preceding cancer diagnosis of the case subjects was selected for the study. For each case, two controls, matched on age and date at sampling, as well as parity at sampling and at cancer diagnosis were selected. AMH was measured by a second-generation AMH ELISA. Conditional logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for invasive serous ovarian cancer associated with AMH concentrations. RESULTS: Overall AMH concentrations were not associated with risk of invasive serous ovarian cancer (OR 0.93; 95 % CI 0.49-1.77 for top vs. bottom tertile, P trend=0.83). In women older than the median age at sampling (32.7 years), a doubling of AMH was associated with decreased risk (OR 0.69; 95 % CI 0.49-0.96), whereas an increased risk (OR 1.64; 95 % CI 1.06-2.54) was observed in younger women, P homogeneity = 0.002. CONCLUSIONS: In this first prospective investigation, risk of invasive serous ovarian cancer was not associated with pre-diagnostic AMH concentrations overall; however, the association may depend on age at AMH measurement.
    Type of Publication: Journal article published
    PubMed ID: 24562905
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    Keywords: brain ; GENE-EXPRESSION ; HYBRIDIZATION ; TUMORS ; UNITED-STATES ; GLIOMAS ; MULTIFORME ; temozolomide ; CODON 132 MUTATION ; IDH2 MUTATIONS
    Abstract: The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. To elucidate the molecular aberrations in glioblastomas of long-term survivors, we performed genome- and/or transcriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-term survivors with 〉36 months overall survival (OS), 20 short-term survivors with 〈12 months OS and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O(6) -methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups of IDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomas in our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients.(c) 2014 UICC.
    Type of Publication: Journal article published
    PubMed ID: 24615357
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    Keywords: EXPRESSION ; SURVIVAL ; HEPATOCELLULAR-CARCINOMA ; TUMORS ; MICE ; prognosis ; INFLAMMATORY-BOWEL-DISEASE ; FOXP3 ; INTERLEUKIN-10 ; EFFECTOR/MEMORY
    Abstract: Regulatory T cells (Treg) are supportive to cancer development in most tissues, but their role in colitis-associated colon cancer (CAC) remains unclear. In this study, we investigated the role of CD4(+)Foxp3(+) Treg in a mouse model of CAC and in patients with colon cancer. These Treg were increased strongly in number in a mouse model of CAC and in the peripheral blood of patients with colon cancer, exhibiting an activated phenotype as defined by elevated expression of GARP, CD103, CTLA-4, and IL10, along with an increased suppressive effect on the proliferation and Th1 cytokine expression of CD4(+)CD25(-) responder T cells ex vivo. Transient ablation of CD4(+)Foxp3(+) Treg during tumor development in the CAC model suppressed tumor outgrowth and distribution, accompanied by an increased number of CD8(+)IFNgamma/granzyme B-producing effector T cells. Conversely, inactivation of IL10 in Treg did not elevate the antitumor response but instead further boosted tumor development. Our results establish a tumor-promoting function for Treg during CAC formation, but they also suggest that a selective, transient ablation of Treg can evoke antitumor responses, with implications for immunotherapeutic interventions in patients with CAC.
    Type of Publication: Journal article published
    PubMed ID: 24906621
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    Cancer Research 74 (17), 4671-4675 
    Keywords: CELLS ; carcinoma ; GENERATION ; TUMORS ; DISCOVERY ; senescence ; PANCREAS CANCER
    Abstract: The Helmholtz Alliance Preclinical Comprehensive Cancer Center (PCCC; www.helmholtz-pccc.de) hosted the "1st International Kloster Seeon Meeting on Mouse Models of Human Cancer" in the Seeon monastery (Germany) from March 8 to 11, 2014. The meeting focused on the development and application of novel mouse models in tumor research and high-throughput technologies to overcome one of the most critical bottlenecks in translational bench-to-bedside tumor biology research. Moreover, the participants discussed basic molecular mechanisms underlying tumor initiation, progression, metastasis, and therapy resistance, which are the prerequisite for the development of novel treatment strategies and clinical applications in cancer therapy. Cancer Res; 74(17); 4671-5. (c)2014 AACR.
