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Japink D.,Atrium Medical | Japink D.,Maastricht University | Nap M.,Atrium Medical | Sosef M.N.,Atrium Medical | And 5 more authors.
Journal of Immunological Methods | Year: 2014

Introduction: We have recently described epitope detection in macrophages (EDIM) by flow cytometry. This is a promising tool for the diagnosis and follow-up of malignancies. However, biological and technical validation is warranted before clinical applicability can be explored. Methods: The pre-analytic and analytic phases were investigated. Five different aspects were assessed: blood sample stability, intra-individual variability in healthy persons, intra-assay variation, inter-assay variation and assay transferability. The post-analytic phase was already partly standardized and described in an earlier study. Results: The outcomes in the pre-analytic phase showed that samples are stable for 24. h after venipuncture. Biological variation over time was similar to that of serum tumor marker assays; each patient has a baseline value. Intra-assay variation showed good reproducibility, while inter-assay variation showed reproducibility similar to that of to established serum tumor marker assays. Furthermore, the assay showed excellent transferability between analyzers. Conclusion: Under optimal analytic conditions the EDIM method is technically stable, reproducible and transferable. Biological variation over time needs further assessment in future work. © 2014 Elsevier B.V.


Bentz S.,University of Zürich | Cee A.,University of Zürich | Endlicher E.,University of Regensburg | Wojtal K.A.,University of Zürich | And 12 more authors.
Digestion | Year: 2013

Background and Aims: Transketolase-like (TKTL) 1 is one of the key enzymes for anaerobic sugar degradation even in the presence of oxygen (aerobic glycolysis). Transketolase-dependent reactions supply malignant tumors with ribose and NADPH. Therefore, TKTL1 activity could be crucial for tumor proliferation and survival. The aim of the study was to evaluate the expression of TKTL1 in colorectal cancer (CRC) and its regulation under hypoxic conditions. Methods: We studied TKTL1 mRNA and protein expression in CRC cell lines and human CRC biopsies by quantitative real-time PCR, Western blotting and immunohistochemistry. Regulation of TKTL1 under oxygen depletion was analyzed by cultivating cells either in a three-dimensional spheroid model or in a hypoxia incubator chamber. Results: TKTL1 mRNA was heterogeneously expressed in monolayers of cells with high levels in HT-29 and SW480. TKTL1 protein was also clearly detectable in HT-29 and SW480. Hypoxia-inducible factor (HIF)-1α protein expression correlated with TKTL1 protein expression in SW480 spheroids over time. On the one hand, induction of hypoxia in T84 spheroids did not induce TKTL1; on the other hand, hypoxia by incubation at 1% O2 in a hypoxia incubator chamber clearly showed an upregulation of TKTL1. In 50% of CRC patients, TKTL1 protein expression was upregulated in tumor compared to non-tumor tissue. The immunohistochemical staining of TKTL1 in CRC patient samples resulted in 14 positive and 30 negative samples. Conclusions: TKTL1 expression correlated with HIF-1α protein expression and was induced upon hypoxic conditions which could facilitate energy supply to tumors under these circumstances. © 2013 S. Karger AG, Basel.


von Karstedt S.,University College London | Conti A.,University College London | Conti A.,Fondazione IRCCS Instituto Nazionale dei Tumori | Nobis M.,Beatson Institute for Cancer Research | And 32 more authors.
Cancer Cell | Year: 2015

Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and invivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients. © 2015 Elsevier Inc.


Rieger J.,Goethe University Frankfurt | Rieger J.,University of Tübingen | Bahr O.,Goethe University Frankfurt | Maurer G.D.,Goethe University Frankfurt | And 10 more authors.
International Journal of Oncology | Year: 2014

Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20 patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients (15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6 weeks. Median PFS of all patients was 5 (range, 3-13) weeks, median survival from enrollment was 32 weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was 20.1 (range, 12-124) weeks, for a PFS at 6 months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (p<0.05). In conclusion, a ketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma. Further clinical trials are necessary to clarify whether calorie restriction or the combination with other therapeutic modalities, such as radiotherapy or anti-angiogenic treatments, could enhance the efficacy of the ketogenic diet.


PubMed | University of Tübingen, University of Würzburg, Tavarlin AG, Johannes Gutenberg University Mainz and 2 more.
Type: Clinical Trial | Journal: International journal of oncology | Year: 2014

Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients(15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6weeks. Median PFS of all patients was 5 (range,3-13)weeks, median survival from enrollment was 32weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was20.1 (range, 12-124) weeks, for a PFS at 6months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (p<0.05). In conclusion, a ketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma. Further clinical trials are necessary to clarify whether calorie restriction or the combination with other therapeutic modalities, such as radiotherapy or anti-angiogenic treatments, could enhance the efficacy of the ketogenic diet.


