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  • DKFZ Publication Database  (1,580)
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Keywords
  • 1
    Keywords: tumor ; PATIENT ; ANTIGENS ; MEMORY ; VACCINES ; vaccination ; CANCER-IMMUNOTHERAPY ; CD4(+) T-CELLS ; ADVANCED MELANOMA ; IPILIMUMAB
    Abstract: The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell-based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T-cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of tumor-associated T-cell antigens based on their exclusive and frequent representation in the HLA ligandome of leukemic cells. These antigens were validated across different stages and mutational subtypes of CLL and found to be robustly represented in HLA ligandomes of patients undergoing standard chemo-/immunotherapy. We demonstrate specific immune recognition of these antigens exclusively in CLL patients, with the frequencies of representation in CLL ligandomes correlating with the frequencies of immune recognition by patient T cells. Moreover, retrospective survival analysis revealed survival benefits for patients displaying immune responses to these antigens. These results directly imply these nonmutant self-peptides as pathophysiologically relevant tumor antigens and encourages their implementation for cancer immunotherapy.
    Type of Publication: Journal article published
    PubMed ID: 25548167
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  • 2
    Keywords: RNA ; PATIENT ; TISSUES ; BREAST-CANCER ; IN-SITU ; resistance ; EVOLUTION ; SINGLE CELLS ; INTRATUMOR HETEROGENEITY ; CHALLENGE
    Abstract: The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. Nature Medicine, Nature Biotechnology and the Volkswagen Foundation organized a meeting focused on identifying the obstacles that need to be overcome to advance translational research in and tumor heterogeneity. Once these key questions were established, the attendees devised potential solutions. Their ideas are presented here.
    Type of Publication: Journal article published
    PubMed ID: 26248267
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  • 3
    Keywords: LUNG ; PATIENT ; DNA ; ASSOCIATION ; p53 ; SQUAMOUS-CELL CARCINOMA ; HUMAN-PAPILLOMAVIRUS TYPE-11 ; JUVENILE LARYNGOTRACHEAL PAPILLOMATOSIS ; LARYNGEAL PAPILLOMAS
    Abstract: BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a rare disease, which is characterised by the growth of papillomavirus-induced papillomas within the respiratory tract. Malignant transformation occurs in less than 1% of the cases. CASE PRESENTATION: We report a case of human papillomavirus (HPV) type 11-associated juvenile-onset RRP (JORRP) initially diagnosed at the age of two years. Remarkably high copy numbers of HPV11 DNA and antibody titres targeting the capsid protein L1 were detected in the patient's serum. The patient developed squamous cell carcinomas in both lungs and extraordinarily an HPV11 DNA-positive papillary endocardial lesion in the left atrium of the heart, which caused thromboembolic events leading to the patient's death at 19 years old. CONCLUSION: We here report a severe case of JORRP hallmarked by HPV11 DNAemia and very high antibody titres directed against the major viral capsid protein L1. Furthermore, the extent of malignant transformation and the discovery of a very rare fatal endocardial lesion highlight the unpredictability of JORRP and the complexity of its clinical management.
    Type of Publication: Journal article published
    PubMed ID: 24942884
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  • 4
    Keywords: THERAPY ; SYSTEM ; RESOLUTION ; PATIENT ; CALIBRATION ; stopping power ; DETECTOR ; CT-HOUNSFIELD UNITS ; PROTON COMPUTED-TOMOGRAPHY
    Abstract: Ion beams offer an excellent tumor-dose conformality due to their inverted depth-dose profile and finite range in tissue, the Bragg peak (BP). However, they introduce sensitivity to range uncertainties. Imaging techniques play an increasingly important role in ion beam therapy to support precise diagnosis and identification of the target volume at the planning stage as well as to ensure the correspondence between the planning and treatment situation at the actual irradiation. For the purpose of improved treatment quality, ion-based radiographic images could be acquired at the treatment site before or during treatment and be employed to monitor the patient positioning and to check the patient-specific ion range. This work presents the initial experimental investigations carried out to address the feasibility of carbon ion radiography at the Heidelberg ion therapy center using a prototype range telescope set-up and an active raster scanning ion beam delivery system. Bragg curves are measured with a stack of ionization chambers (IC) synchronously to the beam delivery. The position of the BP is extracted from the data by locating the channel of maximum current signal for each delivered beam. Each BP is associated to the lateral and vertical positions of the scanned raster point extrapolated from the beam monitor system to build up a radiography. The radiographic images are converted into water equivalent thickness (WET) based on two calibrations of the detector. Radiographies of two phantoms of different complexities are reconstructed and their image quality is analyzed. A novel method proposed to increase the nominal range resolution of the IC stack is applied to the carbon ion radiography of an Alderson head phantom. Moreover, an x-ray digitally reconstructed radiography of the same anthropomorphic head phantom is converted in WET through the clinically used ion range calibration curve and compared with the carbon ion radiography based on a gamma-index approach, yielding a good correspondence in terms of absolute WET within +/-3%, 3 mm distance-to-agreement and, 87% passing ratio. Imaging artifacts at interfaces within the irradiated phantom due to the finite size of the beam, resulting in multiple maxima, are addressed. Overall, this work demonstrates the feasibility of the prototype range telescope to acquire ion-based transmission imaging with a resolution of up to 0.8 mm WET.
    Type of Publication: Journal article published
    PubMed ID: 24842455
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  • 5
    Keywords: PATIENT ; radiography ; CT-HOUNSFIELD UNITS ; PROTON COMPUTED-TOMOGRAPHY ; HEAVY-ION CT ; DETECTOR SYSTEM ; THERAPY CENTER
    Abstract: A detector prototype based on a stack of 61 parallel-plate ionisation chambers (PPIC) interleaved with absorber plates of polymethyl methacrylate (PMMA) was assembled for transmission imaging purposes in ion beam therapy. The thickness of the absorber sheets in the PPIC stack determines the nominal range resolution of the detector. In the current set-up, 3 mm PMMA slabs are used. The signal of the 61 active channels of the stack thereby provides a discrete approximation of the Bragg curve in the detector. In this work, a data processing method to increase the range resolution (MIRR) in a stack of ionization chambers is presented. In the MIRR the position of the maximum of the Bragg curve is deduced from the ratio of measured signals in adjacent PPIC channels. The method is developed based on Bragg curves obtained from Monte Carlo simulations and validated with experimental data of a wedge-shaped PMMA phantom acquired with the PPIC stack using carbon ion beams. The influence of the initial beam energy and of phantom inhomogeneities on the MIRR is quantitatively evaluated. Systematic errors as well as inaccuracies related to signal noise are discussed and quantified. It is shown that with the MIRR an increased range resolution of 0.7 mm PMMA equivalent or 0.8 mm water equivalent thickness is achieved for the considered experimental data.
    Type of Publication: Journal article published
    PubMed ID: 25170567
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  • 6
    Keywords: PATIENT ; VERIFICATION ; COMPUTED-TOMOGRAPHY ; PET ; TUMOR-THERAPY ; CT-HOUNSFIELD UNITS
    Abstract: Ion beams exhibit a finite range and an inverted depth-dose profile, the Bragg peak. These favorable physical properties allow excellent tumor-dose conformality. However, they introduce sensitivity to range uncertainties. Although these uncertainties are typically taken into account in treatment planning, delivery of the intended dose to the patient has to be ensured daily to prevent underdosage of the tumor or overdosage of surrounding critical structures. Thus, imaging techniques play an increasingly important role for treatment planning and in situ monitoring in ion beam therapy. At the Heidelberg Ion Beam Therapy (HIT) center, a prototype detector system based on a stack of 61 ionization chambers has been assembled for the purpose of radiographic and tomographic imaging of transmitted energetic ions. Its applicability to ion-based transmission imaging was investigated experimentally. An extensive characterization of the set-up in terms of beam parameters and settings of the read-out electronics was performed. Overall, the findings of this work support the potential of an efficient experimental set-up as the range telescope equipped with high sensitivity and fast electronics to perform heavy ion radiography and tomography at HIT.
