National Center for Tumour Diseases

Heidelberg, Germany

National Center for Tumour Diseases

Heidelberg, Germany
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Stiborova M.,Charles University | Levova K.,Charles University | Barta F.,Charles University | Shi Z.,University of Cincinnati | And 7 more authors.
Toxicological Sciences | Year: 2012

Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. Individual susceptibility to AAinduced disease likely reflects individual differences in enzymes that metabolize AA. Herein, we evaluated AAI metabolism by human cytochrome P450 (CYP) 1A1 and 1A2 in two CYP1Ahumanized mouse lines that carry functional human CYP1A1 and CYP1A2 genes in the absence of the mouse Cyp1a1/1a2 orthologs. Human and mouse hepatic microsomes and human CYPs were also studied. Human CYP1A1 and 1A2 were found to be principally responsible for reductive activation of AAI to form AAI-DNA adducts and for oxidative detoxication to 8-hydroxyaristolochic acid (AAIa), both in the intact mouse and in microsomes. Overall, AAI-DNA adduct levels were higher in CYP1A-humanized mice relative to wild-type mice, indicating that expression of human CYP1A1 and 1A2 in mice leads to higher AAI bioactivation than in mice containing the mouse CYP1A1 and 1A2 orthologs. Furthermore, an exclusive role of human CYP1A1 and 1A2 in AAI oxidation to AAIa was observed in human liver microsomes under the aerobic (i.e., oxidative) conditions. Because CYP1A2 levels in human liver are at least 100-fold greater than those of CYP1A1 and there exists a > 60-fold genetic variation in CYP1A2 levels in human populations, the role of CYP1A2 in AAI metabolism is clinically relevant. The results suggest that, in addition to CYP1A1 and 1A2 expression levels, in vivo oxygen concentration in specific tissues might affect the balance between AAI nitroreduction and demethylation, which in turn would influence tissue-specific toxicity or carcinogenicity. © The Author 2011. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


Weinhold N.,University of Heidelberg | Johnson D.C.,Institute of Cancer Research | Chubb D.,Institute of Cancer Research | Chen B.,German Cancer Research Center | And 29 more authors.
Nature Genetics | Year: 2013

A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 × 10-11). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation. © 2013 Nature America, Inc. All rights reserved.


Moradi B.,University of Heidelberg | Zahlten-Hinguranage A.,National Center for Tumour Diseases | Lehner B.,University of Heidelberg | Zeifang F.,University of Heidelberg
International Orthopaedics | Year: 2010

The primary objective of this study was to investigate the implications of pathological fractures on therapy outcome in patients with primary malignant bone tumours and to determine whether limb salvage can be safely performed. A retrospective analysis of 447 patients with primary malignant bone tumours, treated between 1985 and 2005, was performed. Multivariate Cox regression analysis was used to investigate the influence of pathological fractures and further independent variables on survival rate. In 52 of the 447 patients, the primary malignant bone tumour was complicated by a pathological fracture. These fractures were more common in malignant fibrous histiocytoma (MFH) of the bone and in the tumour stages IIa/b and III. Ablative surgery was performed in ten patients and limb salvage surgery in 42 patients. The mortality risk for patients with pathological fractures was significantly increased by a factor of 1.82 (p = 0.015), and overall duration of survival was significantly lower in the fracture group, with a median of 6.2 years (p < 0.00001). In univariate and multivariate analysis, fracture, higher tumour stages and resection margins remained a significant predictor of worse survival. Overall survival, rate of local recurrence and distant metastases were not affected by the type of surgical treatment selected; there was no difference between the patients who underwent limb salvage and those who underwent an amputation. Pathological fracture in patients with primary malignant bone tumours is a predictor of worse survival and significantly increases mortality risk. Reconstructive surgery did not influence the survival rate, showing that limb salvage therapy is safe when adequate resection margins are achieved. © 2009 Springer-Verlag.


