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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; tumor ; BLOOD ; CELL ; Germany ; human ; VITRO ; NEW-YORK ; POPULATION ; PROTEIN ; cell line ; LINES ; PATIENT ; RESPONSES ; IFN-GAMMA ; DONOR ; ANTIGENS ; DENDRITIC CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; CELL-LINES ; E7 ; papillomavirus ; LIMITATION ; STIMULATION ; TARGET ; ASSAY ; cervical cancer ; CERVICAL-CANCER ; human papillomavirus ; TYPE-16 ; GENOTYPES ; HPV ; E6 ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; POPULATIONS ; ONCOPROTEIN ; VACCINE ; CANCER-PATIENTS ; CD8(+) ; ELISPOT ; EPITOPE ; EPITOPES ; IMMUNOTHERAPY ; intraepithelial neoplasia ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; E7 ONCOPROTEIN ; IMMUNOGENICITY ; TARGETS ; INTERFERON-GAMMA ; 14 HIGH-RISK ; ENZYME-IMMUNOASSAY ; HUMAN BLOOD ; immunotherapy,T cell response,cytotoxic T cell,uterine cancer,tumor infiltrating lymphocytes ; INFILTRATING LYMPHOCYTES
    Abstract: Purpose. Human papillomavirus (HPV) type 16 and 18 are the most prevalent genotypes in cervical cancers. The viral oncoproteins E6 and E7 are considered to be tumor-specific targets for immunotherapy. HPV E7 antigen-loaded dendritic cells (DC) were evaluated as cellular tumor vaccine. Methods. Autologous monocyte-derived DCs loaded with recombinant HPV16 or HPV18 E7 oncoprotein were used to induce in vitro a specific T cell response. Specificities of activated T cells were determined. Results. E7-specific T cells could be identified in 18/20 T cell lines from healthy blood donors. CD4(+) T cell responses (13/16) were found by proliferation assay. CD8(+) CTLs (12/18) were detectable by interferon-gamma (IFN-gamma) ELISpot analysis. Seven donors reacted in both assays and only 2/20 T cell lines did not react in any assay. Thus, specific T cells could be activated in 〉80% of healthy individuals. T cell lines from suitable donors were specific for HLA-A*0201-restricted epitopes. Furthermore, HPV E7 antigen-loaded DC stimulated specific responses in freshly isolated tumor infiltrating lymphocyte (TIL) populations of cervical cancer patients. Conclusion. Autologous dendritic cells loaded with HPV E7 protein can induce T cell responses in healthy individuals by in vitro stimulation and evoke responses in TIL from cervical cancer biopsies. Since there are no limitations with respect to specific HLA-haplotypes, these findings may be a basis for the development of a therapeutic protein-based DC tumor vaccine against cervical cancer for HPV16- and HPV18-positive patients
    Type of Publication: Journal article published
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  • 2
    Keywords: RECEPTOR ; CANCER ; SURVIVAL ; carcinoma ; MODEL ; THERAPY ; DIAGNOSIS ; FOLLOW-UP ; PATIENT ; IMPACT ; treatment ; BREAST ; breast cancer ; BREAST-CANCER ; PATTERNS ; CARE ; AGE ; WOMEN ; adjuvant systemic therapy ; COMORBIDITY ; GUIDELINES ; OLDER WOMEN ; REGRESSION-MODELS ; treatment recommendations
    Abstract: Purpose: To assess adherence to treatment recommendations regarding adjuvant systemic therapy of postmenopausal patients with early stage breast cancer. Methods: A population-based cohort of women from Eastern Thuringia/Germany with first diagnosis of breast cancer in 1995-2000 was studied. The use of adjuvant therapy was assessed separately for patients with positive and negative nodal status fitting polytomous logistic regression models. Results: Among 396 women with positive lymph nodes and 832 with negative lymph nodes, 92.9% and 87.3% received an adjuvant systemic treatment, respectively. Age, comorbidity, hormone receptor status. histological grading, and additionally, in nodal positives, the number of involved lymph nodes, were associated with treatment