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  • DKFZ Publication Database  (1,288)
  • THERAPY  (1,288)
  • 1
    Keywords: PHASE-I ; THERAPY ; antibody ; B-CELL LYMPHOMA ; MELANOMA-CELLS ; SOLID TUMORS ; cancer therapeutics ; immunotoxin ; REPLICATION-DEFICIENT ; RIBONUCLEASES
    Abstract: Antibody therapy of solid cancers is well established, but suffers from unsatisfactory tumor penetration of large immunoglobulins or from low serum retention of antibody fragments. Oncolytic viruses are in advanced clinical development showing excellent safety, but suboptimal potency due to limited virus spread within tumors. Here, by developing an immunoRNase-encoding oncolytic adenovirus, we combine viral oncolysis with intratumoral genetic delivery of a small antibody-fusion protein for targeted bystander killing of tumor cells (viro-antibody therapy). Specifically, we explore genetic delivery of a small immunoRNase consisting of an EGFR-binding scFv antibody fragment fused to the RNase Onconase (ONCEGFR ) that induces tumor cell death by RNA degradation after cellular internalization. Onconase is a frog RNase that combines lack of immunogenicity and excellent safety in patients with high tumor killing potency due to its resistance to the human cytosolic RNase inhibitor. We show that ONCEGFR expression by oncolytic adenoviruses is feasible with an optimized, replication-dependent gene expression strategy. Virus-encoded ONCEGFR induces potent and EGFR-dependent bystander killing of tumor cells. Importantly, the ONCEGFR -encoding oncolytic adenovirus showed dramatically increased cytotoxicity specifically to EGFR-positive tumor cells in vitro and significantly enhanced therapeutic activity in a mouse tumor xenograft model. The latter demonstrates that ONCEGFR is expressed at levels sufficient to trigger tumor cell killing in vivo. The established ONCEGFR -encoding oncolytic adenovirus represents a novel agent for treatment of EGFR-positive tumors. This viro-antibody therapy platform can be further developed for targeted/personalized cancer therapy by exploiting antibody diversity to target further established or emerging tumor markers or combinations thereof. (c) 2014 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 25303768
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  • 2
    Keywords: THERAPY ; radiation ; LYMPHOMA ; EFFICACY ; OUTCOMES ; carbon ion radiotherapy ; SMALL-MOLECULE INHIBITOR ; C-MET ; MET AMPLIFICATION ; ALK INHIBITOR
    Abstract: Background and purpose: Non-small cell lung cancer (NSCLC) patients with chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) are sensitive to the tyrosine kinase inhibitor crizotinib. We aimed to investigate the effects of combined radiotherapy and crizotinib in ALK-positive vs. wild type NSCLC models. Material and methods: Clonogenic survival, proliferation and apoptosis of cells exposed to crizotinib and radiotherapy (photon and carbon ions) were evaluated in ALK mutation positive (ALK+; H3122) and negative (ALK-; A549 and LLC) NSCLC lines. The syngeneic mouse (LLC) and human (H3122) xenograft tumor models were further studied in vivo. Tumor growth kinetics, microvascular density (MVD), perfusion and proliferation were assessed. Results: Crizotinib exerted potent and selective anti-proliferative and pro-apoptotic effects in ALK+ H3122 cells which were augmented by radiotherapy. The synergistic effect of this combination in ALK+ NSCLC was confirmed by isobologram analysis. Crizotinib also sensitized H3122 cells to particle therapy with carbon ions. In H3122 xenografts, dual combination was most effective in reducing tumor proliferation, MVD and perfusion. In contrast, in the LLC model, crizotinib led only to a transient tumor growth inhibition and combined treatment was inferior to radiotherapy alone. Conclusions: Crizotinib elicits beneficial effects in combination with radiotherapy only in ALK-positive NSCLC.
    Type of Publication: Journal article published
    PubMed ID: 25592111
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  • 3
    Keywords: THERAPY ; UNIT ; COSTS ; cobalt
    Abstract: According to the Directory of Radiotherapy Centres (DIRAC) there are 2348 Cobalt-60 (Co-60) teletherapy units worldwide, most of them in low and middle income countries, compared to 11046 clinical accelerators. To improve teletherapy with Co-60, a mechanical Multi-Leaf Collimator (MLC) was developed, working with pneumatic pressure and thus independent of electricity supply. Instead of tungsten, brass was used as leaf material to make the mechanical MLC more affordable. The physical properties and clinical applicability of this mechanical MLC are presented here. The leakage strongly depends on the fieldsize of the therapy unit due to scatter effects. The maximum transmission through the leaves measured 2.5 cm from the end-to-end gap, within a field size of 20 cm x 30 cm defined by jaws of the therapy unit at 80 cm SAD, amounts 4.2%, normalized to an open 10 cm x 10 cm field, created by the mechanical MLC. Within a precollimated field size of 12.5 cm x 12.5 cm, the end-to-end leakage is 6.5% normalized to an open 10 cm x 10 cm field as well. This characteristic is clinically acceptable considering the criteria for non-IMRT MLCs of the International Electrotechnical Commission (IEC 60601-2-1). The penumbra for a 10 cm x 10 cm field was measured to be 9.14 mm in plane and 8.38 mm cross plane. The clinical applicability of the designed mechanical MLC was affirmed by measurements relating to all relevant clinical properties such as penumbra, leakage, output factors and field widths. Hence this novel device presents an apt way forward to make radiotherapy with conformal fields possible in low-infrastructure environments, using gantry based Co-60 therapy units.
    Type of Publication: Journal article published
    PubMed ID: 25831017
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  • 4
    Keywords: CANCER ; THERAPY ; RESPONSES ; CD8(+) T-CELLS ; BONE-MARROW-TRANSPLANTATION ; IMMUNITY ; ADHESION MOLECULE ; STEM-CELL TRANSPLANTATION ; ACUTE MYELOID-LEUKEMIA ; MEDIATED TUMOR DESTRUCTION
    Abstract: PURPOSE: The graft-versus-leukemia (GVL) reaction is an important example of immune-mediated tumor destruction. A coordinated humoral and cellular response accomplishes leukemia cell killing, but the specific targets remain largely uncharacterized. To learn more about the antigens that elicit antibodies during GVL reactions, we analyzed patients with advanced myelodysplasia (MDS) and acute myelogenous leukemia (AML) who received an autologous, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell vaccine early after allogeneic hematopoietic stem cell transplantation (HSCT). EXPERIMENTAL DESIGN: A combination of tumor-derived cDNA expression library screening, protein microarrays, and antigen-specific ELISAs were used to characterize sera obtained longitudinally from 15 patients with AML/MDS who were vaccinated early after allogeneic HSCT. RESULTS: A broad, therapy-induced antibody response was uncovered, which primarily targeted intracellular proteins that function in growth, transcription/translation, metabolism, and homeostasis. Unexpectedly, antibodies were also elicited against eight secreted angiogenic cytokines that play critical roles in leukemogenesis. Antibodies to the angiogenic cytokines were evident early after therapy, and in some patients manifested a diversification in reactivity over time. Patients that developed antibodies to multiple angiogenic cytokines showed prolonged remission and survival. CONCLUSIONS: These results reveal a potent humoral response during GVL reactions induced with vaccination early after allogeneic HSCT and raise the possibility that antibodies, in conjunction with natural killer cells and T lymphocytes, may contribute to immune-mediated control of myeloid leukemias.
    Type of Publication: Journal article published
    PubMed ID: 25538258
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  • 5
    Keywords: THERAPY ; TRANSPLANTATION ; T-CELLS ; NK cells ; CANCER-PATIENTS ; GENE-EXPRESSION ANALYSIS ; PHASE-II ; ACUTE MYELOID-LEUKEMIA ; EX-VIVO EXPANSION ; LARGE-SCALE
    Abstract: BACKGROUND AIMS: Ex vivo expansion of natural killer (NK) cells is a strategy to produce large numbers of these effector cells for immunotherapy. However, the transfer of bench-top expansion protocols to clinically applicable methods is challenging for NK cell-based therapy because of regulatory aspects and scale-up issues. Therefore, we developed an automated, large-scale NK cell expansion process. METHODS: Enriched NK cells were expanded with interleukin-2 and irradiated clinical-grade Epstein-Barr virus-transformed lymphoblastoid feeder cells with the use of an automated system in comparison to manual expansion, and the cells were investigated for their functionality, phenotype and gene expression. RESULTS: Automated expansion resulted in a mean 850-fold expansion of NK cells by day 14, yielding 1.3 (+/-0.9) x 10(9) activated NK cells. Automatically and manually produced NK cells were comparable in target cell lysis, degranulation and production of interferon-gamma and tumor necrosis factor-alpha and had similar high levels of antibody-dependent cellular cytotoxicity against rituximab-treated leukemic cells. NK cells after automated or manual expansion showed similar gene expression and marker profiles. However, expanded NK cells differed significantly from primary NK cells including upregulation of the functional relevant molecules TRAIL and FasL and NK cell-activating receptors NKp30, NKG2D and DNAM-1. Neither automatically nor manually expanded NK cells showed reduced telomere length indicative of a conserved proliferative potential. CONCLUSIONS: We established an automated method to expand high numbers of clinical-grade NK cells with properties similar to their manually produced counterparts. This automated process represents a highly efficient tool to standardize NK cell processing for therapeutic applications.