    Type of Publication: Journal article published
    PubMed ID: 23296259
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  • 7
    Keywords: CELLS ; THERAPY ; RISK ; PATIENT ; INVOLVEMENT ; RECEPTORS ; TRAIL ; LANSOPRAZOLE ; STEVENS-JOHNSON-SYNDROME
    Abstract: BACKGROUND: Here, we report the first case of patient with intracranial tumors (ICT) who developed a cutaneous adverse drug reaction during lansoprazole and prophylactic anticonvulsant treatment. SCORTEN is a scoring system used to predict mortality in TEN patients. If SCORTEN index is 5 or more, mortality rate is more than 90%. SCORTEN of our patient was calculated as 5. METHODS: Our patient is a 64 year-old white female, who had glioma and had been on post-op prophylactic anticonvulsant therapy. On the 3rd day post operation, lansoprazole was added to the therapy. After the first lansoprazole dose, erythematous dusky red macules occurred on extremities and trunk and on the following day confluent purpuric lesions tended to run together in 95% of the whole body including scalp, oral and genital mucosa. Nikolsky's Sign was positive on the skin. Physical examination; body temperature was 38.4 degrees C with a heart rate of 146 beats/minute and 80/50 mm Hg arterial blood pressure, Glascow Coma Scale was E1 M1e, pupillary light reflex was 2/2 +/+ and she was confused. Her biopsy resulted as toxic epidermal necrolysis. Moreover, sTRAIL and sCD200 levels of serum and blister fluid were investigated as an apoptotic marker and a negative marker for inflammation. RESULTS AND CONCLUSIONS: sTRAIL and sCD200 were evaluated both in the sera and blister fluid. sTRAIL level was lower than for healthy individuals with high levels in blister fluid; and sCD200 level was depressed by up to 10% of the normal values of healthy individuals but with high levels in the blister fluid during the active phase of the disease. After our successful treatment with human albumin, prednisolone pulse therapy, and IVIG at a dose of 400 mg/kg, she was discharged from the hospital on the 23rd day and followed up after 2 months. The increase in sTRAIL (up to two-fold) and sCD200 (up to six-fold) levels may provide useful information in understanding disease pathogenesis and monitoring treatment efficacy.
    Type of Publication: Journal article published
    PubMed ID: 23865370
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  • 8
    Keywords: PATIENT ; MESSENGER-RNA ; T-CELLS ; SUPPRESSION ; MELANOMA ; MUTATIONS ; PEPTIDES ; IMMUNOTHERAPY ; intraepithelial neoplasia ; RESISTANT PROSTATE-CANCER
    Abstract: Every cancer is different and cancer cells differ from normal cells, in particular, through genetic alterations. HLA molecules on the cell surface enable T lymphocytes to recognize cellular alterations as antigens, including mutations, increase in gene product copy numbers or expression of genes usually not used in the adult organism. The search for cancer-associated antigens shared by many patients with a particular cancer has yielded a number of hits used in clinical vaccination trials with indication of survival benefit. Targeting cancer-specific antigens, which are exclusively expressed on cancer cells and not on normal cells, holds the promise for much better results and perhaps even a cure. Such antigens, however, may specifically appear in very few patients or may be mutated appearing just in one patient. Therefore, to target these in a molecularly defined way, the approach has to be individualized.
    Type of Publication: Journal article published
    PubMed ID: 24090147
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  • 9
    Keywords: GROWTH ; PATIENT ; RESPONSES ; SIMULATION ; FLOW ; VELOCITY ; thrombus ; RUPTURE ; WALL SHEAR-STRESS
    Abstract: Objectives: To evaluate hemodynamic changes during aneurysmal dilatation in chronic type B aortic dissections compared to hemodynamic parameters in the healthy aorta with the use of computational fluid dynamics (CFD). Methods: True lumen (TL)/false lumen (FL) dimensional changes, changes in total pressure (TP), and wall shear stress (WSS) were evaluated at follow-up (FU) compared to initial examination (IE) with transient CFD simulation with geometries derived from clinical image data and inflow boundary conditions from magnetic resonance images. The TL/FL pressure gradient between ascending and descending aorta (DAo) and maximum WSS at the site of largest dilatation was compared to values for the healthy aorta. Results: Hemodynamic changes at site of largest FL dilatation included 77% WSS reduction and 69% TP reduction. Compared to the healthy aorta, pressure gradient between ascending and DAo was a factor of 1.4 higher in the TL and a factor of 1.5 in the FL and increased at FU (1.6 and 1.7, respectively). Maximum WSS at the site of largest dilatation was a factor of 3 lower than that for the healthy aorta at IE and decreased by more than a factor of 2 at FU. Conclusions: The FL dilatation at FU favorably reduced TP. In contrast, unfavorable increase in pressure gradient between ascending and DAo was observed with higher values than in the healthy aorta. Maximum WSS was reduced at the site of largest dilation compared to healthy aorta.
    Type of Publication: Journal article published
    PubMed ID: 24048257
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  • 10
    Keywords: CANCER ; SURVIVAL ; LUNG ; LUNG-CANCER ; EPIDEMIOLOGY ; incidence ; liver ; POPULATION ; SITES ; TIME ; PATIENT ; prognosis ; IDENTIFICATION ; RATES ; metastases ; SWEDEN ; adenocarcinoma ; INCIDENCE RATES ; TRENDS ; BIRTH COHORT ; PRIMARY TUMORS ; REGISTRIES ; sex ; PRIMARY-CARCINOMA ; PRIMARY SITE ; cancer of unknown primary ; causes of death ; CONSECUTIVE PATIENTS
    Abstract: Time trends in incidence, causes of death, and prognosis of cancer of unknown primary (CUP) could provide important clues for occult primary sites and thus result in effective organ-specific treatment, although such studies are seldom reported. We aimed at examining time trends in percentage and incidence rates, causes of death, and survival of CUP. A total of 50 545 patients with CUP were identified in the Swedish Cancer Registry from 1960 to 2008. We used direct standardization to standardize age-adjusted incidence rate to the Segi world population. Consistent increase before the late 1990s and dramatic decrease afterward was observed for both percentage and incidence of CUP in Swedes regardless of sex. Comparable time trends were noted in Norwegian and Finnish populations, but with several years earlier peaking times. For most anatomic sites, CUP and lung cancer were the two most common causes of death for patients with CUP irrespective of nodal involvement. Survival probability at 12 months after CUP was approximately 20% and then leveled off at approximately 10%. Adenocarcinoma accounted for most of this incidence variation and experienced the worst prognosis. High incidence rates and comparable time trends for CUP were observed in Sweden, Norway, and Finland. The increasing time trends may partially reflect the change of autopsy rates in these countries. The decreased incidence in the last decade could be due to an increasing identification of unknown primary caused by improving diagnostic methods. Histological types were significantly associated with survival in patients with CUP.