    Type of Publication: Journal article published
    PubMed ID: 25136075
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    Keywords: EXPRESSION ; TUMORS ; WOMEN ; CARCINOMAS ; SUBTYPES ; RECOMMENDATIONS ; THERAPEUTIC TARGETS ; MOLECULAR PORTRAITS ; AMERICAN SOCIETY ; ONCOLOGY/COLLEGE
    Abstract: Mutational profiling of triple-negative breast cancer (TNBC) by whole exome sequencing (WES) yielded a landscape of genomic alterations in this tumor entity. However, the clinical significance of these findings remains enigmatic. Further, integration of WES in routine diagnostics using formalin-fixed paraffin-embedded (FFPE) material is currently not feasible. Therefore, we designed and validated a breast cancer specific gene panel for semiconductor-based sequencing comprising 137 amplicons covering mutational hotspots in 44 genes and applied this panel on a cohort of 104 well-characterized FFPE TNBC with complete clinical follow-up. TP53 mutations were present in more than 80% of cases. PI3K pathway alterations (29.8%) comprising mainly PIK3CA mutations (22.1%) but also mutations and/or amplifications/deletions in other PI3K-associated genes (7.7%) were far more frequently observed, when compared to WES data. Alterations in MAPK signaling genes (8.7%) and cell-cycle regulators (14.4%) were also frequent. Mutational profiles were linked to TNBC subgroups defined by morphology and immunohistochemistry. Alterations in cell-cycle pathway regulators were linked with better overall (p=0.053) but not disease free survival. Taken together, we could demonstrate that breast cancer targeted hotspot sequencing is feasible in a routine setting and yields reliable and clinically meaningful results. Mutational spectra were linked to clinical and immunohistochemically defined parameters.
    Type of Publication: Journal article published
    PubMed ID: 25296970
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    Keywords: radiotherapy ; TUMORS ; IMPACT ; MALIGNANCIES ; PROGNOSTIC-FACTORS ; CHILDREN ; CERVICAL-SPINE ; MANAGEMENT ; CHONDROSARCOMA ; PROTON RADIATION-THERAPY
    Abstract: BACKGROUNDThe current study was conducted to evaluate the long-term results of irradiation with carbon ions in a raster scanning technique in patients with skull base chordomas. METHODSBetween 1998 and 2008, a total of 155 patients (76 men and 79 women) with a median age of 48 years (range, 15 years-85 years) were irradiated with carbon ions using a raster scan technique. The irradiation was performed at the Society for Heavy Ion Research in Darmstadt, Germany. The median total dose was 60 gray (relative biological effectiveness) at 3 gray (relative biological effectiveness) per fraction. The median boost planning target volume was 70 mL (range, 2 mL-294 mL). Local control (LC) and overall survival (OS) were evaluated using the Kaplan-Meier method, whereas long-term toxicity was evaluated via questionnaires. RESULTSThe median follow-up was 72 months (range, 12 months-165 months). All patients had residual macroscopic tumors at the initiation of radiotherapy. The authors observed 55 local recurrences during follow-up, as well as systemic disease progression in 4 patients. The resulting 3-year, 5-year, and 10-year LC rates were 82%, 72%, and 54%, respectively, whereas the 3-year, 5-year, and 10-year OS rates were 95%, 85%, and 75%, respectively. Age 〈48 years and a boost volume 〉75 mL were associated with a significantly improved LC and OS. Primary treatment resulted in a significantly better OS probability. No higher late toxicity could be detected after carbon ion treatment. CONCLUSIONSCarbon ion therapy appears to be a safe and effective treatment for patients with skull base chordoma, resulting in high LC and OS rates.
    Type of Publication: Journal article published
    PubMed ID: 24948519
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