patterns. Age had the strongest impact on treatment decision. Older women more often received hormone- or no adjuvant therapy. However, 26.3% of the women with lymph node involvement and positive hormone receptor status received no hormone therapy, whereas 35.7% of women with negative hormone receptor status received hormone therapy. Conclusion: The number of patients with adjuvant systemic therapy is high in women with positive and those with negative lymph nodes, reflecting adherence to the recommendations. Better outcome could be expected if hormone therapy was used adequately in receptor positives. Further follow-up is required to monitor the outcome and changes in adherence to treatment recommendations
    Type of Publication: Journal article published
    PubMed ID: 12709795
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  • 3
    Keywords: CANCER ; CELLS ; GROWTH ; IN-VITRO ; proliferation ; tumor ; TUMOR-CELLS ; AGENTS ; CELL LUNG-CANCER ; COMBINATION ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; VITRO ; EXPOSURE ; liver ; PATIENT ; RAT ; RATS ; SEQUENCE ; RAT-LIVER ; ASSAY ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; EFFICACY ; metastases ; chemotherapy ; arteries ; CANCER-CELLS ; COLON-CANCER ; LIVER METASTASES ; BOLUS ; AGENT ; GEMCITABINE ; colon cancer ; TUMOR-GROWTH ; END ; COLON ADENOCARCINOMA ; HEPATIC METASTASES ; PHASE-II TRIAL ; STARCH MICROSPHERES ; ANIMAL-MODEL ; liver metastasis ; PEMETREXED DISODIUM ; CC531-lac-Z ; chemoembolization ; chemoluminescence ; INTRAARTERIAL CHEMOTHERAPY ; MULTITARGETED ANTIFOLATE LY231514 ; SELECTIVE CHEMOEMBOLIZATION
    Abstract: Purpose: The aim of this study was to evaluate the combination effect of pemetrexed disodium (MTA; Alimta; LY 231514) and gemcitabine ( GEM) administered by hepatic artery and portal vein chemoembolization (HACE and PVCE) in a colorectal cancer rat liver metastasis model. Materials and methods: Proliferation studies on CC531-lac-Z rat colon cancer cells were performed using the MTT assay to obtain the optimal combination schedule of the two antineoplastic agents. To generate diffuse liver metastasis, 4 x 10(6) tumor cells were implanted into the portal vein of male WAG/Rij rats. MTA ( 30 mg/kg, 60 mg/kg, and 90 mg/kg) was administered locoregionally by portal vein chemoembolization ( PVCE) and compared with repeated systemic intravenous injection. GEM ( 50 mg/kg) was also given locoregionally by hepatic artery chemoembolization ( HACE) as well as systemically. All routes of administration were examined alone as well as in combination. Efficacy of treatment in terms of liver metastases burden was determined at the end of the experiment by measuring the beta-galactosidase activity of CC531-lac-Z cells with a chemoluminescence assay. Results: Combination experiments in vitro showed a more than additive tumor cell reduction after sequential exposure to MTA preceding GEM (observed/expected ratio [O/ E] = 0.73). Experiments with the reverse sequence ( GEM. MTA) resulted only in additive combination effects ( O/ E ratio = 1.08). Simultaneous drug exposure showed less than additive combination effects (O/ E ratios 〉= 1.25). In vivo, locoregional administration by HACE with GEM was significantly more effective than systemic intravenous bolus treatment (P = 0.03). Portal vein chemoembolization with MTA performed immediately after tumor cell inoculation was ineffective. Repeated systemic treatment with MTA yielded a slight reduction in tumor cell load that was significant versus control at the medium and high doses ( 60 mg/kg, P = 0.009; 90 mg/kg, P = 0.046) but not versus intraportal chemoembolization. The combination treatment of systemic ( 60 and 90 mg/kg) or locoregional ( 60 mg/kg) MTA with HACE using GEM ( 50 mg/kg) resulted