    Type of Publication: Journal article published
    PubMed ID: 25881519
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  • 6
    Keywords: SURVIVAL ; THERAPY ; WOMEN ; PROGNOSTIC-FACTORS ; 1ST RECURRENCE
    Abstract: Clinical outcome of patients with stage IV breast cancer is dependent on tumor biology, extent, and localization of metastases. Routine imaging diagnostics for distant metastasis is not recommended by the national guidelines for breast cancer follow-up. In this study, we evaluated different patterns of metastases of cancer subtypes in order to generate hypotheses on individualization of follow-up after breast cancer in the adjuvant setting. Patients of the Regional Breast Cancer Center Dresden diagnosed within the years 2006-2011 were classified into the five intrinsic subtypes luminal A (ER+, Her2-, G1/2), luminal B/Her2 negative (ER+, Her2-, G3), triple positive (ER+, PR+, Her2+), Her2-enriched (ER-, Her2+), and triple negative (ER-, PR-, Her2-) and with a median follow-up of 45 months. Tumor stage at time of first diagnosis of breast cancer as well as time and site of metastasis at first diagnosis of distant metastatic disease was analyzed. Tumor specimen of 2284 female patients with primary breast cancer was classified into five subtypes. Distant recurrence-free survival at 3 years was most unfavorable in Her2-enriched (66.8 %), triple negative (75.9 %), and triple-positive breast cancer (81.7 %). The same subtypes most frequently presented with visceral metastases only at first presentation: Her2-enriched 46.9 %, triple negative 45.5 %, and triple-positive breast cancer 37.5 %. Longest median survival of 2.3 years was seen in luminal A and in Her2-enriched metastatic disease, respectively. Median survival was significantly better in the luminal A, Her2-enriched, and triple-positive subtype compared to triple-negative breast cancer (p 〈 0.005). Differences in time to metastatic disease, first localization of metastases, and overall survival after diagnosis of metastatic disease were shown. Considering new targeted therapies and the option of surgery of oligometastases, screening for visceral metastases might be reasonable after diagnosis of Her2-positive subtypes.
    Type of Publication: Journal article published
    PubMed ID: 25783184
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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: carcinoma ; IN-VIVO ; THERAPY ; TRIAL ; FEASIBILITY ; PIG MODEL ; rectum ; TISSUE ABLATION ; ELECTRIC-FIELD ; NERVES
    Abstract: BACKGROUND: Irreversible electroporation (IRE), a new tissue ablation procedure available since 2007, could meet the requirements for ideal focal therapy (FT) with its postulated features, especially the absence of a thermal ablative effect. Thus far, there is no adequate tumor-entity-specific proof of its effectiveness, and its clinical application has hitherto been confined to very small patient cohorts. This also holds true for prostate cancer (PCA). Nevertheless, it is now being increasingly applied outside clinical trials-to a certain extent due to active advertising in the lay press. AIM OF THE STUDY: In this study, current discrepancies between the clinical application and study situation and the approval and market implementation of the procedure are described. The media portrayal of IRE is discussed from different perspectives, particularly with reference to the FT of PCA. This is followed by a final clinical assessment of IRE using the NanoKnife(R) system. DISCUSSION: Strict requirements govern new drug approvals. According to the German Drug Act (AMG), evidence of additional benefit over existing therapy must be provided through comparative clinical trials. For medicotechnical treatment procedures, on the other hand, such trial-based proof is not required according to the Medical Devices Act (MPG). The use of IRE even outside clinical trials has been actively promoted since the NanoKnife(R) system was put on the market. This has led to an increase in the number of uncontrolled IRE treatments of PCA in the last 2 years. The patients have to cover the high treatment costs themselves in these cases. If articles in the lay press advertise the procedure with promising but unverified contents, false hopes are raised in those concerned. This is disastrous if it delays the use of truly effective treatment options. CONCLUSION: IRE basically still has high potential for the treatment of malignancies; however, whether it can really be used for FT remains unclear due to the lack of data. This also holds true for the treatment of PCA. Only carefully conducted scientific research studies can clarify the unresolved issues regarding IRE of PCA. The urgently needed development of universally valid treatment standards for IRE is unnecessarily hampered by the flow commercially driven patients.
    Type of Publication: Journal article published
    PubMed ID: 26024649
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  • 9
    Keywords: THERAPY ; PROTEIN ; T-CELLS ; leukemia ; NATURAL-KILLER-CELLS ; CANCER-IMMUNOTHERAPY ; PROTOONCOGENE ; CYTOTOXIC ACTIVITY ; LINE NK-92 ; ERBB-2 RECEPTOR
    Abstract: Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Similar to T cells, NK cells can be modified to express chimeric antigen receptors (CARs) to enhance antitumor activity, but experience with CAR-engineered NK cells and their clinical development is still limited. Here, we redirected continuously expanding and clinically usable established human NK-92 cells to the tumor-associated ErbB2 (HER2) antigen. Following GMP-compliant procedures, we generated a stable clonal cell line expressing a humanized CAR based on ErbB2-specific antibody FRP5 harboring CD28 and CD3? signaling domains (CAR 5.28.z). These NK-92/5.28.z cells efficiently lysed ErbB2-expressing tumor cells in vitro and exhibited serial target cell killing. Specific recognition of tumor cells and antitumor activity were retained in vivo, resulting in selective enrichment of NK-92/5.28.z cells in orthotopic breast carcinoma xenografts, and reduction of pulmonary metastasis in a renal cell carcinoma model, respectively. ?-irradiation as a potential safety measure for clinical application prevented NK cell replication, while antitumor activity was preserved. Our data demonstrate that it is feasible to engineer CAR-expressing NK cells as a clonal, molecularly and functionally well-defined and continuously expandable cell therapeutic agent, and suggest NK-92/5.28.z cells as a promising candidate for use in adoptive cancer immunotherapy.Molecular Therapy (2014); doi:10.1038/mt.2014.219.
    Type of Publication: Journal article published
    PubMed ID: 25373520
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  • 10
    Keywords: RECEPTOR ; THERAPY ; tomography ; adenocarcinoma ; MEMBRANE ANTIGEN-EXPRESSION ; INITIAL-EXPERIENCE ; LYMPH-NODE METASTASES ; PET/MRI ; ANDROGEN-DEPRIVATION ; PRIMARY TUMOR
    Abstract: Purpose Since the introduction of positron emission tomography (PET) imaging with Ga-68-PSMA-HBED-CC (-(68)GaDKFZ-PSMA-11), this method has been regarded as a significant step forward in the diagnosis of recurrent prostate cancer (PCa). However, published data exist for small patient cohorts only. The aim of this evaluation was to analyse the diagnostic value of Ga-68-PSMA-ligand PET/CT in a large cohort and the influence of several possibly interacting variables. Methods We performed a retrospective analysis in 319 patients who underwent Ga-68-PSMA-ligand PET/CT from 2011 to 2014. Potential influences of several factors such as prostate-specific antigen (PSA) level and doubling time (DT), Gleason score (GSC), androgen deprivation therapy ADT), age and amount of injected tracer were evaluated. Histological verification was performed in 42 patients after the Ga-68-PSMA-ligand PET/CT. Tracer uptake was measured in 901 representative tumour lesions. Results In 82.8 % of the patients at least one lesion indicative of PCa was detected. Tumor-detection was positively associated with PSA level and ADT. GSC and PSA-DT were not associated with tumor-detection. The average maximum standardized uptake value (SUVmax) of tumour lesionswas 13.3 +/- 14.6 (0.7-122.5). Amongst lesions investigated by histology, 30 were false-negative in 4 different patients, and all other lesions (n=416) were true-positive or true-negative. A lesion-based analysis of sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) revealed values of 76.6 %, 100 %, 91.4 % and 100 %. A patientbased analysis revealed a sensitivity of 88.1 %. Of 116 patients available for follow-up, 50 received local therapy after Ga-68-PSMA-ligand PET/CT. Conclusion Ga-68-PSMA-ligand PET/CT can detect recurrent PCa in a high number of patients. In addition, the radiotracer is highly specific for PCa. Tumour detection is positively associated with PSA and ADT. Ga-68-PSMA-ligand PET/CT can help delay systemic therapy of PCa.
    Type of Publication: Journal article published
    PubMed ID: 25411132
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  • 11
    Keywords: ANGIOGENESIS ; ADVANCED SOLID TUMORS ; carcinoma ; ENDOTHELIAL GROWTH-FACTOR ; THERAPY ; GENE-EXPRESSION ; CELL-LINES ; adenocarcinoma ; VEGF ; tyrosine kinase inhibitors
    Abstract: Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. Methods: A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000 mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000 mg/m(2) d1 + 8 and sunitinib 50 mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). Results: The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N = 106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p = 0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p = 0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p = 0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p = 0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p = 0.045, two sided log-rank). Conclusions: The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.