Grimm M.,University Hospital of Tuebingen | Schmitt S.,German Cancer Research Center | Teriete P.,Sanford Burnham Institute for Medical Research | Biegner T.,University Hospital of Tuebingen | And 11 more authors.
BMC Cancer | Year: 2013

Background: Biomarkers allowing the characterization of malignancy and therapy response of oral squamous cell carcinomas (OSCC) or other types of carcinomas are still outstanding. The biochemical suicide molecule endonuclease DNaseX (DNaseI-like 1) has been used to identify the Apo10 protein epitope that marks tumor cells with abnormal apoptosis and proliferation. The transketolase-like protein 1 (TKTL1) represents the enzymatic basis for an anaerobic glucose metabolism even in the presence of oxygen (aerobic glycolysis/Warburg effect), which is concomitant with a more malignant phenotype due to invasive growth/metastasis and resistance to radical and apoptosis inducing therapies.Methods: Expression of Apo10 and TKTL1 was analysed retrospectively in OSCC specimen (n = 161) by immunohistochemistry. Both markers represent independent markers for poor survival. Furthermore Apo10 and TKTL1 have been used prospectively for epitope detection in monocytes (EDIM)-blood test in patients with OSCC (n = 50), breast cancer (n = 48), prostate cancer (n = 115), and blood donors/controls (n = 74).Results: Positive Apo10 and TKTL1 expression were associated with recurrence of the tumor. Multivariate analysis demonstrated Apo10 and TKTL1 expression as an independent prognostic factor for reduced tumor-specific survival. Apo10+/TKTL1+ subgroup showed the worst disease-free survival rate in OSCC.EDIM-Apo10 and EDIM-TKTL1 blood tests allowed a sensitive and specific detection of patients with OSCC, breast cancer and prostate cancer before surgery and in after care. A combined score of Apo10+/TKTL1+ led to a sensitivity of 95.8% and a specificity of 97.3% for the detection of carcinomas independent of the tumor entity.Conclusions: The combined detection of two independent fundamental biophysical processes by the two biomarkers Apo10 and TKTL1 allows a sensitive and specific detection of neoplasia in a noninvasive and cost-effective way. Further prospective trials are warranted to validate this new concept for the diagnosis of neoplasia and tumor recurrence. © 2013 Grimm et al.; licensee BioMed Central Ltd.


Feyen O.,TAVARLIN AG | Coy J.F.,TAVARLIN AG | Prasad V.,Center for Molecular Imaging | Prasad V.,Charite University Hospital | And 3 more authors.
Future Oncology | Year: 2012

Aim: To determine whether the TKTL1 protein epitope detection in monocytes (EDIM) test allows detection of upregulated glucose metabolism in malignancies. Materials & methods: The EDIM-TKTL1 blood test was conducted in 240 patients with 17 different confirmed or suspected malignancies. Test scores were compared with 18F-fluoro-2-deoxy-D-glucose (FDG)-PET/computed tomography (CT) results. Results: EDIM-TKTL1 score and FDG-PET results showed a concordance of 90% with a sensitivity of 94% and specificity of 81%. Including CT data, all values were enhanced. A subgroup analysis of non-small-cell lung cancer patients showed a significant correlation between the EDIM-TKTL1 score and the primary tumor size determined by FDG-PET/CT. Conclusion: EDIM-TKTL1 blood test revealed good concordance with FDG-PET/CT results in patients with malignancies demonstrating its efficacy to detect upregulation of glucose metabolism in primary tumors or metastases. © 2012 Oliver Feyen.


Fritz P.,Robert Bosch GmbH | Fritz P.,Institute For Digitale Medizin Stuttgart San Franzisco | Coy J.F.,TAVARLIN AG | Murdter T.E.,Robert Bosch GmbH | And 3 more authors.
Pathology Research and Practice | Year: 2012

Study of the physiological changes associated with the development of malignancy demonstrates a metabolic signature for the different stages of tumorigenesis. Increased glucose uptake and lactate production have been detected during malignant transformation. Based on energy production, malignancies can be divided into two subclasses: (a) tumor cells which use the mitochondrial machinery for ATP synthesis, and (b) tumor cells which generate ATP by glucose fermentation and lactate production even in the presence of oxygen (aerobic glycolysis). Recently, transketolase-like protein 1 (TKTL1) gene expression has been shown to contribute to carcinogenesis through increased aerobic glycolysis and hypoxia-inducible factor alpha stabilization. In the present study, 197 patients suffering from lung cancer were investigated by immunohistochemistry for the presence of TKTL1 protein expression. We detected: (1) moderate to strong TKTL1 expression (immune reactive score. >. 100) in 39.1% of the investigated lung cancer patients; (2) a complete lack of TKTL1 by immunohistochemistry in 12.7% of lung cancer cases, with small cell lung cancer (SCLC) being most frequent in this subgroup; (3) no correlation of TKTL1 with overall survival, disease-free survival, any of the established variables of the TNM system, grading, stage, smoking status, or gender. Based on this data, we conclude that TKTL1 could be a target protein for improved therapeutic strategies in some cases of lung cancer. © 2012 Elsevier GmbH.


Jansen N.,General Practitioner | Coy J.F.,TAVARLIN AG
Future Oncology | Year: 2013

A follow-up strategy in cancer aftercare can result in early detection of metastasis and/or recurrence. Therefore, sensitive and reliable diagnostic tests that are easy to perform are needed. Here, the authors present the combined use of the epitope detection in monocytes (EDIM)-TKTL1 and EDIM-Apo10 blood test in aftercare monitoring of a patient with colon carcinoma. Whereas the established tumor markers CEA and CA19-9 did not indicate metastasis even at a timepoint where clinical signs and imaging techniques already demonstrated metastasis, the combined application of the EDIM-TKTL1 and the EDIM-Apo10 blood tests was positive 9 months before detection of metastasis. These findings - taken together with recently published evaluation data of the EDIM-TKTL1 blood test - suggest that the combined application of the EDIM-TKTL1 and the EDIM-Apo10 blood tests might indicate metastasis earlier than established tumor markers and could serve as sensitive and noninvasive methods that might be used for early detection of colon cancer metastasis. © 2013 Future Medicine Ltd.

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