in more than 80 % tumor growth inhibition; this antineoplastic combination effect was maximally additive. Conclusion: A regimen-dependent synergistic combination effect of both drugs was found in vitro. In animals, hepatic artery chemoembolization with GEM was superior to systemic intravenous bolus treatment. Portal vein chemoembolization with MTA was ineffective. The optimal in vitro regimen of MTA ( intravenous or PVCE) preceding GEM ( HACE) resulted in a maximally additive tumor growth inhibition. The results indicate that MTA and GEM can successfully be combined and favor further evaluation in patients
    Type of Publication: Journal article published
    PubMed ID: 15657768
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  • 4
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; PATHWAY ; PATHWAYS ; FOLLOW-UP ; DISEASE ; TIME ; PATIENT ; DNA ; INFECTION ; SUSCEPTIBILITY ; LESIONS ; NEOPLASIA ; NUMBER ; WOMEN ; CERVICAL-CANCER ; HPV ; ONCOGENE ; TRANSFORMATION ; SQUAMOUS-CELL CARCINOMA ; POLYMERASE-CHAIN-REACTION ; intraepithelial neoplasia ; SERIES ; INFECTIONS ; RAPID DETECTION ; BIOPSY ; MANAGEMENT ; HUMAN-IMMUNODEFICIENCY-VIRUS ; FEATURES ; ONCOLOGY ; RE ; GRADE ; p16(INK4A) ; VIN ; ONCOGENE EXPRESSION ; P16 ; analysis ; methods ; USA ; female ; SPECIMENS ; BIOPSIES ; HPV types ; 2 SEPARATE ; AIN ; CIN ; HUMAN-PAPILLOMAVIRUS INFECTION ; multicentricity ; p16 expression ; SIMPLEX DIFFERENTIATED TYPE ; VAIN ; VULVA
    Abstract: Purpose HPV associated cervical transformation is characterized by well-defined steps, including persistent HPV infection and deregulated oncogene expression. Recent studies have suggested that a number of lower genital tract lesions are clonally related to cervical lesions. In the current study, HPV infections and oncogene expression were assessed in a large series of patients with multicentric lower genital tract disease to analyze the transformation steps in extracervical disease. Methods One hundred and thirty biopsies of 52 women treated for multicentric synchronous or metachronous lower genital tract intraepithelial neoplasias were collected. Up to seven multicentric specimens taken from one patient were studied with a maximum follow up of 20 years. HPV typing and p16(ink4a) immunostaining was performed. Results HPV DNA was present in 121 of 130 specimens (93%). HPV16 was frequently found in VIN, VaIN and AIN (73, 60 and 77%, respectively), whereas only 37% of CIN were HPV16 positive. Infections with identical HPV types in multicentric lesions were diagnosed in 46% of the HPV positive patients. p16INK4a expression was negative in the nine HPV negative lesions whereas about 90% of the high grade lesions showed diffuse p16 staining. Conlcusions Our findings indicate that multicentric lower genital tract disease evolves through different pathways. Some cases were related to a high susceptibility towards HPV infections, while others exhibited features of clonal propagation of transformed cervical cell clones. The clinical management of the latter group is particularly challenging, because malignant cell clones can persist over a long time course
    Type of Publication: Journal article published
    PubMed ID: 17294241
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  • 5
    Keywords: CANCER ; SURVIVAL ; COMBINATION ; Germany ; PERFUSION ; THERAPY ; DISEASE ; LONG-TERM ; SITE ; SURGERY ; TIME ; PATIENT ; RESPONSES ; CONTRAST ; STAGE ; TRIAL ; METASTASIS ; EFFICACY ; RATES ; chemotherapy ; MELANOMA ; FOTEMUSTINE ; METASTATIC MALIGNANT-MELANOMA ; RANDOMIZED PHASE-III ; ONCOLOGY ; RE ; tumor immunity ; methods ; USA ; retrospective ; CONTACT ; 2,4-DINITROCHLOROBENZENE ; contact dermatitis ; dinitrochlorobenzene ; DNCB ; IMMUNOCHEMOTHERAPY ; RECURRENT MELANOMA