    Type of Publication: Journal article published
    PubMed ID: 25459392
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  • 12
    Keywords: IN-VIVO ; THERAPY ; ACTIVATION ; GENOME-WIDE ANALYSIS ; SEVERE COMBINED IMMUNODEFICIENCY ; RETROVIRAL DNA-INTEGRATION ; VECTOR INTEGRATION ; BETA-THALASSEMIA ; VIRUS TYPE-1 ; CONSEQUENT
    Abstract: Gene therapy utilizing lentiviral-vectors (LVs) is postulated as a dynamic therapeutic alternative for monogenic diseases. However, retroviral gene transfer may cause insertional mutagenesis. Although, such risks had been originally estimated as extremely low, several reports of leukemias or clonal dominance, have led to a re-evaluation of the mechanisms operating in insertional mutagenesis. Therefore, unraveling the mechanism of retroviral integration is mandatory towards safer gene therapy applications. In the present study, we undertook an experimental approach which enabled direct correlation of the cell cycle stage of the target cell with the integration profile of LVs. CD34+ cells arrested at different stages of cell cycle, were transduced with a GFP-LV. LAM-PCR was employed for integration site detection, followed by microarray analysis to correlate transcribed genes with integration sites. The results indicate that approximately 10% of integration events occurred in actively transcribed genes and that the cell cycle stage of target cells affects integration pattern. Specifically, use of thymine promoted a safer profile, since it significantly reduced integration within cell cycle-related genes, while we observed increased possibility for integration into genes related to development, and decreased possibility for integration within cell cycle and cancer-related genes, when transduction occurs during mitosis.Molecular Therapy (2014); doi:10.1038/mt.2014.246.
    Type of Publication: Journal article published
    PubMed ID: 25523760
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  • 13
    Keywords: EXPRESSION ; THERAPY ; MARKER ; INDUCTION ; REVEALS ; PLK1 ; MELANOMAS ; BOX DOMAIN ; CANCER-CELL-PROLIFERATION ; POLO-LIKE-KINASE-3
    Abstract: The Polo-like kinase 1 (Plk1) plays a key role in regulating a broad spectrum of critical cell cycle events. Plk1 is a marker of cellular proliferation and has prognostic potential in different types of human tumors. In a series of preclinical studies, Plk1 has been validated as a cancer target. This prompted many pharmaceutical companies to develop small-molecule inhibitors targeting the classical ATP-binding site of Plk1 for anticancer drug development. Recently, FDA has granted a Breakthrough Therapy designation to the Plk inhibitor BI 6727 (volasertib), which provided a survival benefit for patients suffering from acute myeloid leukemia. Remarkably, a new generation of Plk1 inhibitors that target the second druggable domain of Plk1, the Polo-box domain, is currently being tested preclinically. Since various ATP-competitive compounds of Plk1 inhibit also the activities of Plk2 and Plk3, which act as tumor suppressors, the roles of closely related Plk-family members in cancer cells need to be considered carefully. In this article, the authors highlight recent insights into the biology of Plks in cancer cells and discuss the progress in the development of small-molecule Plk1 inhibitors. The authors believe that the greatest therapeutic benefit might come through leukemic cells that are in direct contact with the inhibitor in the blood stream. The identification of biomarkers and studies that document Plk activities in treated patients would also be beneficial to better understand the role of Plk inhibition in tumor development and anticancer therapy.
    Type of Publication: Journal article published
    PubMed ID: 25263688
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  • 14
    Keywords: EXPRESSION ; GROWTH ; THERAPY ; ASSOCIATION ; AMPLIFICATION ; resistance ; COLORECTAL-CANCER ; K-RAS ; cetuximab ; ONCOGENIC KRAS
    Abstract: KRAS mutations occur in one third of human cancers and cluster in several hotspots, with codons 12 and 13 being most commonly affected. It has been suggested that the position and type of amino acid exchange influence the transforming capacity of mutant KRAS proteins. We used MCF10A human mammary epithelial cells to establish isogenic cell lines that express different cancer-associated KRAS mutations (G12C, G12D, G12V, G13C, G13D, A18D, Q61H, K117N) at physiological or elevated levels, and investigated the biochemical and functional consequences of the different variants. The overall effects of low-expressing mutants were moderate compared to overexpressed variants, but allowed delineation of biological functions that were related to specific alleles rather than KRAS expression level. None of the mutations induced morphological changes, migratory abilities, or increased phosphorylation of ERK, PDK1, and AKT. KRAS-G12D, G12V, G13D, and K117N mediated EGF-independent proliferation, whereas anchorage-independent growth was primarily induced by K117N and Q61H. Both codon 13 mutations were associated with increased EGFR expression. Finally, global gene expression analysis of MCF10A-G13D versus MCF10A-G12D revealed distinct transcriptional changes. Together, we describe a useful resource for investigating the function of multiple KRAS mutations and provide insights into the differential effects of these variants in MCF10A cells.
    Type of Publication: Journal article published
    PubMed ID: 25705018
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  • 15
  • 16
    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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  • 17
    Keywords: THERAPY ; HEALTH ; WOMEN
    Abstract: BACKGROUND: Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. METHODS: Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. FINDINGS: During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with 〈5 years of use (RR 1.43, 95% CI 1.31-1.56; p〈0.0001). Combining current-or-recent use (any duration, but stopped 〈5 years before diagnosis) resulted in an RR of 1.37 (95% CI 1.29-1.46; p〈0.0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p〈0.0001), being definitely increased only for the two most common types, serous (RR 1.53, 95% CI 1.40-1.66; p〈0.0001) and endometrioid (1.42, 1.20-1.67; p〈0.0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1.25, 95% CI 1.07-1.46, p=0.005). INTERPRETATION: The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users. FUNDING: Medical Research Council, Cancer Research UK.
    Type of Publication: Journal article published
    PubMed ID: 25684585
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  • 18
    Keywords: brain ; CANCER ; GROWTH ; INHIBITION ; THERAPY ; ACTIVATION ; resistance ; MYELOID-LEUKEMIA ; SUBTYPES ; PROLONGS SURVIVAL
    Abstract: Glioblastoma is a highly lethal cancer for which novel therapeutics are urgently needed. Two distinct subtypes of glioblastoma stem-like cells (GSCs) were recently identified: mesenchymal (MES) and proneural (PN). To identify mechanisms to target the more aggressive MES GSCs, we combined transcriptomic expression analysis and kinome-wide short hairpin RNA screening of MES and PN GSCs. In comparison to PN GSCs, we found significant upregulation and phosphorylation of the receptor tyrosine kinase AXL in MES GSCs. Knockdown of AXL significantly decreased MES GSC self-renewal capacity in vitro and inhibited the growth of glioblastoma patient-derived xenografts. Moreover, inhibition of AXL with shRNA or pharmacologic inhibitors also increased cell death significantly more in MES GSCs. Clinically, AXL expression was elevated in the MES GBM subtype and significantly correlated with poor prognosis in multiple cancers. In conclusion, we identified AXL as a potential molecular target for novel approaches to treat glioblastoma and other solid cancers.
    Type of Publication: Journal article published
    PubMed ID: 25921812
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  • 19
    Keywords: THERAPY ; DIAGNOSIS ; LIGAND ; antibody ; PET ; Ga-68 ; ANALOGS ; MEMBRANE ANTIGEN PSMA
    Abstract: Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-containing DOTA-conjugated PSMA inhibitor has been developed. METHODS: The peptidomimetic structure was synthesized by solid-phase peptide chemistry and characterized using reversed-phase high-performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent (67/68)Ga and (177)Lu labeling resulted in radiochemical yields of greater than 97% or greater than 99%, respectively. Competitive binding and internalization experiments were performed using the PSMA-positive LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts. RESULTS: The chemically modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equilibrium dissociation constant [Ki] = 2.34 +/- 2.94 nM on LNCaP; Ki = 0.37 +/- 0.21 nM enzymatically determined) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-to-background contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compound exhibited a rapid clearance from the kidneys from 113.3 +/- 24.4 at 1 h to 2.13 +/- 1.36 percentage injected dose per gram at 24 h. The favorable pharmacokinetics of the molecule led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), respectively, 24 h after injection. CONCLUSION: The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chemical modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clinical management of prostate cancer in the future.