    Type of Publication: Journal article published
    PubMed ID: 21968687
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  • 11
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; carcinoma ; SYSTEM ; GENE ; GENE-EXPRESSION ; GENES ; transcription ; LINES ; TIME ; PATIENT ; ACTIVATION ; BREAST ; BREAST-CANCER ; CARCINOMA CELLS ; COLORECTAL CANCERS ; CARCINOMA-CELLS ; ESTROGEN-RECEPTOR ; ESTROGEN ; RESISTANT ; SYNTHETIC LETHALITY ; ANTICANCER THERAPY ; IRES
    Abstract: Within the large group of Estrogen Receptor alpha (ER alpha)-negative breast cancer patients, there is a subgroup carrying the phenotype ER alpha(-), PR-, and Her2(-), named accordingly "Triple-Negative'' (TN). Using cell lines derived from this TN group, we wished to establish cell clones, in which ER alpha is ectopically expressed, forming part of a synthetic lethality screening system. Initially, we generated cell transfectants expressing a mono-cistronic ER alpha transcription unit, adjacent to a separate dominant selectable marker transcription unit. However, the yield of ER alpha expressing colonies was rather low (5-12.5%), and only about half of these displayed stable ectopic ER alpha expression over time. Generation and maintenance of such cell clones under minimal exposure to the ER alpha ligand, did not improve yield or expression stability. Indeed, other groups have also reported grave difficulties in obtaining ectopic expression of ER alpha in ER alpha-deficient breast carcinoma cells. We therefore switched to transfecting these cell lines with pER alpha-IRES, a plasmid vector encoding a bicistronic translation mRNA template: ER alpha Open Reading Frame (ORF) being upstream followed by a dominant-positive selectable marker (hygro(R)) ORF, directed for translation from an Internal Ribosome Entry Site (IRES). Through usage of this bicistronic vector linkage system, it was possible to generate a very high yield of ER alpha expressing cell clones (50-100%). The stability over time of these clones was also somewhat improved, though variations between individual cell clones were evident. Our successful experience with ER alpha in this system may serve as a paradigm for other genes where ectopic expression meets similar hardships
    Type of Publication: Journal article published
    PubMed ID: 22363779
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  • 12
    Keywords: EXPRESSION ; COHORT ; RISK ; GENE ; GENES ; PATIENT ; INFECTION ; DENDRITIC CELLS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; IMMUNE-RESPONSES ; SNP ; STEM-CELL TRANSPLANTATION ; PROMOTER POLYMORPHISM ; CRITERIA ; BETA-GLUCAN RECEPTOR ; FUMIGATUS CONIDIA ; GENE-GENE INTERACTIONS ; MCP-1 EXPRESSION ; MULTIFACTOR DIMENSIONALITY REDUCTION ; VIRUS TYPE-1 INFECTION
    Abstract: The recognition of pathogen-derived structures by C-type lectins and the chemotactic activity mediated by the CCL2/CCR2 axis are critical steps in determining the host immune response to fungi. The present study was designed to investigate whether the presence of single nucleotide polymorphisms (SNPs) within DC-SIGN, Dectin-1, Dectin-2, CCL2 and CCR2 genes influence the risk of developing Invasive Pulmonary Aspergillosis (IPA). Twenty-seven SNPs were selected using a hybrid functional/tagging approach and genotyped in 182 haematological patients, fifty-seven of them diagnosed with proven or probable IPA according to the 2008 EORTC/MSG criteria. Association analysis revealed that carriers of the Dectin-1(rs3901533) (T/T) and Dectin-1(rs7309123) (G/G) genotypes and DC-SIGN(rs4804800) (G), DC-SIGN(rs11465384) T, DC-SIGN(7248637 A) and DC-SIGN(7252229) (C) alleles had a significantly increased risk of IPA infection (OR = 5.59 95% CI 1.37-22.77; OR = 4.91 95% CI 1.52-15.89; OR = 2.75 95% CI 1.27-5.95; OR = 2.70 95% CI 1.24-5.90; OR = 2.39 95% CI 1.09-5.22 and OR = 2.05 95% CI 1.00-4.22, respectively). There was also a significantly increased frequency of galactomannan positivity among patients carrying the Dectin-1(rs3901533_T) allele and Dectin-1(rs7309123_G/G) genotype. In addition, healthy individuals with this latter genotype showed a significantly decreased level of Dectin-1 mRNA expression compared to C-allele carriers, suggesting a role of the Dectin-1(rs7309123) polymorphism in determining the levels of Dectin-1 and, consequently, the level of susceptibility to IPA infection. SNP-SNP interaction (epistasis) analysis revealed significant interactions models including SNPs in Dectin-1, Dectin-2, CCL2 and CCR2 genes, with synergistic genetic effects. Although these results need to be further validated in larger cohorts, they suggest that Dectin-1, DC-SIGN, Dectin-2, CCL2 and CCR2 genetic variants influence the risk of IPA infection and might be useful in developing a risk-adapted prophylaxis
    Type of Publication: Journal article published
    PubMed ID: 22384201
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  • 13
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; carcinoma ; SYSTEM ; PROTEIN ; PATIENT ; COMPLEX ; DOMAIN ; ANTIGEN ; BREAST-CANCER ; antibodies ; antibody ; FORM ; PLASMA ; COLORECTAL-CANCER ; adenocarcinoma ; tumor marker ; AUTOANTIBODIES ; SERUM ; ELISA ; colon cancer ; OSTEOPONTIN ; EpCAM ; LYMPHOCYTE ; Enzyme linked immunosorbent assay ; Humoral tolerance
    Abstract: The measurement of tumor-associated proteins is of high diagnostic value in the follow-up of cancer patients. Most tests ignore that various forms of the protein can exist; especially in epithelial cancers and the soluble receptors they produce. We choose EpCAM as model-antigen to analyze whether tests recognizing different domains of the protein give different results in patients' sera. EpCAM-reactive autoantibodies are present in the sera of patients with colorectal carcinoma, however little is known about the existence and possible relevance of circulating soluble EpCAM protein. Most monoclonal EpCAM-antibodies recognize the first EGF-like repeat and fail to detect N-terminal trimmed protein. We developed a novel ELISA to determine the concentration of serum EpCAM with mAbs recognizing the second EGF-like repeat. In 59 healthy controls, EpCAM concentrations ranged from 232 to 8893 ng/ml (mean 1525 ng/ml). Levels of EpCAM in 412 patients with adenocarcinoma were somewhat higher with concentrations ranging from 176 to 36,259 ng/ml (mean 1971 ng/ml). In direct comparison, the untrimmed protein specific ELISA detected lower levels and frequencies as compared to the EGFII-specific ELISA. Only sera with less than 1 mu g/m1 circulating EGFII-EpCAM (66% of the sera) contained EpCAM-specific IgG antibodies. The absence of IgG antibodies in the sera with more than 1 mu g/ml circulating EpCAM was not due to immune complex formation. Anti-EpCAM IgA and IgM antibodies did not show such a correlation. It will be important to assess whether the presence of high levels of circulating EGFII-EpCAM is associated with side effects in patients given immunotherapy.
    Type of Publication: Journal article published
    PubMed ID: 22387297
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  • 14
    Keywords: DISEASE ; POPULATION ; METABOLISM ; PATIENT ; QUALITY ; RISK-FACTORS ; FORM ; score ; AGE ; COMPONENT ; VALIDITY ; DIABETES-MELLITUS ; PREVALENCE ; PROJECT ; MELLITUS ; ADULTS ; pooled analysis ; sex ; Type 2 diabetes mellitus ; CROSS-SECTIONAL SURVEY ; health-related quality of life
    Abstract: Aims To estimate population values of health-related quality of life (HRQL) in subjects with and without Type 2 diabetes mellitus across several large population-based survey studies in Germany. Systematic differences in relation to age and sex were of particular interest. Methods Individual data from four population-based studies from different regions throughout Germany and the nationwide German National Health Interview and Examination Survey (GNHIES98) were included in a pooled analysis of primary data (N = 9579). HRQL was assessed using the generic index instrument SF-36 (36-item Short Form Health Survey) or its shorter version, the SF-12 (12 items). Regression analysis was carried out to examine the association between Type 2 diabetes and the two component scores derived from the SF-36/SF-12, the physical component summary score (PCS-12) and the mental component summary score (MCS-12), as well as interaction effects with age and sex. Results The PCS-12 differed significantly by -4.1 points in subjects with Type 2 diabetes in comparison with subjects without Type 2 diabetes. Type 2 diabetes was associated with significantly lower MCS-12 in women only. Higher age was associated with lower PCS-12, but with an increase in MCS-12, for subjects with and without Type 2 diabetes. Conclusions Pooled analysis of population-based primary data offers HRQL values for subjects with Type 2 diabetes in Germany, stratified by age and sex. Type 2 diabetes has negative consequences for HRQL, particularly for women. This underlines the burden of disease and the importance of diabetes prevention. Factors that disadvantage women with Type 2 diabetes need to be researched more thoroughly
    Type of Publication: Journal article published
    PubMed ID: 21978176
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  • 15
    Keywords: CANCER ; DIAGNOSIS ; DEATH ; DISEASE ; MORTALITY ; RISK ; PATIENT ; statistics ; SWEDEN ; PEPTIDES ; MYOCARDIAL-INFARCTION ; DIABETES-MELLITUS ; MELLITUS ; REGISTRIES ; FAMILIAL RISKS ; HOSPITALIZATIONS ; Type 2 diabetes mellitus ; causes of death ; CARDIOTOXICITY ; death causes
    Abstract: Cancer patients diagnosed with type 2 diabetes mellitus (T2DM) are at an increased risk of death due to cancer. However, whether T2DM comorbidity increases other causes of death in cancer patients is the novel theme of this study. Patients with T2DM were identified from the nationwide Swedish Hospital Discharge Register and linked with patients with cancer recorded from the Swedish Cancer Registry. Hazard ratios (HRs) were calculated for death due to all causes among cancer patients with and without T2DM; both underlying and multiple causes of death were examined using the Cox regression model. A total of 13 325 cancer patients were identified with comorbidity of T2DM. The total number of deaths of cancer patients was 276 021. Of these, 5900 occurred after T2DM diagnosis. For underlying causes of death, except for T2DM, the highest cause-specific HRs were found for complications of bacterial disease (HR, 3.93; 95% CI, 3.04-5.09), urinary system disease (HR, 3.39; 95% CI, 2.78-4.12), and myocardial infarction (HR, 2.93; 95% CI, 2.75-3.12). When risk of death was examined for both underlying and multiple causes of death, the highest HRs were found for hypertensive disease (HR, 3.42; 95% CI, 3.15-3.72), urinary system disease (HR, 3.39; 95% CI, 3.17-3.63), and arterial disease (HR, 3.26; 95% CI, 3.08-3.46). The diagnosis of T2DM in cancer patients is associated with an increased risk of death due to various causes, including myocardial infarction, other bacterial disease, urinary system disease, hypertensive disease, arterial disease, and so on, which may be related to both cancer and treatment. Clinicians that treat cancer patients with T2DM should pay more attention to comorbidities.