Moradi B.,University of Heidelberg | Zahlten-Hinguranage A.,National Center for Tumour Diseases | Barie A.,University of Heidelberg | Caldeira F.,University of Erfurt | And 3 more authors.
European Journal of Pain | Year: 2010

Background: Musculoskeletal pain represents a continuous process ranging from single-site to multiple-site pain, with an increase in pain sites accompanied by an increasing risk of chronification and the development of further comorbidities. Within this context, the impact of pain spread on therapy outcome is still unknown. Aims: This prospective clinical study aimed to evaluate whether and to what extent patients with pain at multiple sites would also benefit from multidisciplinary therapy or whether therapy success is limited by pain spread. Methods: Patients' characteristics were assessed, including socio-demographic variables, occupational and workplace characteristics, pain intensity and dimensions of pain, psychological aspects and functional back capacity, as well as the generic health status. Data were prospectively collected at day 1 (baseline) and at 6-month follow-up from a sample of 389 patients undergoing multidisciplinary treatment. Patients were distributed into three groups based on the number of pain sites (single-site, dual-site and multiple-site) and the outcome parameters were compared. Results: All three groups improved significantly from baseline to the 6-month follow-up. Compared to patients with multiple-site pain, patients with single-site and dual-site pain displayed significantly better outcome on almost all measures. Only the subcategory mental health of the SF-36 did not show any statistically significant differences among the three groups. Conclusions: Our results display that patients with two or more pain sites also improve significantly in the outcome measures. Therefore, treatment should be offered independent of the extent of pain spread. However, therapy is significantly less successful in patients with pain at multiple sites. © 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.


Schouten P.C.,Netherlands Cancer Institute | Marme F.,Netherlands Cancer Institute | Marme F.,University of Heidelberg | Aulmann S.,University of Heidelberg | And 8 more authors.
Clinical Cancer Research | Year: 2015

Purpose: Breast cancers in carriers of inactivating mutations of the BRCA1 gene carry a specific DNA copy-number signature ("BRCA1-like"). This signature is shared with cancers that inactivate BRCA1 through other mechanisms. Because BRCA1 is important in repair of DNA double-strand breaks through error-free homologous recombination, patients with a BRCA1-like tumor may benefit from high-dose alkylating (HD) chemotherapy, which induces DNA double-strand breaks. Experimental Design: We investigated a single institution cohort of high-risk patients that received tandem HD chemotherapy schedule comprising ifosfamide, epirubicin, and carboplatin or conventional chemotherapy. We classified copy-number profiles to be BRCA1-like or non-BRCA1- like and analyzed clinical associations and performed survival analysis with a treatment by biomarker interaction design. Results: BRCA1-like status associated with high-grade and triple-negative breast cancers. BRCA1-like cases benefitted from the HD compared with a conventional regimen on disease-free survival (DFS): [hazard ratio (HR), 0.05; 95% confidence interval (CI), 0.01-0.38; P 1/4 0.003]; distant DFS (DDFS): (HR, 0.06; 95% CI, 0.01-0.43; P 1/4 0.01); and overall survival (OS; HR, 0.15; 95% CI, 0.03-0.83; P0.03) after correction for prognostic factors.No such benefit was observed in the non-BRCA1-like cases on DFS (HR, 0.74; 95% CI, 0.38-1.46; P 1/4 0.39), DDFS (HR, 0.79; 95% CI, 0.41-1.52; P 1/4 0.47), and OS (HR, 0.93; 95% CI, 0.52-1.64; P 1/4 0.79). The P values for interaction were 0.01 (DFS), 0.01 (DDFS), and 0.045 (OS). Conclusions: BRCA1-like tumors recurred significantly less often after HD than conventional chemotherapy. BRCA1-like copy-number profile classification may be a predictive marker for HD alkylating chemotherapy. © 2015 American Association for Cancer Research.