    Type of Publication: Journal article published
    PubMed ID: 25883127
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  • 20
    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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  • 21
    Keywords: THERAPY ; chemotherapy ; PCR ; COLON-CANCER ; microsatellite instability ; HIGH-THROUGHPUT ; K-RAS MUTATIONS ; cetuximab ; METASTATIC COLORECTAL-CANCER ; RESOLUTION MELTING ANALYSIS
    Abstract: BACKGROUND: According to current clinical guidelines mutational analysis for KRAS and NRAS is recommended prior to EGFR-directed therapy of colorectal cancer (CRC) in the metastatic setting. Therefore, reliable, fast, sensitive and cost-effective methods for routine tissue based molecular diagnostics are required that allow the assessment of the CRC mutational status in a high throughput fashion. METHODS: We have developed a custom designed assay for routine mass-spectrometric (MS) (MassARRAY((R)), Agena Bioscience) analysis to test the presence/absence of 18 KRAS, 14 NRAS and 4 BRAF mutations. We have applied this assay to 93 samples from patients with CRC and have compared the results with Sanger sequencing and a chip hybridization assay (KRAS LCD-array Kit, Chipron). In cases with discordant results, next-generation sequencing (NGS) was performed. RESULTS: MS detected a KRAS mutation in 46/93 (49 %), a NRAS mutation in 2/93 (2 %) and a BRAF mutation in 1/93 (1 %) of the cases. MS results were in agreement with results obtained by combination of the two other methods in 92 (99 %) of 93 cases. In 1/93 (1 %) of the cases a G12V mutation has been detected by Sanger sequencing and MS, but not by the chip assay. In this case, NGS has confirmed the G12V mutation in KRAS. CONCLUSIONS: Mutational analysis by MS is a reliable method for routine diagnostic use, which can be easily extended for testing of additional mutations.
    Type of Publication: Journal article published
    PubMed ID: 26220423
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  • 22
    Keywords: THERAPY ; SYSTEM ; PROTON ; DELIVERY ; dosimetry ; FLUENCE CORRECTION FACTORS
    Abstract: For regular quality assurance and patient-specific dosimetric verification under non-horizontal gantry angles in ion beam radiotherapy, we developed and commissioned a motorized solid state phantom. The phantom is set up under the selected gantry angle and moves an array of 24 ionization chambers to the measurement position by means of three eccentrically-mounted cylinders. Hence, the phantom allows 3D dosimetry at oblique gantry angles. To achieve the high standards in dosimetry, the mechanical and dosimetric accuracy of the phantom was investigated and corrections for residual uncertainties were derived. Furthermore, the exact geometry as well as a coordinate transformation from cylindrical into Cartesian coordinates was determined. The developed phantom proved to be suitable for quality assurance and 3D-dose verifications for proton- and carbon ion treatment plans at oblique gantry angles. Comparing dose measurements with the new phantom under oblique gantry angles with those in a water phantom and horizontal beams, the dose deviations averaged over the 24 ionization chambers were within 1.5%. Integrating the phantom into the HIT treatment plan verification environment, allows the use of established workflow for verification measurements. Application of the phantom increases the safety of patient plan application at gantry beam lines.
    Type of Publication: Journal article published
    PubMed ID: 26334387
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  • 23
    Keywords: THERAPY ; DIAGNOSIS ; LIGAND ; MRI ; metastases ; DISSECTION ; ANDROGEN RECEPTOR ; COMPUTERIZED-TOMOGRAPHY ; MEMBRANE ANTIGEN
    Abstract: PURPOSE: PET/CT with the PSMA ligand is a powerful new method for the early detection of nodal metastases in patients with biochemical relapse. The purpose of this retrospective investigation was to evaluate the volume and dimensions of nodes identified by Glu-urea-Lys-(Ahx)-[(68)Ga(HBED-CC)] ((68)Ga-PSMA-11) in the setting of recurrent prostate cancer. METHODS: All PET/CT images were acquired 60 +/- 10 min after intravenous injection of (68)Ga-PSMA-11 (mean dose 176 MBq). In 21 patients with recurrent prostate cancer and rising PSA, 49 PSMA-positive lymph nodes were identified. Using semiautomated lymph node segmentation software, node volume and short-axis and long-axis dimensions were measured and compared with the maximum standardized uptake values (SUVmax). Round nodes greater than or equal to 8 mm were considered positive by morphological criteria alone. The percentage of nodes identified by elevated SUVmax but not by conventional morphological criteria was determined. RESULTS: The mean volume of (68)Ga-PSMA-11-positive nodes was 0.5 ml (range 0.2 - 2.3 ml), and the mean short-axis diameter was 5.8 mm (range 2.4 - 13.3 mm). In 7 patients (33.3 %) with 31 PSMA-positive nodes only 11 (36 %) were morphologically positive based on diameters 〉8 mm on CT. In the remaining 14 patients (66.7 %), 18 (37 %) of PSMA positive lymph nodes had short-axis diameters 〈8 mm with a mean short-axis diameter of 5.0 mm (range 2.4 - 7.9 mm). Thus, in this population, (68)Ga-PSMA-11 PET/CT detected nodal recurrence in two-thirds of patients who would have been missed using conventional morphological criteria. CONCLUSION: (68)Ga-PSMA-11 PET/CT is more sensitive than CT based 3D volumetric lymph node evaluation in determining the node status of patients with recurrent prostate cancer, and is a promising method of restaging prostate cancers in this setting.
    Type of Publication: Journal article published
    PubMed ID: 26162799
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  • 24
    Keywords: radiotherapy ; THERAPY ; resistance ; COLON-CANCER ; ADHESION ; RECTAL-CANCER ; capecitabine ; cetuximab ; OPEN-LABEL ; PHASE-3 TRIAL
    Abstract: BACKGROUND AND PURPOSE: Simultaneous targeting of beta1 integrin receptor and epidermal growth factor receptor (EGFR) showed higher level of radiosensitization in head and neck cancers than monotherapies. As EGFR inhibition is similarly performed in colorectal cancer (CRC), we investigated the radiosensitizing and anti-invasive potential of beta1-integrin/EGFR inhibition in CRC cell lines grown in more physiological three-dimensional (3D) matrix-based cell cultures. MATERIALS AND METHODS: DLD-1 and HT-29 cells were used for 3D-colony formation, invasion and proliferation assays and Western blotting. beta1 integrin, focal adhesion kinase and EGFR were inhibited by AIIB2, TAE226 and Cetuximab, respectively. KRAS and BRAF knockdown were accomplished using small-interfering RNA technology. Single doses of X-rays ranged from 2Gy to 6Gy and 5-fluorouracil (5-FU) concentration was 10muM. RESULTS: Neither beta1-integrin/EGFR inhibition nor KRAS or BRAF depletion nor 5-FU significantly modified CRC cell radiosensitivity. Cetuximab, AIIB2 and Cetuximab/AIIB2 differentially modulated MAPK, JNK and AKT phosphorylation. AIIB2 and TAE226 significantly decreased cell invasion. CONCLUSIONS: Our data show inefficiency of Cetuximab and AIIB2 on top of radiochemotherapy. The functions of KRAS and BRAF in therapy resistance remain unanswered and warrant further preclinical molecular-driven investigations. One promising approach might be beta1 integrin targeting for reducing metastatic CRC cell spread.
    Type of Publication: Journal article published
    PubMed ID: 26096850
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  • 25
    Keywords: carcinoma ; COMBINATION ; THERAPY ; AMPLIFICATION ; paclitaxel ; PHASE-II TRIAL ; docetaxel ; FARNESYLTRANSFERASE INHIBITOR LONAFARNIB ; TRANSFERASE ; FARNESYLATION
    Abstract: AIM: Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ss-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib. METHODS: The influence of rs11623866 (c.-609G 〉 C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel +/- lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan-Meier analysis. RESULTS: The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HRPFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HROS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group. CONCLUSIONS: Discrepancies between preclinical success and clinical failure may be due to the patients' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response.
    Type of Publication: Journal article published
    PubMed ID: 26033044
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  • 26
    Keywords: CANCER ; MODEL ; PERFUSION ; THERAPY ; liver ; TISSUE ; BLOOD-FLOW ; NUCLEAR-MAGNETIC-RESONANCE ; WEIGHTED MRI ; B-VALUES
    Abstract: PurposeThe pseudo-diffusion coefficient D-* in intravoxel incoherent motion (IVIM) imaging was found difficult to seize. Flow-compensated diffusion gradients were used to test the validity of the commonly assumed biexponential limit and to determine not only D-*, but also characteristic timescale and velocity v of the incoherent motion. Theory and MethodsBipolar and flow-compensated diffusion gradients were inserted into a flow-compensated single-shot EPI sequence. Images were obtained from a pipe-shaped flow phantom and from healthy volunteers. To calculate the IVIM signal outside the biexponential limit, a formalism based on normalized phase distributions was developed. ResultsThe flow-compensated diffusion gradients caused less signal attenuation than the bipolar ones. A signal dependence on the duration of the flow-compensated gradients was found at low b-values in the volunteer datasets. The characteristic IVIM parameters were estimated to be v=4.600.34 mm/s and =144 +/- 10 ms for liver and v=3.91 +/- 0.54 mm/s and =224 +/- 47 ms for pancreas. ConclusionOur results strongly indicate that the biexponential limit does not adequately model the diffusion signal in liver and pancreas. By using both bipolar and flow-compensated diffusion gradients of different duration, the characteristic timescale and velocity of the incoherent motion can be determined.