    Type of Publication: Journal article published
    PubMed ID: 21960185
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  • 16
    Keywords: ALGORITHM ; IMAGES ; PATIENT ; COMPLEX ; QUALITY ; ASSOCIATION ; RECONSTRUCTION ; quantitative ; ERRORS ; FIXATION ; SCAN ; CONE-BEAM CT ; SLICE ; HIP PROSTHESES ; metal artifact reduction ; metal artifacts ; metal implants ; MULTISLICE ; REFORMATTED PROJECTIONS
    Abstract: Purpose: The problem of metal artifact reduction (MAR) is almost as old as the clinical use of computed tomography itself. When metal implants are present in the field of measurement, severe artifacts degrade the image quality and the diagnostic value of CT images. Up to now, no generally accepted solution to this issue has been found. In this work, a method based on a new MAR concept is presented: frequency split metal artifact reduction (FSMAR). It ensures efficient reduction of metal artifacts at high image quality with enhanced preservation of details close to metal implants. Methods: FSMAR combines a raw data inpainting-based MAR method with an image-based frequency split approach. Many typical methods for metal artifact reduction are inpainting-based MAR methods and simply replace unreliable parts of the projection data, for example, by linear interpolation. Frequency split approaches were used in CT, for example, by combining two reconstruction methods in order to reduce cone-beam artifacts. FSMAR combines the high frequencies of an uncorrected image, where all available data were used for the reconstruction with the more reliable low frequencies of an image which was corrected with an inpainting-based MAR method. The algorithm is tested in combination with normalized metal artifact reduction (NMAR) and with a standard inpainting-based MAR approach. NMAR is a more sophisticated inpainting-based MAR method, which introduces less new artifacts which may result from interpolation errors. A quantitative evaluation was performed using the examples of a simulation of the XCAT phantom and a scan of a spine phantom. Further evaluation includes patients with different types of metal implants: hip prostheses, dental fillings, neurocoil, and spine fixation, which were scanned with a modern clinical dual source CT scanner. Results: FSMAR ensures sharp edges and a preservation of anatomical details which is in many cases better than after applying an inpainting-based MAR method only. In contrast to other MAR methods, FSMAR yields images without the usual blurring close to implants. Conclusions: FSMAR should be used together with NMAR, a combination which ensures an accurate correction of both high and low frequencies. The algorithm is computationally inexpensive compared to iterative methods and methods with complex inpainting schemes. No parameters were chosen manually; it is ready for an application in clinical routine.
    Type of Publication: Journal article published
    PubMed ID: 22482612
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  • 17
    Keywords: CANCER ; SURVIVAL ; PROSTATE ; DIAGNOSIS ; COHORT ; MORTALITY ; RISK ; PATIENT ; IMPACT ; prognosis ; BREAST ; BREAST-CANCER ; prostate cancer ; PROSTATE-CANCER ; SWEDEN ; OUTCOMES ; DIABETES-MELLITUS ; insulin ; MELLITUS ; national database ; REGISTRIES ; FAMILIAL RISKS ; HOSPITALIZATIONS ; cancer-specific survival ; TNM classification ; Type 2 diabetes mellitus
    Abstract: BACKGROUND: Earlier studies have suggested that type 2 diabetes mellitus (T2DM) alters the risk of developing a variety of cancers, but little has been known about the impact of T2DM on cancer prognosis. On the basis of nationwide population-based Swedish registries, the authors of this report compared the cause-specific survival among cancer patients with and without T2DM. METHODS: Patients with T2DM were identified from the nationwide Swedish Hospital Discharge Register, and cancers were recorded from the Swedish Cancer Registry. Hazard ratios (HRs) were calculated using Cox regression models to compare variations in cause-specific survival between cancer patients with and without T2DM. RESULTS: Of the 1016,105 cancer patients, 16,123 had been hospitalized with T2DM before their diagnosis of cancer. The mortality rate was significantly higher among cancer patients with T2DM than among those without T2DM (cause-specific HR, 1.38; 95% confidence interval, 1.35-1.41). There were no differences in TNM stage distribution among cancer patients with or without T2DM for the main cancers, with an exception of tumor and metastatic classifications for breast cancer and prostate cancer, respectively. CONCLUSIONS: The current results indicated that patients with T2DM who are diagnosed with a subsequent cancer are at an increased risk for cause-specific mortality compared with patients who have cancer without T2DM.
    Type of Publication: Journal article published
    PubMed ID: 21800292
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  • 18
    Keywords: radiotherapy ; LUNG ; THERAPY ; ALGORITHM ; IMAGES ; RISK ; ACCURACY ; validation ; radiation ; PATIENT ; ASSOCIATION ; RADIATION-THERAPY ; UNCERTAINTY ; sensitivity ; DEFORMABLE IMAGE REGISTRATION ; ERRORS ; 4D CT IMAGES ; b-spline registration ; dose accumulation ; dose mapping ; fractionated radiation therapy
    Abstract: Purpose: In fractionated radiation therapy, image guidance with daily tomographic imaging becomes more and more clinical routine. In principle, this allows for daily computation of the delivered dose and for accumulation of these daily dose distributions to determine the actually delivered total dose to the patient. However, uncertainties in the mapping of the images can translate into errors of the accumulated total dose, depending on the dose gradient. In this work, an approach to estimate the uncertainty of mapping between medical images is proposed that identifies areas bearing a significant risk of inaccurate dose accumulation.Methods: This method accounts for the geometric uncertainty of image registration and the heterogeneity of the dose distribution, which is to be mapped. Its performance is demonstrated in context of dose mapping based on b-spline registration. It is based on evaluation of the sensitivity of dose mapping to variations of the b-spline coefficients combined with evaluation of the sensitivity of the registration metric with respect to the variations of the coefficients. It was evaluated based on patient data that was deformed based on a breathing model, where the ground truth of the deformation, and hence the actual true dose mapping error, is known.Results: The proposed approach has the potential to distinguish areas of the image where dose mapping is likely to be accurate from other areas of the same image, where a larger uncertainty must be expected.Conclusions: An approach to identify areas where dose mapping is likely to be inaccurate was developed and implemented. This method was tested for dose mapping, but it may be applied in context of other mapping tasks as well.