    Abstract: Purpose To scrutinize published data from small mono-centric studies and case reports which implicated high response rates and promising survival times for a combination therapy consisting of epifocal dinitrochlorobenzene (DNCB) and dacarbazine (DTIC) for metastasized melanoma. This therapy merges the effects of an allergic contact dermatitis elicited at the site of a cutaneous metastasis, and systemic chemotherapy. Methods We performed a retrospective survey with nine German centers and evaluated 72 patients treated from 1993 to 2005. Results The objective response rate in stage III melanoma (n = 39) was 62%. In contrast, only 9% objective responses were observed in 33 stage IV patients. Interestingly, more than half of patients with objective remissions remained progression-free for more than 1 year irrespective of the stage of disease. Conclusions Epifocal DNCB combined with DTIC is effective in patients with regionally metastasized melanoma not amenable to surgery or isolated limb perfusion, whereas in stage IV disease in spite of few durable remissions the addition of DNCB does not improve the therapeutic efficacy of DTIC
    Type of Publication: Journal article published
    PubMed ID: 17334785
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  • 6
    Keywords: CANCER ; tumor ; neoplasms ; PROSTATE ; DISEASE ; DISEASES ; incidence ; NEW-YORK ; RISK ; RISKS ; GENES ; TISSUE ; TUMORS ; FAMILY ; ASSOCIATION ; BREAST ; breast cancer ; BREAST-CANCER ; LYMPHOMA ; genetics ; MELANOMA ; p53 ; DATABASE ; MUTATIONS ; familial risk ; SARCOMA ; CANCER DATABASE ; ONCOLOGY ; CHILDHOOD ; RE ; FAMILIES ; LI-FRAUMENI-SYNDROME ; methods ; USA ; population-based ; fibrosarcoma ; retinoblastoma ; LEIOMYOSARCOMA ; rhabdomyosarcoma ; soft tissue tumors ; comparison ; CANCER GENETICS ; SWEDISH
    Abstract: Purpose Reliable data on familial risks are important for clinical counseling and cancer genetics. However, population-based studies on familial soft tissue tumors are limited, which we will examine. Methods Adjusted standardized incidence ratios (SIRs), calculated from the nation-wide Swedish Family Cancer Database, were used to measure the familial risk. Results There were 17 offspring-parent pairs with concordant soft tissue tumuors, the SIR was increased but not significant. Offspring soft tissue tumors were associated with paternal prostate and endocrine gland tumors and Hodgkin's disease. Offspring myxosarcoma was associated with paternal endocrine gland tumors. Offspring fibrosarcoma was associated with parental stomach cancer and liposarcoma was associated with parental bladder cancer and maternal breast cancer. Leiomyosarcoma was associated with maternal breast cancer. The associations of myxosarcoma with melanoma and liposarcoma with non-Hodgkin's lymphoma were noted among siblings. Conclusions The present study showed that familial clustering of soft tissue tumors was limited to specific subtypes. Because of multiple comparisons, some of observed associations may be negative. Aggregation of melanoma and myxosarcoma among siblings may suggest Werner syndrome. A very small proportion of soft tissue sarcomas may be explained by Li-Fraumeni syndrome. Other novel associations, such as offspring liposarcoma with parental bladder cancer, and liposarcoma and non-Hodgkin's lyhphoma among siblings, may be related to other unidentified familial diseases
    Type of Publication: Journal article published
    PubMed ID: 17929055
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  • 7
    Keywords: CANCER ; SURVIVAL ; DISEASE ; HISTORY ; TIME ; PATIENT ; FAMILY ; prognosis ; T-CELL ; MEMBERS ; BREAST-CANCER ; LYMPHOMA ; CARE ; family history ; PROSTATE-CANCER ; leukemia ; SWEDEN ; DATABASE ; CANCER DATABASE ; non-hodgkin's lymphoma ; FOLLICULAR LYMPHOMA ; MYCOSIS-FUNGOIDES ; FAMILIES ; T-CELL LYMPHOMA ; CELL LYMPHOMA ; SUBTYPE ; WALDENSTROMS MACROGLOBULINEMIA ; HISTOLOGY ; FAMILY-HISTORY ; USA ; survival time ; hazard ratio ; SWEDISH ; 33 ; CRC ; offspring ; GRADE-3