    Type of Publication: Journal article published
    PubMed ID: 25116325
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  • 27
    Keywords: THERAPY ; STEM-CELL TRANSPLANTATION ; QUALITY-OF-LIFE ; GAS-EXCHANGE ; prescription ; AEROBIC EXERCISE ; MAXIMAL OXYGEN-UPTAKE ; HEART-RATE RESERVE ; PERCENT-VO2 RESERVE ; PERCENT-HRMAX
    Abstract: Objective: Exercise intervention studies during and after cancer treatment show beneficial effects for various physical and psychosocial outcomes. Current exercise intensity guidelines for cancer patients are rather general and have been adapted from American College of Sports Medicine (ACSM) recommendations for healthy individuals. Intensive cancer treatment regimens such as allogeneic hematopoietic stem cell transplantation (allo-HCT) may change the cardiovascular response to acute exercise. Therefore, we evaluated the relationships between % (V) over dotO(2) reserve (% (V) over dotO(2)R, reference) and % HRR, % HRmax, and % (V) over dotO(2max) and compared calculated intensities with given intensities by ACSM. Methods: Measurements before and 180 d after allo-HCT from a randomized controlled trial were used. Only patients who reached maximal effort and at least two exercise stages in our maximal incremental cycling test were included. Before allo-HCT, 106 patients were included, and 180 d after treatment, 49 patients met our inclusion criteria. Individual regression lines were calculated with (V) over dotO(2)R as the reference. Calculated exercise intensities for endurance training prescription were compared with ACSM values. Results: Before allo-HCT, % HRR values of patients were significantly lower than ACSM values, and % HRmax and % (V) over dotO(2max) values were significantly higher (except 90% HRmax, which was significantly lower, all P 〈 0.01). One hundred eighty days after allo-HCT, values for % HRR were not significantly different to ACSM values (except 90%, which was significantly lower, P = 0.01), whereas % HRmax and % (V) over dotO(2max) were significantly higher (all P 〈 0.05). Furthermore, regression models revealed no influence of beta-blockers on calculated intensities. Conclusions: ACSM's exercise intensity recommendations for endurance training may not be applicable for cancer patients during and 180 d after allo-HCT because they may not meet the targeted intensity class, with the exception of % HRR 180 d after allo-HCT.
    Type of Publication: Journal article published
    PubMed ID: 25202849
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  • 28
    Keywords: CANCER ; EXPRESSION ; THERAPY ; T-LYMPHOCYTES ; ANTITUMOR IMMUNITY ; FIBRILLARY ACIDIC PROTEIN ; INDUCED CELL-DEATH ; CD137 ; 4-1BB ; ANTI-CD137
    Abstract: AIMS: The prognosis of patients with malignant gliomas is still dismal despite maximum treatment. Novel therapeutic alternatives targeting tumorigenic pathways are, therefore, demanded. In murine glioma models, targeting of tumor necrosis factor receptor superfamily (TNFRSF) 9 led to complete tumor eradication. Thus, TNFRSF9 might also constitute a promising target in human diffuse gliomas. Since there is a lack of data, we aimed to define the expression pattern and cellular source of TNFRSF9 in human gliomas. METHODS: We investigated TNFRSF9 expression in normal human CNS tissue and glioma specimens using immunohistochemistry, immunofluorescence and western blotting techniques. RESULTS: Our results show that TNFRSF9 is considerably upregulated in human gliomas when compared to normal brain tissue. In addition, our data provides evidence for an immune cell-independent de novo expression pattern of TNFRSF9 in mainly non-neoplastic reactive astrocytes and excludes classic immunological cell types, namely lymphocytes and microglia as the source of TNFRSF9. Moreover, TNFRSF9 is predominantly expressed in a perivascular and peri-tumoral distribution with significantly higher expression in IDH1 mutant gliomas. CONCLUSIONS: Our findings provide a novel, TNFRSF9-positive, reactive astrocytic phenotype and challenge the therapeutic suitability of TNFRSF9 as a promising target for human gliomas.
    Type of Publication: Journal article published
    PubMed ID: 24606203
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  • 29
    Keywords: PATHWAY ; THERAPY ; MORTALITY ; RISK ; prognosis ; PROSPECTIVE COHORT ; microsatellite instability ; colonoscopy ; DRUGS ; BETA-BLOCKER USE
    Abstract: Background: Statins have been associated with moderate reductions in mortality among colorectal cancer (CRC) patients, but these studies lacked adjustment for some potentially relevant factors associated with statin use. We aimed to provide more detailed results on this association from a population-based patient cohort study. Methods: Use of statins and other risk or protective factors were assessed in standardized interviews with 2697 patients from southern Germany with a diagnosis of incident CRC between 2003 and 2009 (Darmkrebs: Chancen der Verhutung durch Screening [DACHS] study). Follow-up included assessment of therapy details, recurrence, vital status, and cause of death. Information about molecular pathological subtypes of CRC was available for 1209 patients. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). All statistical tests were two-sided. Results: Patients were age 68 years on average, 412 used statins (15%), and 769 died during follow-up (29%). After a median follow-up time of 3.4 years, use of statins was not associated with overall (HR = 1.10, 95% CI = 0.85 to 1.41), CRC-specific (HR = 1.11, 95% CI = 0.82 to 1.50), or recurrence-free survival (HR = 0.90, 95% CI = 0.63 to 1.27). Analyses in relevant subgroups also showed no association of statin use with overall and CRC-specific survival, and no associations were observed after stratifying for major pathological subtypes. Among stage I and II patients, statin use was associated with better recurrence-free but not with better CRC-specific survival. Conclusions: Statin use was not associated with reduced mortality among CRC patients. Effects reported in previous studies might reflect incomplete control for stage at diagnosis and other factors associated with the use of statins.
    Type of Publication: Journal article published
    PubMed ID: 25770147
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  • 30
    Keywords: CELLS ; THERAPY ; RESPONSES ; BREAST-CANCER ; exosomes ; CANCER BIOMARKERS ; IMAGING MASS-SPECTROMETRY
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival of 6 months. Late diagnosis due to the absence of specific symptoms during disease development, in addition to extensive metastatic potential and resistance to chemotherapy and radiotherapy, are the most important reasons for short survival. Research efforts have therefore been focused on the development of early disease detection. However, the only US FDA-approved clinical biomarker, CA19-9, is considered inapplicable for screening and/or early detection of PDAC. The following editorial provides the reader with a short introduction to the topic of PDAC and gives focus to the current state of proteomic research in the field of PDAC biomarker discovery. This editorial also highlights the efforts made to subdivide this tumor entity and the potential clinical impact of patient stratification. Finally, the author provides opinions on the impact of proteomics to PDAC subtype stratification over the next 5 years.
    Type of Publication: Journal article published
    PubMed ID: 25407217
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  • 31
    Keywords: THERAPY ; FLUOROURACIL ; OXALIPLATIN ; PROGRESSION-FREE SURVIVAL ; METASTATIC COLORECTAL-CANCER ; LEUCOVORIN ; CETUXIMAB PLUS IRINOTECAN ; PLACEBO-CONTROLLED PHASE-2 ; DIFFERENT SCHEDULES ; III NONINFERIORITY
    Abstract: Abstract Purpose. To evaluate progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) as potential surrogate endpoints (SEP) for overall survival (OS) in second-line treatment for metastatic colorectal cancer (mCRC). Methods. A systematic literature search of randomised trials of second-line chemotherapy for mCRC reported from January 2000 to July 2013 was performed. Correlation coefficients weighted by number of patients in the treatment arms between median PFS, ORR and DCR with median OS were estimated. Results. Twenty-three trials reflecting 10 800 patients met the inclusion criteria. Median PFS and OS across all trials were 4.5 months and 11.5 months and median ORR and DCR were 11.4% and 65%, respectively. PFS showed moderate correlation with OS [RPFS = 0.73; 95% confidence interval (CI) 0.61-0.82]. In contrast, ORR only weakly correlated with OS (RORR = 0.58; 95% CI 0.38-0.72, n = 22). Despite a small number of studies (n = 10) reporting on DCR, moderate correlation with OS was observed (RDCR = 0.74; 95% CI 0.56-0.86). Conclusion. Based on the available trial-level data, PFS may serve as an appropriate SEP in second-line chemotherapy for mCRC. A small number of studies revealed moderate correlation of DCR with OS that justifies further investigation.