    Type of Publication: Journal article published
    PubMed ID: 22482640
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  • 19
    Keywords: PATIENT ; FREQUENT ; DEFICIENCY ; ACUTE MYELOID-LEUKEMIA ; ORGANIC-ACIDS ; ISOCITRATE DEHYDROGENASE ; IDH2 MUTATIONS ; 2-hydroxyglutarate ; D-2-HYDROXYGLUTARIC ACIDURIA ; (R)-2-HYDROXYGLUTARATE
    Abstract: Levels of (D)-2-hydroxyglutarate [D2HG, (R)-2-hydroxyglutarate] are increased in some metabolic diseases and in neoplasms with mutations in the isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) genes. Determination of D2HG is of relevance to diagnosis and monitoring of disease. Standard detection methods of D2HG levels are liquid-chromatography-mass spectrometry or gas-chromatography-mass spectrometry. Here we present a rapid, inexpensive and sensitive enzymatic assay for the detection of D2HG levels. The assay is based on the conversion of D2HG to alpha-ketoglutarate (alphaKG) in the presence of the enzyme (D)-2-hydroxyglutarate dehydrogenase (HGDH) and nicotinamide adenine dinucleotide (NAD(+)). Determination of D2HG concentration is based on the detection of stoichiometrically generated NADH. The quantification limit of the enzymatic assay for D2HG in tumor tissue is 0.44 muM and in serum 2.77 muM. These limits enable detection of basal D2HG levels in human tumor tissues and serum without IDH mutations. Levels of D2HG in frozen and paraffin-embedded tumor tissues containing IDH mutations or in serum from acute myeloid leukemia patients with IDH mutations are significantly higher and can be easily identified with this assay. In conclusion, the assay presented is useful for differentiating basal from elevated D2HG levels in tumor tissue, serum, urine, cultured cells and culture supernatants.
    Type of Publication: Journal article published
    PubMed ID: 23117877
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  • 20
    Keywords: THERAPY ; PATIENT ; TRIALS ; AGE ; REPRODUCIBILITY ; POSTMENOPAUSAL WOMEN ; REQUIRING PROLONGED OBSERVATION ; RECALL ; COLLABORATIVE REANALYSIS ; SEX-HORMONES
    Abstract: BACKGROUND: Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women. METHODS: Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression. FINDINGS: Breast cancer risk increased by a factor of 1.050 (95% CI 1.044-1.057; p〈0.0001) for every year younger at menarche, and independently by a smaller amount (1.029, 1.025-1.032; p〈0.0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1.43, 1.33-1.52, p〈0.001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p〈0.006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p〈0.01 for both comparisons). INTERPRETATION: The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours. FUNDING: Cancer Research UK.
    Type of Publication: Journal article published
    PubMed ID: 23084519
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  • 21
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; VITRO ; DISEASE ; RISK ; GENE ; PROTEIN ; validation ; PATIENT ; DNA ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; BREAST ; BREAST-CANCER ; TRIAL ; CARCINOMA CELLS ; OVARIAN-CANCER ; SNP ; PCR ; PROGNOSTIC-FACTORS ; PROGNOSTIC FACTORS ; P-SELECTIN ; POOR-PROGNOSIS ; MULTIPLE-SCLEROSIS ; PATIENT SURVIVAL ; AUTOIMMUNE-DISEASES ; PROGNOSTIC MARKER ; NEOADJUVANT CHEMOTHERAPY ; AUTOREACTIVE T-CELLS ; pathologic complete response ; primary breast cancer ; LYMPHOCYTE ; ANTICANCER CHEMOTHERAPY ; Predictive marker
    Abstract: Overexpression of CD24 is an independent prognostic factor for breast cancer. Recently, two polymorphisms in the CD24 gene were linked to disease risk and progression in autoimmune diseases. Here, we evaluated the clinical relevance of these polymorphisms with respect to their potential to predict a pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) for primary breast cancer (PBC), one of the strongest prognostic factors in this setting. A total of 257 patients were randomized to either doxorubicin/cyclophosphamide (AC) or doxorubicin/pemetrexed (AP), both followed by docetaxel (Doc) as NCT for T2-4 N0-2 M0 PBC as part of an international, multicenter, randomized phase II trial. CD24 polymorphisms were analyzed on germ line DNA and correlated with clinicopathologic variables and pCR. No significant associations were found between either of the polymorphisms and any of the clinicopathologic variables. In a multivariate analysis, CD24 Val/Val genotype was the only significant predictor of pCR (OR: 4.97; P = 0.003). The predictive potential was significant in both treatment arms and in the hormone receptor-positive subgroup. There was no correlation between CD24 3'UTR (TG/Del) genotype and pCR. We did not observe any association between CD24 genotype and CD24 protein expression or in vitro chemosensitivity, but there was a significant correlation between CD24 Val/Val and intratumoral lymphocyte aggregates. In conclusion, CD24 Ala/Val SNP is a strong and independent predictor of pCR after NCT for PBC and may affect immune functions rather than tumor characteristics. Further evaluation of the CD24 function and validation of its predictive potential are clearly warranted.
    Type of Publication: Journal article published
    PubMed ID: 21960110
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  • 22
    Keywords: SYSTEM ; PATIENT ; MECHANISM ; TRIAL ; DESIGN ; REPAIR ; SELECTION ; MULTICENTER ; ENDOVASCULAR PROCEDURES ; endovascular repair ; SCANS ; SCAN ; ABDOMINAL AORTIC-ANEURYSMS ; Aortic Aneurysm,Abdominal ; SLICE ; Blood vessel prosthesis ; DEPLOYMENT ; ENDURANT STENT GRAFT
    Abstract: Technical aspects are crucial for planning and performing successful endovascular repair of abdominal aortic aneurysms (AAA). Planning should be based on high-quality computed tomography angiography scans with a slice thickness of 〈/= 1 mm. However, even without a workstation for image postprocessing, important angle estimations can be easily performed. Several devices are available today to treat abdominal aneurysms. In most elective cases all currently available 3rd generation devices perform comparably if minimal requirements are kept in mind. A safe and technically precise implantation requires cooperation with the involved anesthesiologist in order to manage anticoagulation, blood pressure regulation in general and in currently evolving regional anesthesia. Modern endograft implantation involves highly technical resources, for example guide wires or catheters. Beside patient selection, an optimal procedure planning, graft model choice and endovascular skills are mandatory aspects. In the near future, further improvements in device design and deployment mechanism will allow better device alignment, paving the way for an even broader application of endovascular aneurysm repair (EVAR).
    Type of Publication: Journal article published
    PubMed ID: 22433730
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  • 23
    Keywords: CANCER ; EXPRESSION ; CT ; QUANTIFICATION ; VOLUME ; TUMORS ; PATIENT ; MICROCIRCULATION ; MRI ; EXCHANGE ; CEREBRAL-BLOOD-FLOW ; deconvolution ; ERRORS ; PHARMACOKINETIC ANALYSIS ; TRACER KINETICS ; Compartmental modeling ; Contrast-enhanced dynamic imaging ; Indicator dilution theory
    Abstract: Concentration-time courses measured by dynamic contrast-enhanced (DCE) imaging can be described by a convolution of the arterial input with an impulse response function, Q(T)(t), characterizing tissue microcirculation. Data analysis is based on two different approaches: computation of Q(T)(t) by algebraic deconvolution (AD) and subsequent evaluation according to the indicator dilution theory (IDT) or parameterization of Q(T)(t) by analytical expressions derived by compartmental modeling. Pitfalls of both strategies will be addressed in this study. Tissue data acquired by DCE-CT in patients with head-and-neck cancer and simulated by a reference model (MMID4) were analyzed by a two-compartment model (TCM), a permeability-limited two-compartment model (PL-TCM) and AD. Additionally, MMID4 was used to compute the 'true' response function that corresponds to the simulated tumor data. TCM and AD yielded accurate fits, whereas PL-TCM performed worse. Nevertheless, the corresponding response functions diverge markedly. The response curves obtained by TCM decrease exponentially in the early perfusion phase and overestimate the tissue perfusion, Q(T)(0). AD also resulted in response curves starting with a negative slope and not - as the 'true' response function in accordance with the IDT - with a horizontal plateau. They are thus not valid responses in the sense of the IDT that can be used unconditionally for parameter estimation. Response functions differing considerably in shape can result in virtually identical tissue curves. This non-uniqueness makes a strong argument not to use algebraic but rather analytical deconvolution to reduce the class of solutions to representatives that are in accordance with a-priori knowledge. To avoid misinterpretations and systematic errors, users must be aware of the pitfalls inherent to the different concepts.