    Abstract: Although survival has been studied for various subtypes of non-Hodgkin's lymphoma (NHL), there have been few comprehensive studies to quantify the prognosis, including all specific histologies. The effect of family history on survival in NHL has not been examined. We used the Swedish Family-Cancer Database to estimate hazard ratios in NHL by histology and family history. Using diffuse centroblastic lymphoma as reference (HR 1.0), patients with Waldenstrom's macroglobulinemia and hairy-cell leukemia had the best survival. Survival advantage was also noted among patients with lymphoplasmacytic lymphoma and different kinds of follicular lymphomas. For T-cell lymphoma, mycosis fungoides showed a favorable prognosis. As for survival by family history, a total of 98 familial cases were noted in our Database with a similar prognosis compared to sporadic cases in both parental and offspring generations. A non-significant familial concordance of either good or poor survival was noted among family members when probands' prognosis was stratified by survival time. Our results provide quantitative prognosis data for patients with NHL according to specific histologies. Patients with a familial NHL had a similar prognosis compared to patients with sporadic disease. The data suggest familial concordance in either good or poor survival among family members
    Type of Publication: Journal article published
    PubMed ID: 19533171
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  • 8
    Abstract: In binding competition assays using a protein kinase C preparation from mouse brain (particulate fraction) 3H-labelled 12-O-tetradecanoylphorbol-13-acetate (TPA), for a series of new diterpene esters (DTE) the relative binding affinity [rba = Kia(TPA)/Kia(DTE)] in relation to TPA was determined. A wide range of values was noticed, some of the DTE binding more strongly than TPA (rba greater than 1), others binding less strongly than TPA (rba less than 1) In comparative terms, competition for specific binding sites appears to correlate better with irritant than with promoting activity of the DTE. Using mouse peritoneal neutrophils, binding of [3H]-TPA was determined by a modification of the "cold-acetone filter assay"; saturation of high-affinity sites (Kda = 0.2 nM) was obtained at concentrations less than or equal to 1 nM, but there was also evidence for specific binding at "low-affinity" sites (Kda = 26 nM). Induction of chemoluminescence in the presence of luminol in mouse peritoneal neutrophils with a set of DTE usually elecited two peaks; at concentrations greater than or equal to 10 nM DTE a short-lived, "spike-like" response lasting only from 0 to about 5 min (phase A) its followed by a "plateau" response from about 5-120 min (phase B). This latter phase of chemoluminescence stimulation with luminol correlated well with the irritant potential of the DTE used. The sequence of the two phases can be inverted partially by using first TPA at 2,5 nM followed by a quick concentration increase to 100 nM; this indicates two different concentration-dependent events. As regards the intensity of the chemoluminescent response, quantitative but not qualitative differences between DTE were observed, which show some correlation with strong and weak tumour-promoting activity. Inhibition studies suggest the involvement of the myeloperoxidase/H2O2/Cl- system in the luminogenic response; it is suggested that the release of hypochlorite or a closely related oxidant may be instrumental in tumour promotion.