    Type of Publication: Journal article published
    PubMed ID: 25017379
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  • 32
    Keywords: PEPTIDE ; CELLS ; THERAPY ; LIBRARIES ; ADENOASSOCIATED VIRUS TYPE-2 ; RIBOSOME DISPLAY ; TROPISM ; AAV VECTORS ; SULFATE PROTEOGLYCAN BINDING ; DARPINS
    Abstract: We describe receptor-targeted adeno-associated viral (AAV) vectors that allow genetic modification of rare cell types ex vivo and in vivo while showing no detectable off-targeting. Displaying designed ankyrin repeat proteins (DARPins) on the viral capsid and carefully depleting DARPin-deficient particles, AAV vectors were made specific for Her2/neu, EpCAM or CD4. A single intravenous administration of vector targeted to the tumour antigen Her2/neu was sufficient to track 75% of all tumour sites and to extend survival longer than the cytostatic antibody Herceptin. CD4-targeted AAVs hit human CD4-positive cells present in spleen of a humanized mouse model, while CD8-positive cells as well as liver or other off-target organs remained unmodified. Mimicking conditions of circulating tumour cells, EpCAM-AAV detected single tumour cells in human blood opening the avenue for tumour stem cell tracking. Thus, the approach developed here delivers genes to target cell types of choice with antibody-like specificity.
    Type of Publication: Journal article published
    PubMed ID: 25665714
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  • 33
    Keywords: GROWTH ; IRRADIATION ; radiotherapy ; carcinoma ; THERAPY ; DEPENDENCE ; ACCELERATED ELECTRONS ; FADU
    Abstract: The long-term goal to integrate laser-based particle accelerators into radiotherapy clinics not only requires technological development of high-intensity lasers and new techniques for beam detection and dose delivery, but also characterization of the biological consequences of this new particle beam quality, i.e. ultra-short, ultra-intense pulses. In the present work, we describe successful in vivo experiments with laser-driven electron pulses by utilization of a small tumour model on the mouse ear for the human squamous cell carcinoma model FaDu. The already established in vitro irradiation technology at the laser system JETI was further enhanced for 3D tumour irradiation in vivo in terms of beam transport, beam monitoring, dose delivery and dosimetry in order to precisely apply a prescribed dose to each tumour in full-scale radiobiological experiments. Tumour growth delay was determined after irradiation with doses of 3 and 6 Gy by laser-accelerated electrons. Reference irradiation was performed with continuous electron beams at a clinical linear accelerator in order to both validate the dedicated dosimetry employed for laser-accelerated JETI electrons and above all review the biological results. No significant difference in radiation-induced tumour growth delay was revealed for the two investigated electron beams. These data provide evidence that the ultra-high dose rate generated by laser acceleration does not impact the biological effectiveness of the particles.
    Type of Publication: Journal article published
    PubMed ID: 25600561
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  • 34
    Keywords: radiotherapy ; THERAPY ; SURGERY ; PREOPERATIVE CHEMOTHERAPY ; chemoradiation ; PHASE-II TRIAL ; RANDOMIZED CONTROLLED-TRIAL ; surgical resection ; CHEMORADIOTHERAPY ; PATHOLOGICAL COMPLETE RESPONSE
    Abstract: BACKGROUND: Outcome of consecutive patients with locally advanced non-small cell lung cancer and histopathologically proven mediastional lymph node metastases treated with induction chemotherapy, neoadjuvant radiochemotherapy and thoracotomy at the West German Cancer Center between 08/2000 and 06/2012 was analysed. A clinico-pathological prognostic model for survival was built including partial or complete response according to computed tomography imaging (CT) as clinical parameters as well as pathologic complete remission (pCR) and mediastinal nodal clearance (MNC) as histopathologic factors. METHODS: Proportional hazard analysis (PHA) and recursive partitioning analysis (RPA) were used to identify prognostic factors for survival. Long-term survival was defined as survival 〉/= 36 months. RESULTS: A total of 157 patients were treated, median follow-up was 97 months. Among these patients, pCR and MNC were observed in 41 and 85 patients, respectively. Overall survival was 56 +/- 4% and 36 +/- 4% at 24 and 60 months, respectively. Sensitivities of pCR and MNC to detect long-term survivors were 38% and 61%, specificities were 84% and 52%, respectively. Multivariable survival analysis revealed pCR, cN3 category, and gender, as prognostic factors at a level of alpha 〈 0.05. Considering only preoperative available parameters, CT response became significant. Classifying patients with a predicted hazard above the median as high risk group and the remaining as low risk patients yielded better separation of the survival curves by the inclusion of histopathologic factors than by preoperative factors alone (p 〈 0.0001, log rank test). Using RPA, pCR was identified as the top prognostic factor above clinical factors (p = 0.0006). No long term survivors were observed in patients with cT3-4 cN3 tumors without pCR. CONCLUSIONS: pCR is the dominant histopathologic response parameter and improves prognostic classifiers, based on clinical parameters. The validated prognostic model can be used to estimate individual prognosis and forms a basis for patient selection for treatment intensification.
    Type of Publication: Journal article published
    PubMed ID: 25943191
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  • 35
    Keywords: RECEPTOR ; SURVIVAL ; ENDOTHELIAL GROWTH-FACTOR ; MICROVESSEL DENSITY ; THERAPY ; MULTIPLE-MYELOMA ; PROGNOSTIC-FACTOR ; VASCULAR MORPHOGENESIS ; LEG TYPE ; TIE2 EXPRESSION
    Abstract: Primary cutaneous large B-cell lymphomas, leg type (PCLBCL/LT) are primary cutaneous B-cell lymphoma (PCBCL) with an intermediate prognosis. Therefore, antracycline-based polychemotherapy combined with rituximab has been recommended as first-line treatment. Yet, despite this regimen, the 5-year survival rate remains 50-66% only. Angiogenesis, the formation of a vascular network, is essential for the pathogenesis of nodal lymphomas. So far, no study has analysed angiogenesis and its key factors in PCLBCL/LT. The present study was aimed at characterizing angiogenesis in PCLBCL/LT to identify the angiogenic molecules as potential therapeutic targets. The intra-tumoral microvessel density (MVD) was assessed by immunohistochemical studies of CD20 and CD31. The MVD was higher in PCLBCL/LT compared with indolent PCBCL. Analyses of open-source microarray data showed correlation between the angiogenic molecule angiopoietin-2 (Ang-2) and pan-endothelial cell markers. ELISA studies determined a shift between Ang-2 and Ang-1 towards Ang-2 in the peripheral blood of PCLBCL/LT patients. Immunofluorescence costainings against the Ang receptor Tie2/angiogenic integrins/CD34 revealed that the vasculature in both aggressive and indolent PCBCL tumors harbours an endothelial cell subpopulation with reduced expression of Tie2. In contrast, the alternative Ang-2 binding partners, angiogenic integrins, are strongly expressed in PCBCL. In line with these findings, downstream targets of Ang-2-integrin signalling, that is phosphorylation of focal adhesion kinase at Tyr397, and sprouting angiogenesis are enhanced in PCLBCL/LT. Our data present Ang-2 as a promising therapeutic target and anti-angiogenic therapy as a new line in treatment of PCLBCL/LT as a hitherto intractable disease.
    Type of Publication: Journal article published
    PubMed ID: 25776770
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  • 36
    Keywords: EXPRESSION ; SURVIVAL ; THERAPY ; SITES ; TRIAL ; PROGRESSION ; AMPLIFICATION ; MARKERS ; PREDICTION
    Abstract: BACKGROUND: In metastatic breast cancer (MBC), antigen profiles of metastatic tissue and primary tumor differ in up to 20 % of patients. Reassessment of predictive markers, including human epidermal growth factor receptor 2 (HER2) expression, might help to optimize MBC treatment. While tissue sampling is invasive and often difficult to repeat, circulating tumor cell (CTC) analysis requires only a blood sample and might provide an easy-to-repeat, real-time "liquid biopsy" approach. The present retrospective study was conducted to compare HER2 expression in primary tumors, metastatic tissue, and circulating tumor cells (CTCs) from MBC patients and to analyze the potential impact of HER2 overexpression by CTCs on progression-free (PFS) and overall survival (OS) in MBC. METHODS: CTC-positive (five or more CTCs/7.5 mL blood; CellSearch(R), Janssen Diagnostics) MBC patients starting a new line of systemic treatment were eligible for the study. HER2 status of CTCs was determined by immunofluorescence (CellSearch(R)). HER2 status of primary (PRIM) and metastatic (MET) tumor tissue was determined by immunohistochemistry. Data were analyzed using descriptive statistics and Kaplan-Meier plots. RESULTS: One hundred seven patients (median age (range) 57 (33-81) years) were included. 100/107 (93 %) patients were followed-up for a median [95 % confidence interval (CI)] of 28.5 [25.1-40.1] months. Of 37/107 (35 %) CTC-HER2-positive patients only 10 (27 %) were PRIM-HER2-positive. 6/46 (13 %) patients were MET-HER2-positive; only 2/10 (20 %) CTC-HER2-positive patients were MET-HER2-positive. Overall accuracy between CTC-HER2 expression and PRIM-HER2 and MET-HER2 status was 69 % and 74 %, respectively. Kaplan-Meier plots of PFS and OS by CTC-HER2 status revealed significantly longer median [95 % CI] PFS of CTC-HER2-positive versus CTC-HER2-negative patients (7.4 [4.7-13.7] versus 4.34 [3.5-5.9] months; p = 0.035). CTC-HER2-positive status showed no significant difference for OS (13.7 [7.7-30.0] versus 8.7 [5.9-15.3] months; p = 0.287). CONCLUSIONS: HER2 status can change during the course of breast cancer. CTC phenotyping may serve as an easy-to-perform "liquid biopsy" to reevaluate HER2 status and potentially guide treatment decisions. Further, prospective studies are needed.