    Type of Publication: Journal article published
    PubMed ID: 21497123
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  • 24
    Keywords: APOPTOSIS ; CANCER ; proliferation ; SURVIVAL ; COHORT ; DEATH ; RISK ; GENE ; PATIENT ; DNA ; RISK-FACTORS ; BIOLOGY ; MELANOMA ; DNA-REPAIR GENES ; TRANSCRIPTIONAL REGULATION ; MELANOCYTES ; survival analysis ; RECEPTOR GENE ; MITF ; GENOME-WIDE ASSOCIATION ; MC1R ; BRAF-MUTANT MELANOMA ; CDKN2A MUTATION CARRIERS ; forest plot
    Abstract: Inherited MC1R variants modulate MITF transcription factor signaling, which in turn affects tumor cell proliferation, apoptosis, and DNA repair. The aim of this BioGenoMEL collaborative study in 10 melanoma cohorts was to test the hypothesis that inherited variants thereby moderate survival expectation. A survival analysis in the largest cohort (Leeds) was carried out adjusting for factors known to impact on survival. The results were then compared with data from nine smaller cohorts. The absence of any consensus MC1R alleles was associated with a significantly lower risk of death in the Leeds set (HR, 0.64; 95% CI, 0.46-0.89) and overall in the 10 data sets (HR, 0.78; 95% CI, 0.65-0.94) with some support from the nine smaller data sets considered together (HR, 0.83; 95% CI, 0.67-1.04). The data are suggestive of a survival benefit for inherited MC1R variants in melanoma patients.
    Type of Publication: Journal article published
    PubMed ID: 22325793
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  • 25
    Keywords: SURVIVAL ; AGENTS ; GENE ; GENE-EXPRESSION ; PROTEIN ; PATIENT ; DNA ; TISSUES ; TRIAL ; ASSAY ; PROMOTER ; REPAIR ; PROGNOSTIC-FACTORS ; PROGNOSTIC FACTORS ; PREDICTION ; METHYLATION ; GLIOMAS ; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE ; temozolomide ; CPG ISLAND HYPERMETHYLATION ; CLINICAL-RESPONSE ; GLIOBLASTOMA ; quantitative ; clinical trial
    Abstract: Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O(6)-methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide. Hence, the MGMT status is widely determined in most clinical trials and frequently requested in routine diagnostics of glioblastoma. Since various different techniques are available for MGMT promoter methylation analysis, a generally accepted consensus as to the most suitable diagnostic method remains an unmet need. Here, we assessed methylation-specific polymerase chain reaction (MSP) as a qualitative and semi-quantitative method, pyrosequencing (PSQ) as a quantitative method, and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a semi-quantitative method in a series of 35 formalin-fixed, paraffin-embedded glioblastoma tissues derived from patients treated in a prospective clinical phase II trial that tested up-front chemoradiotherapy with dose-intensified temozolomide (UKT-05). Our goal was to determine which of these three diagnostic methods provides the most accurate prediction of progression-free survival (PFS). The MGMT promoter methylation status was assessable by each method in almost all cases (n = 33/35 for MSP; n = 35/35 for PSQ; n = 34/35 for MS-MLPA). We were able to calculate significant cut-points for the continuous methylation signals at each CpG site analysed by PSQ (range, 11.5 to 44.9%) and at one CpG site assessed by MS-MLPA (3.6%) indicating that a dichotomisation of continuous methylation data as a prerequisite for comparative survival analyses is feasible. Our results show that, unlike MS-MLPA, MSP and PSQ provide a significant improvement of predicting PFS compared with established clinical prognostic factors alone (likelihood ratio tests: p〈0.001). Conclusively, taking into consideration prognostic value, cost effectiveness and ease of use, we recommend pyrosequencing for analyses of MGMT promoter methylation in high-throughput settings and MSP for clinical routine diagnostics with low sample numbers.
    Type of Publication: Journal article published
    PubMed ID: 22428052
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  • 26
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; SURVIVAL ; IN-VIVO ; THERAPY ; PROTEIN ; PATIENT ; COMPLEX ; DOMAIN ; ANTIGEN ; T-CELLS ; BIOLOGY ; antibodies ; antibody ; antigen presentation ; GENE-THERAPY ; AUTOANTIBODIES ; JUNCTIONAL EPIDERMOLYSIS-BULLOSA ; REGULATORY CELLS ; TOLERANCE INDUCTION ; BP180 ; DEC-205 ; DEC205 ; skin grafting ; type XVII collagen
    Abstract: Antibodies, specific to murine DEC205, can be used to target antigens to dendritic cells. The immunodominant domain of human type XVII collagen, hNC16A, was fused to this antibody (DEC-hNC16A) and was administered as expression plasmid by gene gun transfection with the aim of inducing tolerance to human type XVII collagen in a skin transplantation model. Mice transfected with DEC-hNC16A were challenged with skin grafts from transgenic mice engineered to express human type XVII collagen. Graft survival was either prolonged or grafts were accepted infinitely (33% and 16%, respectively) upon treatment with DEC-hNC16A while 100% of grafts were rejected in untreated controls. Graft acceptance was associated with the absence of a CD4+ infiltrate and a dense CD8+ T-cell infiltrate and was not strictly dependent on antibody production. Our results show that DEC-hNC16A targets dendritic cells in vivo leading to prolonged survival of transgenic skin grafts. This indicates that DEC205-targeting may be used for the induction of tolerance to skin antigens, which would increase the chances of successful skin gene therapy of epidermolysis bullosa patients.
    Type of Publication: Journal article published
    PubMed ID: 22509840
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  • 27
    Keywords: brain ; CELLS ; EXPRESSION ; IN-VITRO ; IN-VIVO ; VITRO ; PROTEIN ; PATIENT ; TISSUES ; ANTIGEN ; T-CELLS ; IDENTIFICATION ; PROGRESSION ; PEPTIDES ; IMMUNOTHERAPY ; MALIGNANT GLIOMA ; HUMAN BRAIN-TUMORS ; GLIOBLASTOMA ; CHONDROITIN SULFATE PROTEOGLYCAN ; LYMPHOCYTE ; AVIDITY ; peptidome ; TENASCIN-C ; tumour antigen ; tumour-infiltrating lymphocytes ; V-BETA REPERTOIRE
    Abstract: Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover 〉6000 HLA-bound peptides from HLA-A*02(+) glioblastoma, of which over 3000 were restricted by HLA-A*02. We prioritized in-depth investigation of 10 glioblastoma-associated antigens based on high expression in tumours, very low or absent expression in healthy tissues, implication in gliomagenesis and immunogenicity. Patients with glioblastoma showed no T cell tolerance to these peptides. Moreover, we demonstrated specific lysis of tumour cells by patients' CD8(+) T cells in vitro. In vivo, glioblastoma-specific CD8(+) T cells were present at the tumour site. Overall, our data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy. The peptides identified in our study are currently being tested as a multipeptide vaccine (IMA950) in patients with glioblastoma.