Goeppert B.,University of Heidelberg | Frauenschuh L.,University of Heidelberg | Zucknick M.,German Cancer Research Center | Roessler S.,University of Heidelberg | And 10 more authors.
British Journal of Cancer | Year: 2015

Background:Biliary tract cancers (BTC) are rare malignant tumours with a poor prognosis. Previously, we have presented a detailed characterisation of the inflammatory infiltrate in BTC. Here, we analysed the impact of the expression of major histocompatibility complex class I (MHC I) on patient survival and the quantity, as well as the quality of tumour-infiltrating immune cell types in BTC.Methods:MHC I expression was assessed semi-quantitatively in 334 BTC, including extrahepatic (n=129) and intrahepatic cholangiocarcinomas (n=146), as well as adenocarcinomas of the gallbladder (n=59). In addition, 71 high-grade biliary intraepithelial lesions (BilIN 3) were included. Results were correlated with data on antitumour inflammation and investigated with respect to their association with clinicopathological variables and patient survival.Results:BTC showed a wide spectrum of different MHC I expression patterns ranging from complete negativity in some tumours to strong homogenous expression in others. In BilIN 3, significantly higher MHC I expression levels were seen compared to invasive tumours (P=0.004). Patients with strong tumoural MHC I expression had a significantly higher overall survival probability (median survival benefit: 8 months; P=0.006). MHC I expression strongly correlated with the number of tumour-infiltrating T-lymphocytes (CD4 + and CD8 +) and macrophages.Conclusions:Differences of MHC I expression predict patient outcome and show correlations with specific components of the inflammatory infiltrate in BTC. These findings contribute to a better understanding of immune response and immune escape phenomena in cholangiocarcinogenesis. © 2015 Cancer Research UK. All rights reserved.


Schmidt M.E.,National Center for Tumour Diseases | Wiskemann J.,University of Heidelberg | Armbrust P.,University of Heidelberg | Schneeweiss A.,University of Heidelberg | And 2 more authors.
International Journal of Cancer | Year: 2015

Multiple exercise interventions have shown beneficial effects on fatigue and quality of life (QoL) in cancer patients, but various psychosocial interventions as well. It is unclear to what extent the observed effects of exercise interventions are based on physical adaptations or rather on psychosocial factors associated with supervised, group-based programs. It needs to be determined which aspects of exercise programs are truly effective. Therefore, we aimed to investigate whether resistance exercise during chemotherapy provides benefits on fatigue and QoL beyond potential psychosocial effects of group-based interventions. One-hundred-one breast cancer patients starting chemotherapy were randomly assigned to resistance exercise (EX) or a relaxation control (RC) group. Both interventions were supervised, group-based, 2/week over 12 weeks. The primary endpoint fatigue was assessed with a 20-item multidimensional questionnaire, QoL with the EORTC QLQ-C30/BR23. Analyses of covariance for individual changes from baseline to Week 13 were calculated. In RC, total and physical fatigue worsened during chemotherapy, whereas EX showed no such impairments (between-group p = 0.098 and 0.052 overall, and p = 0.038 and 0.034 among patients without severe baseline depression). Differences regarding affective or cognitive fatigue were not significant. Benefits of EX were also seen to affect role and social function. Effect sizes were between 0.43 and 0.48. Explorative analyses indicated significant effect modification by thyroxin use (p-interaction = 0.044). In conclusion, resistance exercise appeared to mitigate physical fatigue and maintain QoL during chemotherapy beyond psychosocial effects inherent to supervised group-based settings. Thus, resistance exercise could be an integral part of supportive care for breast cancer patients undergoing chemotherapy. © 2014 UICC.