    Type of Publication: Journal article published
    PubMed ID: 25972110
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  • 37
    Keywords: IN-VIVO ; THERAPY ; LIVER-TRANSPLANTATION ; DRUG-INDUCED APOPTOSIS ; INHIBITORS ; PANCREATIC-CANCER ; DEPENDENT APOPTOSIS ; URSOLIC ACID ; ENDONUCLEASE-G ; BARDOXOLONE METHYL
    Abstract: Chemotherapy resistance of hepatocellular carcinoma (HCC) is still a major unsolved problem highlighting the need to develop novel therapeutic strategies. Here, we identify a novel synergistic induction of cell death by the combination of the Smac mimetic BV6, which antagonizes Inhibitor of apoptosis (IAP) proteins, and the triterpenoid oleanolic acid (OA) in human HCC cells. Importantly, BV6 and OA also cooperate to suppress long-term clonogenic survival as well as tumor growth in a preclinical in vivo model of HCC underscoring the clinical relevance of our findings. In contrast, BV6/OA cotreatment does not exert cytotoxic effects against normal primary hepatocytes, pointing to some tumor selectivity. Mechanistic studies show that BV6/OA cotreatment leads to DNA fragmentation and caspase-3 cleavage, while supply of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) revealed a cell type-dependent requirement of caspases for BV6/OA-induced cell death. The receptor interacting protein (RIP)1 kinase Inhibitor Necrostatin-1 (Nec-1) or genetic knockdown of RIP1 fails to rescue BV6/OA-mediated cell death, indicating that BV6/OA cotreatment does not primarily engage necroptotic cell death. Notably, the addition of several reactive oxygen species (ROS) scavengers significantly decreases BV6/OA-triggered cell death, indicating that ROS production contributes to BV6/OA-induced cell death. In conclusion, cotreatment of Smac mimetic and OA represents a novel approach for the induction of cell death in HCC and implicates further studies.
    Type of Publication: Journal article published
    PubMed ID: 25917078
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  • 38
    Keywords: brain ; THERAPY ; dosimetry ; MONTE-CARLO-SIMULATION ; diffraction ; Palliation ; FORTHCOMING CLINICAL-TRIALS ; MICROBEAMS
    Abstract: The aim of this study was to validate the kilovoltage X-ray energy spectrum on the ID17 beamline at the European Synchrotron Radiation Facility (ESRF). The purpose of such validation was to provide an accurate energy spectrum as the input to a computerized treatment planning system, which will be used in synchrotron microbeam radiotherapy trials at the ESRF. Calculated and measured energy spectra on ID17 have been reported previously but recent additions and safety modifications to the beamline for veterinary trials warranted a fresh investigation. The authors used an established methodology to compare X-ray attenuation measurements in copper sheets (referred to as half value layer measurements in the radiotherapy field) with the predictions of a theoretical model. A cylindrical ionization chamber in air was used to record the relative attenuation of the X-ray beam intensity by increasing thicknesses of high-purity copper sheets. The authors measured the half value layers in copper for two beamline configurations, which corresponded to differing spectral conditions. The authors obtained good agreement between the measured and predicted half value layers for the two beamline configurations. The measured first half value layer was 1.754 +/- 0.035 mm Cu and 1.962 +/- 0.039 mm Cu for the two spectral conditions, compared with theoretical predictions of 1.763 +/- 0.039 mm Cu and 1.984 +/- 0.044 mm Cu, respectively. The calculated mean energies for the two conditions were 105 keV and 110 keV and there was not a substantial difference in the calculated percentage depth dose curves in water between the different spectral conditions. The authors observed a difference between their calculated energy spectra and the spectra previously reported by other authors, particularly at energies greater than 100 keV. The validation of the beam spectrum by the copper half value layer measurements means the authors can provide an accurate spectrum as an input to a treatment planning system for the forthcoming veterinary trials of microbeam radiotherapy to spontaneous tumours in cats and dogs.
    Type of Publication: Journal article published
    PubMed ID: 26134808
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  • 39
    Keywords: SURVIVAL ; INHIBITION ; THERAPY ; EFFICACY ; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ; CYCLOOXYGENASE-2 ; PHASE-II TRIAL ; ADJUVANT TEMOZOLOMIDE ; RECURRENT MALIGNANT GLIOMA ; RADIOTHERAPY PLUS CONCOMITANT
    Abstract: Chemotherapy is often omitted in elderly patients with glioblastoma multiforme due to a fear of side effects. We applied metronomic chemotherapy with low-dose temozolomide and celecoxib (LD-TEM/CEL) during and after external beam radiotherapy (EBRT) and here report on how this regimen compares to standard temozolomide radiochemotherapy (SD-TEM) in elderly patients. We retrospectively analyzed records of 146 patients aged 65 years and older that underwent EBRT. Factors of interest were age, performance status, comorbidities, MGMT status, therapy (resection/biopsy, radiotherapy/dose, chemotherapy/regimen/dose), progression-free (PFS) and overall survival (OS) status. Irrespective of the regimen, addition of chemotherapy more than doubled median survival rates (EBRT only: 4.2 months; EBRT + LD-TEM/CEL: 8.5 months; EBRT + SD-TEM: 10.8 months; p a parts per thousand currency sign 0.008). Although patients receiving metronomic LD-TEM/CEL were significantly older (62 % were a parts per thousand yen75 years vs. 22 %; p 〈 0.001), had significantly lower performance scores (50 % had a KPS 〈 70 vs. 28 %; p = 0.049) and were significantly more comorbid (73 % had a parts per thousand yen4 comorbidities vs. 37 %; p = 0.002) than patients of the SD-TEM group, there were no significant differences in PFS and OS. Independent of other factors, omission of chemotherapy significantly impairs progression-free and overall survival. With all the limitations of a retrospective analysis, our data suggest that metronomic chemotherapy with LD-TEM/CEL may be equieffective and eventually better tolerated than SD-TEM. It may be offered to elderly patients that are not eligible for standard chemotherapy.
    Type of Publication: Journal article published
    PubMed ID: 26045360
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  • 40
    Keywords: THERAPY ; DOWN-REGULATION ; GROWTH-FACTOR RECEPTOR ; MUTATIONS ; DEGRADATION ; UBIQUITINATION ; ACQUIRED-RESISTANCE ; TYROSINE KINASES ; ubiquitylation ; ERBB FAMILY
    Abstract: Transmembrane receptors, such as the EGFR, are regulated by their turnover, which is dependent on the ubiquitin-proteasome system. We tested in two independent study cohorts whether SNPs in genes involved in EGFR turnover predict clinical outcome in cetuximab-treated metastatic colorectal cancer (mCRC) patients. The following SNPs involved in EGFR degradation were analyzed in a screening cohort of 108 patients treated with cetuximab in the chemorefractory setting: c-CBL (rs7105971; rs4938637; rs4938638; rs251837), EPS15 (rs17567; rs7308; rs1065754), NAE1 (rs363169; rs363170; rs363172), SH3KBP1 (rs7051590; rs5955820; rs1017874; rs11795873), SGIP1 (rs604737; rs6570808; rs7526812), UBE2M (rs895364; rs895374), and UBE2L3 (rs5754216). SNPs showing an association with response or survival were analyzed in BRAF and RAS wild-type samples from the FIRE-3 study. One hundred and fifty-three FOLFIRI plus cetuximab-treated patients served as validation set, and 168 patients of the FOLFIRI plus bevacizumab arm served as controls. EGFR FISH was done in 138 samples to test whether significant SNPs were associated with EGFR expression. UBE2M rs895374 was significantly associated with progression-free survival (log-rank P = 0.005; HR, 0.60) within cetuximab-treated patients. No association with bevacizumab-treated patients (n = 168) could be established (P = 0.56; HR, 0.90). rs895374 genotype did not affect EGFR FISH measurements. EGFR recycling is an interesting mechanism of secondary resistance to cetuximab in mCRC. This is the first report suggesting that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC. Mol Cancer Ther; 14(10); 2374-81. (c)2015 AACR.