    Type of Publication: Journal article published
    PubMed ID: 22418738
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  • 28
    Keywords: CANCER ; radiotherapy ; SURVIVAL ; LUNG ; LUNG-CANCER ; TIME ; PATIENT ; prognosis ; score ; RADIATION-THERAPY ; RATES ; SAFETY ; CRITERIA ; external beam radiotherapy ; Palliation ; Airway stent ; ESOPHAGEAL STENTS ; Malignant airway obstruction ; TEMPORARY ; Therapeutic bronchoscopy
    Abstract: Purpose: We retrospectively evaluated the outcome and toxicity of external beam radiotherapy (EBRT) after airway stents were placed in patients treated for malignant airway obstruction. Methods and Materials: Between 2004 and 2009, we performed airway stenting followed by EBRT in 43 patients for symptomatic primary lung cancer (n = 31) or other thoracic malignancies (n = 12). The median time interval between stent placement and first irradiation was 14 days. A median total dose of 50 Gy was delivered. Sixty-seven percent of the patients had reduced performance status (Karnofsky performance score, 〈= 70). Results: EBRT had to be stopped prematurely in 16 patients (37%), at a median total dose of 17 Gy, for various reasons. In this group of patients, the survival was poor, with a median overall survival (OS) of only 21 days. Twenty-seven patients (63%) completed radiotherapy as planned, with a median OS of 8.4 months. Fourteen of 43 patients (33%) developed at least one Common Terminology Criteria for Adverse Event of grade 3 to 5. The most common event was a malignant restenosis of the stent leading to asphyxia (n = 7), followed by fistula formation (n = 4), necrosis (n = 3), mediastinitis with abscess (n = 1), secondary nonmalignant airway stenosis (n = 1), and hemoptysis (n = 1). With the exception of one event, all events were associated with a local progression of the tumor. Conclusions: Although the long-term prognosis for patients with malignant airway obstruction is poor, airway stenting combined with EBRT offers a possible therapeutic option, achieving fast relief of acute respiratory distress with an associated antitumor effect, resulting in a potential survival benefit. However, due to local advanced tumor growth, increased rates of adverse events are to be expected, necessitating careful monitoring.
    Type of Publication: Journal article published
    PubMed ID: 22516383
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  • 29
    Keywords: brain ; PATIENT ; MRI ; ASSOCIATION ; MAGNETIC-RESONANCE ; magnetic resonance imaging ; ONSET SCHIZOPHRENIA ; SCHIZOPHRENIA ; AGE ; NEUROLEPTIC-NAIVE ; neurological soft signs ; VOXEL-BASED MORPHOMETRY ; BASAL GANGLIA ; THALAMUS ; 1ST-EPISODE SCHIZOPHRENIA ; 1ST EPISODE PSYCHOSIS ; ANTIPSYCHOTIC-NAIVE SCHIZOPHRENIA ; ATYPICAL ANTIPSYCHOTICS ; BASAL GANGLIA VOLUMES ; ILLNESS ; NONPSYCHOTIC SIBLINGS ; SHAPE ABNORMALITIES ; THALAMIC VOLUME
    Abstract: BACKGROUND: Minor motor and sensory deficits or neurological soft signs (NSS) are frequently found in patients with schizophrenia at any stage of their illness. The thalamus and basal ganglia are accepted as being important for both motor control and integration of sensory input. However, whether NSS are related to alterations of these brain regions remains controversial. METHOD: Twenty patients with recent onset schizophrenia were investigated using high-resolution magnetic resonance imaging (MRI) at 3 Tesla. NSS were examined on the Heidelberg Scale after remission of acute symptoms and related to both volumetric and shape measurements of thalamus, caudate nucleus, putamen, and globus pallidus, respectively. Age, education, medication and duration of illness were considered as potential confounders. RESULTS: NSS were associated with structural alterations predominantly in the thalamus, the left caudate nucleus, and in the right globus pallidus. According to shape analyses these associations referred to regionally specific morphometric alterations rather than to global atrophy of the respective structures. CONCLUSION: Our findings provide new insights into the association of NSS with brain morphometric alterations and lend further support to an involvement of multiple subcortical regions in schizophrenia.
    Type of Publication: Journal article published
    PubMed ID: 22316638
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  • 30
    Keywords: OPTIMIZATION ; radiotherapy ; THERAPY ; VOLUME ; RISK ; TUMORS ; PATIENT ; MANAGEMENT ; INTRACRANIAL MENINGIOMAS ; PROTON RADIATION-THERAPY ; conformal therapy ; fractionated stereotactic radiotherapy ; carbon ions ; BEAMS ; Protons ; PHOTON IMRT ; Gantry ; CAVERNOUS SINUS ; Plan comparison ; BENIGN MENINGIOMA ; PARANASAL SINUS ; PHOTON RADIOTHERAPY
    Abstract: Background: To examine the potential improvement in treatment planning for patients with skull base meningioma using IMRT compared to carbon ion or proton beams with and without a gantry. Methods: Five patients originally treated with photon IMRT were selected for the study. Ion beams were chosen using a horizontal beam or an ion gantry. Intensity controlled raster scanning and the intensity modulated particle therapy mode were used for plan optimization. The evaluation included analysis of dose-volume histograms of the target volumes and organs at risk. Results: In comparison with carbon and proton beams only with horizontal beams, carbon ion treatment plans could spare the OARs more and concentrated on the target volumes more than proton and photon IMRT treatment plans. Using only a horizontal fixed beam, satisfactory plans could be achieved for skull base tumors. Conclusion: The results of the case studies showed that using IMPT has the potential to overcome the lack of a gantry for skull base tumors. Carbon ion plans offered slightly better dose distributions than proton plans, but the differences were not clinically significant with established dose prescription concepts
    Type of Publication: Journal article published
    PubMed ID: 22439607
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  • 31
    Keywords: CANCER ; CELLS ; EXPRESSION ; MODELS ; PROSTATE ; CLASSIFICATION ; INFORMATION ; COHORT ; DISEASE ; PATIENT ; prognosis ; BIOMARKERS ; BIOLOGY ; BREAST-CANCER ; prostate cancer ; PROSTATE-CANCER ; PREDICTION ; SELECTION ; INTEGRATION ; REGRESSION ; ERROR ; MICRORNA EXPRESSION ; VARIABLE SELECTION ; CROSS-VALIDATION
    Abstract: BACKGROUND: One of the main goals in cancer studies including high-throughput microRNA (miRNA) and mRNA data is to find and assess prognostic signatures capable of predicting clinical outcome. Both mRNA and miRNA expression changes in cancer diseases are described to reflect clinical characteristics like staging and prognosis. Furthermore, miRNA abundance can directly affect target transcripts and translation in tumor cells. Prediction models are trained to identify either mRNA or miRNA signatures for patient stratification. With the increasing number of microarray studies collecting mRNA and miRNA from the same patient cohort there is a need for statistical methods to integrate or fuse both kinds of data into one prediction model in order to find a combined signature that improves the prediction. RESULTS: Here, we propose a new method to fuse miRNA and mRNA data into one prediction model. Since miRNAs are known regulators of mRNAs we used the correlations between them as well as the target prediction information to build a bipartite graph representing the relations between miRNAs and mRNAs. This graph was used to guide the feature selection in order to improve the prediction. The method is illustrated on a prostate cancer data set comprising 98 patient samples with miRNA and mRNA expression data. The biochemical relapse was used as clinical endpoint. It could be shown that the bipartite graph in combination with both data sets could improve prediction performance as well as the stability of the feature selection. CONCLUSIONS: Fusion of mRNA and miRNA expression data into one prediction model improves clinical outcome prediction in terms of prediction error and stable feature selection. The R source code of the proposed method is available in the supplement.