    Type of Publication: Journal article published
    PubMed ID: 1653779
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  • 9
    Keywords: APOPTOSIS ; GROWTH ; AGENTS ; PATHWAY ; LINES ; EFFICACY ; BONE-MARROW-CELLS ; PERIFOSINE ; Hexadecylphosphocholine ; ALKYLPHOSPHOCHOLINE DERIVATIVES
    Abstract: PURPOSE: This study investigated the antineoplastic effect of the membrane active alkylphosphocholine erufosine in breast carcinoma models in vitro and in vivo and determined its influence on the PI3K/Akt and Ras/Raf/MAPK signaling pathways. METHODS: The antiproliferative effect of erufosine in vitro was determined by the MTT dye reduction assay, and the antineoplastic efficacy on tumor growth was investigated by relating the mean total tumor volumes of treated and control rats. Immunoblot analysis was used for detecting changes in the expression level of the signal molecules p-PI3K (p-p85), p-Akt at Thr 308 and p-cRaf. RESULTS: Based on their IC(50) (40 muM, respectively), the breast carcinoma cell lines MCF-7 and MDA-MB 231, which are estrogen receptor positive and negative, respectively, were equally sensitive to erufosine. In addition, erufosine caused dose-dependent decreases in the phosphorylation of PI3K (p85), Akt (PKB) at Thr 308 and cRaf in both cell lines. Moreover, administration of erufosine to rats bearing autochthonous methylnitrosourea-induced rat mammary carcinomas caused a significant dose-related tumor remission by more than 85 % (p 〈 0.05), which was well tolerated, as evidenced by a body weight loss of maximally 7 % and reduced tumor-related mortality (2 of 35 instead of 6 of 18 controls, p 〈 0.002). CONCLUSIONS: The results clearly indicate that erufosine possesses high antineoplastic activity not only in human breast cancer cell lines in vitro but also in rat mammary carcinoma in vivo. In addition, it can be derived that the mechanism of action of erufosine involves influence on both, PI3K/Akt and Ras/Raf/MAPK signaling pathways.
    Type of Publication: Journal article published
    PubMed ID: 22752602
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  • 10
    Keywords: ANGIOGENESIS ; GROWTH ; TUMOR-CELLS ; IN-VIVO ; THERAPY ; GENE ; breast cancer ; PROSTATE-CANCER ; CANCER-CELLS ; INTEGRIN ; PERMEABILITY ; INTEGRINS ; F-18-FDG PET ; BONE METASTASES ; BREAST-CANCER CELLS ; ALPHA-V-BETA-3 ; RAT MODEL ; gene expression analysis ; Cilengitide ; THERAPEUTIC OPPORTUNITIES
    Abstract: Aim of this study was to investigate the specific treatment effects of inhibiting alpha v beta 3/alpha v beta 5 integrins by cilengitide in an animal model of breast cancer bone metastases using dynamic F-18-FDG PET and gene expression analysis. For this purpose, nude rats bearing bone metastases were treated with cilengitide, a small molecule inhibitor of alpha v beta 3 and alpha v beta 5 integrins, from day 30 to 55 after tumor cell inoculation of MDA-MB-231 breast cancer cells (25 mg/kg, 5 days per week; n = 8 rats) and compared to control rats (n = 8). Dynamic F-18-FDG PET data were assessed at days 30, 35 and 55 after tumor cell inoculation determining the vascular fraction VB and the metabolic variables k1-k4. At day 55, genome-wide mRNA expression analysis was performed to assess the treatment-specific expression changes from cilengitide-treated and control rats. In a longitudinal F-18-FDG PET study, the vascular fraction VB was significantly decreased in bone metastases between days 30/35, 30/55 and 35/55, whereas the kinetic parameters k1 and k4 were significantly decreased between days 30/55 in skeletal lesions of treated animals. Gene expression analysis from bone metastases at day 55 revealed that tumor-produced integrins (alpha v beta 5) as well as factors relevant for angiogenesis (alpha v beta 3, VEGF, PDGF), bone resorption (PTHrP and RANKL), extracellular matrix remodeling (collagen, CD44) and bone marrow microenvironment (CXCR4) were significantly reduced upon therapy with cilengitide. Here, we provide evidence that cilengitide inhibits pivotal factors of all compartments of bone metastases including tumor cells, vasculature and bone microenvironment in vivo and by whole-genome transcriptome analysis
    Type of Publication: Journal article published
    PubMed ID: 23229276
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