    Type of Publication: Journal article published
    PubMed ID: 26206335
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  • 41
    Keywords: INVASION ; SURVIVAL ; tumor ; THERAPY ; CLASSIFICATION ; MANAGEMENT ; SOCIETY ; LUNG-CANCER PATIENTS ; CHEMORADIOTHERAPY ; SECTION CT FINDINGS
    Abstract: OBJECTIVE: To characterize the morphological computed tomography (CT) features of pulmonary squamous cell carcinomas (SQCC) submitted to therapeutic resection; to correlate these features with patients' outcomes; and to compare with pulmonary adenocarcinomas (ADC). MATERIALS AND METHODS: Two chest radiologists retrospectively evaluated CT exams of 123 patients with SQCC resected between 2002 and 2008. Tumors' size, location (central vs. peripheral), shape, margins, attenuation, enhancement, presence of calcification, cavitation, internal air bronchograms and pleural tags were assigned by consensus. Prevalence of features was compared with patients' survival data and a previously studied population of ADC surgically resected at the same time period. RESULTS: Cavitation correlated negatively with overall (hazard ratio=3.04), disease-specific (HR=3.67) and disease-free survival (HR=2.69), independent from age, gender, tumor pathological stage, size, and location. In relation to ADC, SQCC presented different shape, margins, attenuation, enhancement, with more cavitation, rare internal air bronchograms, and less pleural tags. Differences were also significant when comparing only the peripheral type of tumors. CONCLUSIONS: Cavitation at CT was an independent and negative predictive factor for SQCC. Different CT morphological features were described for SQCC and ADC. Image evaluation of lung lesions should go beyond measuring and addressing adjacent structures invasion. Adequate imaging characterization not only helps to differentiate benign versus malignant disease and to determine malignancy staging, it may also imply the histologic subtype and improve the prognostic assessment of lung cancer patients.
    Type of Publication: Journal article published
    PubMed ID: 24840477
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  • 42
    Keywords: SURVIVAL ; THERAPY ; SYSTEM ; TRIAL ; IDENTIFICATION ; chemotherapy ; MARKERS ; PERIPHERAL-BLOOD ; DISEASE PROGRESSION
    Abstract: BACKGROUND: To prospectively assess circulating tumor cell (CTC) status at baseline (CTCBL) and after one cycle of a new line of systemic therapy (CTC1C), and changes from CTCBL to CTC1C (CTC kinetics, CTCKIN) for their utility in predicting response, progression-free (PFS) and overall survival (OS) in metastatic breast cancer (MBC). METHODS: CTCBL and CTC1C status was determined as negative (-) or positive (+) for 〈 5 or 〉/= 5 CTCs/7.5 ml blood using CellSearch (Veridex). CTCKIN was categorized as favorable (CTC1C-) or unfavorable (CTC1C+). Tumor response was to be assessed every 2-3 months using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Statistical analysis focused on the relation between CTC status and CTCKIN, and response, PFS, and OS. RESULTS: 133/393 (34%) patients enrolled were CTCBL+. CTC1C status after one cycle and radiological tumor response were assessed after median (range) periods of 1.2 (0.5-3.2) and 2.9 (0.5-4.8) months, respectively. 57/201 (28%) were CTC1C+. Median [95% confidence interval] PFS and OS (months) were significantly reduced in CTCBL+ vs. CTCBL- patients (PFS 4.7 [3.7-6.1] vs. 7.8 [6.4-9.2]; OS 10.4 [7.9-15.0] vs. 27.2 [22.3-29.9]), and for CTC1C+ vs. CTC1C- patients (PFS 4.3 [3.6-6.0] vs. 8.5 [6.6-10.4]; OS 7.7 [6.4-13.9] vs. 30.6 [22.6-not available]). Unfavorable CTCKIN was significantly associated with progressive disease. Multivariate Cox regression analysis revealed prognostic factors for shorter PFS (CTCBL+, persistent CTCs after one cycle, 〉/= 3rd-line therapy, and triple-negative receptor status) and shorter OS (CTCBL+, persistent CTCs after one cycle, bone-and-visceral/local metastases, 〉/= 3rd-line therapy, and triple-negative receptor status). CONCLUSIONS: CTCBL, CTC1C, and CTCKIN are predictive of outcome in MBC. Serial CTC enumeration is useful in tailoring systemic treatment of MBC. TRIAL REGISTRATION: Not applicable.
    Type of Publication: Journal article published
    PubMed ID: 25015676
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  • 43
    Keywords: THERAPY ; DIAGNOSIS ; TRIAL ; CHILDREN ; TRENDS ; PERIOD ANALYSIS ; EMPIRICAL-EVALUATION ; UP-TO-DATE ; CANCER-PATIENT SURVIVAL ; EARLY 21ST-CENTURY
    Abstract: Background: Adulthood acute lymphoblastic leukemia (ALL) is a rare disease. In contrast to childhood ALL, survival for adults with ALL is poor. Recently, new protocols, including use of pediatric protocols in young adults, have improved survival in clinical trials. Here, we examine population level survival in Germany and the United States (US) to gain insight into the extent to which changes in clinical trials have translated into better survival on the population level. Methods: Data were extracted from the Surveillance, Epidemiology, and End Results database in the US and 11 cancer registries in Germany. Patients age 15-69 diagnosed with ALL were included. Period analysis was used to estimate 5-year relative survival (RS). Results: Overall 5-year RS was estimated at 43.4% for Germany and 35.5% for the US (p = 0.004), with a decrease in survival with increasing age. Survival was higher in Germany than the US for men (43.6% versus 37.7%, p = 0.002) but not for women (42.4% versus 40.3%, p 〉 0.1). Five-year RS estimates increased in Germany and the US between 2002 and 2006 by 11.8 and 7.3 percent units, respectively (p = 0.02 and 0.04, respectively). Conclusions: Survival for adults with ALL continues to be low compared with that for children, but a substantial increase in 5-year survival estimates was seen from 2002 to 2006 in both Germany and the US. The reasons for the survival differences between both countries require clarification.
    Type of Publication: Journal article published
    PubMed ID: 24475044
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  • 44
    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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  • 45
    Keywords: EXPRESSION ; THERAPY ; GENE ; leukemia ; MUTATIONS ; EGFR ; GEFITINIB ; LYSATE MICROARRAYS ; FACTOR RECEPTOR INHIBITORS ; DRUG SUSCEPTIBILITY
    Abstract: The reverse phase protein array (RPPA) approach was employed for a quantitative analysis of 71 cancer-relevant proteins and phosphoproteins in 84 non-small cell lung cancer (NSCLC) cell lines and by monitoring the activation state of selected receptor tyrosine kinases, PI3K/AKT and MEK/ERK1/2 signaling, cell cycle control, apoptosis, and DNA damage. Additional information on NSCLC cell lines such as that of transcriptomic data, genomic aberrations, and drug sensitivity was analyzed in the context of proteomic data using supervised and non-supervised approaches for data analysis. First, the unsupervised analysis of proteomic data indicated that proteins clustering closely together reflect well-known signaling modules, e.g. PI3K/AKT- and RAS/RAF/ERK-signaling, cell cycle regulation, and apoptosis. However, mutations of EGFR, ERBB2, RAF, RAS, TP53, and PI3K were found dispersed across different signaling pathway clusters. Merely cell lines with an amplification of EGFR and/or ERBB2 clustered closely together on the proteomic, but not on the transcriptomic level. Secondly, supervised data analysis revealed that sensitivity towards anti-EGFR drugs generally correlated better with high level EGFR phosphorylation than with EGFR abundance itself. High level phosphorylation of RB and high abundance of AURKA were identified as candidates that can potentially predict sensitivity towards the aurora kinase inhibitor VX680. Examples shown demonstrate that the RPPA approach presents a useful platform for targeted proteomics with high potential for biomarker discovery. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.
    Type of Publication: Journal article published
    PubMed ID: 24361481
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  • 46
    Keywords: CANCER ; radiotherapy ; THERAPY ; HEAD ; Protons ; MODEL-BASED APPROACH
    Abstract: BACKGROUND: Identifying those patients who have a higher chance to be cured with fewer side effects by particle beam therapy than by state-of-the-art photon therapy is essential to guarantee a fair and sufficient access to specialized radiotherapy. The individualized identification requires initiatives by particle as well as non-particle radiotherapy centers to form networks, to establish procedures for the decision process, and to implement means for the remote exchange of relevant patient information. In this work, we want to contribute a practical concept that addresses these requirements. METHODS: We proposed a concept for individualized patient allocation to photon or particle beam therapy at a non-particle radiotherapy institution that bases on remote treatment plan comparison. We translated this concept into the web-based software tool ReCompare (REmote COMparison of PARticlE and photon treatment plans). RESULTS: We substantiated the feasibility of the proposed concept by demonstrating remote exchange of treatment plans between radiotherapy institutions and the direct comparison of photon and particle treatment plans in photon treatment planning systems. ReCompare worked with several tested standard treatment planning systems, ensured patient data protection, and integrated in the clinical workflow. CONCLUSIONS: Our concept supports non-particle radiotherapy institutions with the patient-specific treatment decision on the optimal irradiation modality by providing expertise from a particle therapy center. The software tool ReCompare may help to improve and standardize this personalized treatment decision. It will be available from our website when proton therapy is operational at our facility.
    Type of Publication: Journal article published
    PubMed ID: 24548333