    Type of Publication: Journal article published
    PubMed ID: 22188670
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  • 32
    Keywords: PATIENT ; radiation ; Germany ; THERAPY ; imaging ; CANCER ; RADIATION-THERAPY ; Jun ; pancreatic cancer ; RECURRENT ; ONCOLOGY ; PANCREATIC-CANCER ; radiation therapy
    Type of Publication: Meeting abstract published
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  • 33
    Keywords: journals ; tumor ; brain ; THERAPY ; TUMORS ; PATIENT ; Jun ; ONCOLOGY ; BRAIN-TUMORS ; brain tumor
    Type of Publication: Meeting abstract published
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  • 34
    Keywords: AGENTS ; Germany ; DIAGNOSIS ; DISEASE ; HISTORY ; PATIENT ; FAILURE ; RENAL-FAILURE ; FEATURES ; RENAL BIOPSIES ; acute interstitial nephritis ; renal failure ; HYPERSENSITIVITY REACTIONS ; renal biopsy ; allergy to penicillin ; homeopathic agent trigger ; PENICILLIN
    Abstract: History and clinical findings: A 70-year-old woman was admitted to hospital with fatigue, pallor and shortness of breath on mild exertion. In her past medical history only borderline hypertension and allergy to penicillin were to note. Investigations: Actual laboratory findings revealed renal failure with metabolic acidosis and hyperkalaemia. A normochrome normocytic anemia and secondary hyperparathyreoidism were suggestive of a subacute course. The renal biopsy showed histological features of a subacute tubulo-interstitial nephritis. Diagnosis, treatment and course: The chronic renal failure caused by an interstitial nephritis was treated with corticosteroids and hemodialysis treatment was started. The trigger for AIN could not be found, there was no infectious or systemically disease nor a nephrotoxic medication identified. For nearly six months the patient had taken a homeopathic agent which is a dilution of penicillium chrysogenum. In case of a determined allergy to penicillin, an extract of the fungus producing penicillin could possibly cause an interstitial nephritis. The patient was dialysis-independent with a GFR about 8-10 ml/min at the time of discharge. Conclusion: With interstitial nephritis all agents should be considered a potential suspect, even homeopathic agents
    Type of Publication: Journal article published
    PubMed ID: 20533155
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  • 35
    Keywords: CANCER ; radiotherapy ; SURVIVAL ; tumor ; COMBINATION ; THERAPY ; GENE-EXPRESSION ; HYBRIDIZATION ; TUMORS ; SURGERY ; PATIENT ; MECHANISM ; prognosis ; TARGET ; IN-SITU ; AGE ; MUTATION ; chemotherapy ; leukemia ; MUTATIONS ; pathology ; GLIOMAS ; MULTIFORME ; HETEROGENEITY ; overall survival ; PROGNOSTIC-FACTOR ; SUBTYPES ; telomere ; temozolomide ; HUMAN-CELLS ; GLIOBLASTOMA ; retrospective ; MAINTENANCE ; ELONGATION ; IDH1 ; Genetic ; ISOCITRATE DEHYDROGENASE ; Type ; prognostic ; Alternative lengthening of telomeres ; Glioblastoma subtypes
    Abstract: Patients with glioblastoma (GBM) have variable clinical courses, but the factors that underlie this heterogeneity are not understood. To determine whether the presence of the telomerase-independent alternative lengthening of telomeres (ALTs) mechanism is a significant prognostic factor for survival, we performed a retrospective analysis of 573 GBM patients. The presence of ALT was identified in paraffin sections using a combination of immunofluorescence for promyelocytic leukemia body and telomere fluorescence in situ hybridization. Alternative lengthening of telomere was present in 15% of the GBM patients. Patients with ALT had longer survival that was independent of age, surgery, and other treatments. Mutations in isocitrate dehydrogenase (IDH1mut) 1 frequently accompanied ALT, and in the presence of both molecular events, there was significantly longer overall survival. These data suggest that most ALT+ tumors may be less aggressive proneural GBMs, and the better prognosis may relate to the set of genetic changes associated with this tumor subtype. Despite improved overall survival of patients treated with the addition of chemotherapy to radiotherapy and surgery, ALT and chemotherapy independently provided a survival advantage, but these factors were not found to be additive. These results suggest a critical need for developing new therapies to target these specific GBM subtypes
    Type of Publication: Journal article published
    PubMed ID: 205350338
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  • 36
    Keywords: CANCER ; tumor ; carcinoma ; CELL ; Germany ; MODEL ; PERFUSION ; imaging ; DIFFERENTIATION ; TUMORS ; SURGERY ; PATIENT ; IMPACT ; CONTRAST ; MRI ; SEQUENCE ; MAGNETIC-RESONANCE ; magnetic resonance imaging ; NUMBER ; tomography ; CARCINOMAS ; CONTRAST-ENHANCED MRI ; CELL CARCINOMA ; renal cell carcinoma ; ONCOLOGY ; dynamic contrast enhanced MRI ; SUBTYPES ; dCE MRI ; PHARMACOKINETIC PARAMETERS ; NEPHRON-SPARING SURGERY ; FUNCTIONAL ASSESSMENT ; grading ; AREA ; CELL CARCINOMAS
    Abstract: In this study, we investigated whether assessment of the tumor perfusion by dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) enables to estimate the morphologic grading of renal cell carcinomas. A total of 21 patients with suspected renal cell cancer were examined using a Gadobutrol-enhanced, dynamic saturation-recovery, turbo-fast, low-angle shot sequence. Tumor perfusion and the tissue-blood ratio within the entire tumor and the most highly vascularized part of the tumor were calculated according to the model of Miles. Immediately after examination, patients underwent surgery, and the results from imaging were compared with the morphological analysis of the histologic grading. Fourteen patients had G2 tumors, and seven patients had G3 tumors. Significantly higher perfusion values (p 〈 0.05) were obtained in G3 tumors than in G2 tumors when the entire tumor area was considered (1.59 +/- 0.44 (ml/g/min) vs. 1.08 +/- 0.38 (ml/g/min)) or its most highly vascularized part (2.14 + 0.89 (ml/g/min) vs. 1.40 + 0.49 (ml/g/min)). By contrast, the tissue-blood ratios did not differ significantly between the two groups. In conclusion, unlike tissue-blood ratio, surrogate parameters of the tumor perfusion determined by DCE MRI seem to allow an estimation of the grading of renal cell carcinoma. However, further studies with high case numbers and including patients with G1 tumors are required to evaluate the full potential and clinical impact. (C) 2009 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19540690
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    Keywords: CANCER ; CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; tumor ; TUMOR-CELLS ; AGENTS ; CELL ; Germany ; MODEL ; MODELS ; THERAPY ; TUMORS ; MICE ; PATIENT ; ACTIVATION ; INFECTION ; DENDRITIC CELLS ; T-CELLS ; TOLERANCE ; BIOLOGY ; H-1 ; TRIAL ; LYMPHOMA ; HUMANS ; adenocarcinoma ; MINUTE VIRUS ; CANCER-THERAPY ; rodent ; CYTOKINE ; review ; DUCTAL ADENOCARCINOMA ; GLIOMA ; oncolysis ; non-Hodgkin lymphoma ; PHASE ; oncolytic ; PARVOVIRUSES ; cancer therapeutics ; clinical trial ; immunomodulation ; THERAPEUTICS ; non-Hodgkin ; CELL BIOLOGY ; viruses ; PANCREATIC-CARCINOMA ; IMMUNE ; Preclinical models ; Cancer immunotherapy ; Cancer virotherapy ; Oncosuppression
    Abstract: The experimental infectivity and excellent tolerance of some rodent autonomous parvoviruses in humans, together with their oncosuppressive effects in preclinical models, speak for the inclusion of these agents in the arsenal of oncolytic viruses under consideration for cancer therapy. In particular, wild-type parvovirus H-1PV can achieve a complete cure of various tumors in animal models and kill tumor cells that resist conventional anticancer treatments. There is growing evidence that H-1PV oncosuppression involves an immune component in addition to the direct viral oncolytic effect. This article summarizes the recent assessment of H-1PV antineoplastic activity in glioma, pancreatic ductal adenocarcinoma, and non-Hodgkin lymphoma models, laying the foundation for the present launch of a first phase I/IIa clinical trial on glioma patients. (C) 2010 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20211577
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  • 38
    Keywords: EXPRESSION ; SURVIVAL ; Germany ; MODEL ; MODELS ; CLASSIFICATION ; DIAGNOSIS ; COHORT ; DEATH ; DISEASE ; MORTALITY ; RISK ; GENE ; GENE-EXPRESSION ; microarray ; PATIENT ; MARKER ; IMPACT ; STAGE ; AMPLIFICATION ; gene expression ; microarrays ; AGE ; MARKERS ; HIGH-RISK ; STRATEGIES ;