Hillengass J.,University of Heidelberg | Hillengass J.,German Cancer Research Center | Bauerle T.,German Cancer Research Center | Bartl R.,Ludwig Maximilians University of Munich | And 17 more authors.
British Journal of Haematology | Year: 2011

Bone marrow plasma cell infiltration is a crucial parameter of disease activity in monoclonal plasma cell disorders. Until now, the only way to quantify such infiltration was bone marrow biopsy or aspiration. Diffusion-weighted imaging (DWI) is a magnetic resonance imaging-technique that may mirror tissue cellularity by measuring random movements of water molecules. To investigate if DWI is capable of assessing bone marrow cellularity in monoclonal plasma cell disease, we investigated 56 patients with multiple myeloma or monoclonal gammopathy of undetermined significance, and 30 healthy controls using DWI of the pelvis and/or the lumbar spine. In 25 of 30 patients who underwent biopsy, bone marrow trephine and DWI could be compared. Of the patients with symptomatic disease 15 could be evaluated after systemic treatment. There was a positive correlation between the DWI-parameter apparent diffusion coefficient (ADC) and bone marrow cellularity as well as micro-vessel density (P<0·001 respectively). ADC was significantly different between patients and controls (P<0·01) and before and after systemic therapy (P<0·001). In conclusion, DWI enabled bone marrow infiltration to be monitored in a non-invasive, quantitative way, suggesting that after further investigations on larger patient groups this might become an useful tool in the clinical work-up to assess tumour burden. © 2011 Blackwell Publishing Ltd.


Muller B.,University of Heidelberg | Bovet M.,University of Heidelberg | Yin Y.,French Institute for Research in Computer Science and Automation | Yin Y.,Paris-Sorbonne University | And 23 more authors.
Journal of Pathology | Year: 2015

Transcription factors integrate a variety of oncogenic input information, facilitate tumour growth and cell dissemination, and therefore represent promising therapeutic target structures. Because over-expression of DNA-interacting far upstream element binding protein (FBP) supports non-small cell lung cancer (NSCLC) migration, we asked whether its repressor, FBP-interacting repressor (FIR) is functionally inactivated and how FIR might affect NSCLC cell biology. Different FIR splice variants were highly expressed in the majority of NSCLCs, with the highest levels in tumours carrying genomic gains of chromosome 8q24.3, which contained the FIR gene locus. Nuclear FIR expression was significantly enriched at the invasion front of primary NSCLCs, but this did not correlate with tumour cell proliferation. FIR accumulation was associated with worse patient survival and tumour recurrence; in addition, FIR over-expression significantly correlated with lymph node metastasis in squamous cell carcinomas (SCCs). In vitro, we applied newly developed methods and modelling approaches for the quantitative and time-resolved description of the pro-migratory and pro-invasive capacities of SCC cells. siRNA-mediated silencing of all FIR variants significantly reduced the speed and directional movement of tumour cells in all phases of migration. Furthermore, sprouting efficiency and single cell invasiveness were diminished following FIR inhibition. Interestingly, the silencing of FIR isoforms lacking exon 2 (FIRΔexon2) alone was sufficient to reduce lateral migration and invasion. In summary, by using scale-spanning data derived from primary human tissues, quantitative cellular analyses and mathematical modelling, we have demonstrated that concomitant over-expression of FIR and its splice variants drives NSCLC migration and dissemination. © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Hillengass J.,University of Heidelberg | Hillengass J.,German Cancer Research Center | Ayyaz S.,University of Heidelberg | Kilk K.,University of Heidelberg | And 8 more authors.
Haematologica | Year: 2012

In multiple myeloma, focal lesions, as well as diffuse and variegated infiltration patterns, can be detected by magnetic resonance imaging. In the current study, we compared treatment response in 100 myeloma patients with changes in infiltration patterns in whole body magnetic resonance imaging before and after autologous stem cell transplantation. We found an agreement between serological response and changes in imaging (P<0.001). In detail, a significant agreement of treatment response was observed for diffuse (P=0.004) as well as for focal (P=0.01) infiltration patterns. The number of focal lesions at second magnetic resonance imaging was of prognostic significance for overall survival (P=0.001). We conclude that treatment response in myeloma goes along with a decrease in imaging findings. We suggest that residual disease after high-dose chemotherapy detected by magnetic resonance imaging increases the risk of relapse. Therefore, myeloma patients with such findings after treatment might benefit from further cytoreduction. ©2012 Ferrata Storti Foundation.

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