Biomedical subjects

T Mattfeldt

Publications and source records attributed to T Mattfeldt.

At least 19 recordsLinked to original sources

PubMed2006

Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation.

The suppressors of cytokine signaling (SOCS) are critically involved in the regulation of cellular proliferation, survival, and apoptosis via cytokine-induced JAK/STAT signaling. SOCS-1 silencing by aberrant DNA methylation contributes to oncogenesis in various B-cell neoplasias and carcinomas. Recently, we showed an alternative loss of SOCS-1 function due to deleterious SOCS-1 mutations in a major subset of primary mediastinal B-cell lymphoma (PMBL) and in the PMBL line MedB-1, and a biallelic SOCS-1 deletion in PMBL line Karpas1106P. For both cell lines our previous data demonstrated retarded JAK2 degradation and sustained phospho-JAK2 action leading to enhanced DNA binding of phospho-STAT5. Here, we analysed SOCS-1 in laser-microdissected Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We detected SOCS-1 mutations in HRS cells of eight of 19 cHL samples and in three of five Hodgkin lymphoma (HL)-derived cell lines by sequencing analysis. Moreover, we found a significant association between mutated SOCS-1 of isolated HRS cells and nuclear phospho-STAT5 accumulation in HRS cells of cHL tumor tissue (P < 0.01). Collectively, these findings support the concept that PMBL and cHL share many overlapping features, and that defective tumor suppressor gene SOCS-1 triggers an oncogenic pathway operative in both lymphomas.

Amino Acid Sequence↗

PubMed2006

Statistical analysis of reduced pair correlation functions of capillaries in the prostate gland.

Blood capillaries are thread-like structures that may be considered as an example of a spatial fibre process in three dimensions. At light microscopy, the capillary profiles appear as a planar point process on sections. It has recently been shown that the observed pair correlation function g(r) of the centres of the fibre profiles on two-dimensional sections may be used to estimate the reduced pair correlation function of stationary and isotropic fibre processes in three dimensions. In the present study, we explored how this approach may be extended to statistical analysis of reduced g-functions of capillaries from multiple specimens of different groups and with replicated observations. The methods were applied to normal prostatic tissue compared with prostate cancer. Confidence intervals for the mean reduced g-functions of groups were estimated for fixed r-values parametrically using the t-distribution, and by bootstrap methods. Each estimated reduced g-function was furthermore characterized in terms of its first maximum and minimum. The mean length of capillaries per unit tissue volume was significantly higher in prostate cancer tissue than in normal prostate tissue. Significant differences between the mean reduced g-functions of malignant and benign lesions could be demonstrated for two domains of r-values. In general, bootstrap-based confidence intervals were slightly wider than parametrically estimated confidence intervals. Falsely negative lower bounds of the intervals, which sometimes arose using the parametric approach, could be avoided by the bootstrap method. Testing of group mean values for significant differences by the bootstrap method yielded more conservative results than multiple t-tests. The functional value of the first maximum of the reduced g-function and a global statistical parameter of short-range ordering was significantly reduced in the carcinoma group. Prostate cancer tissue is more densely supplied with capillaries than normal prostate tissue and the three-dimensional arrangement of the vessels differs with respect to interaction at various distance ranges. In the local approach used here, bootstrap methods can be used as a robust statistical tool for the computation of confidence intervals and group comparisons of mean reduced g-functions at specific ranges of interaction.

Capillaries↗

PubMed2006

Sex-specific telomere length profiles and age-dependent erosion dynamics of individual chromosome arms in humans.

During aging, telomeres are gradually shortened, eventually leading to cellular senescence. By T/C-FISH (telomere/centromere-FISH), we investigated human telomere length differences on single chromosome arms of 205 individuals in different age groups and sexes. For all chromosome arms, we found a linear correlation between telomere length and donor age. Generally, males had shorter telomeres and higher attrition rates. Every chromosome arm had its individual age-specific telomere length and erosion pattern, resulting in an unexpected heterogeneity in chromosome-specific regression lines. This differential erosion pattern, however, does not seem to be accidental, since we found a correlation between average telomere length of single chromosome arms in newborns and their annual attrition rate. Apart from the above-mentioned sex-specific discrepancies, chromosome arm-specific telomere lengths were strikingly similar in men and women. This implies a mechanism that arm specifically regulates the telomere length independent of gender, thus leading to interchromosomal telomere variations.

Adolescent↗

PubMed2005

Bootstrap methods for statistical inference from stereological estimates of volume fraction.

We suggest the use of bootstrap methods for inference from stereological estimates of volume fraction. An informal introduction to stereological estimation of volume fraction and to principles of bootstrap techniques is given. The bootstrap method is a robust computer-intensive resampling technique, based on independent random sampling from a data set with replacement. Bootstrap methods were used to estimate confidence intervals for volume fractions, and to test for a significant difference between estimated volume fractions from two samples. Two sampling designs are considered: independent replicated samples (visual fields) from a single object, and estimates of volume fraction from multiple independent objects. The methods are presented as worked examples on real data sets obtained from tumour pathology (mammary cancer, pancreatic cancer). The volume fraction of glandular lumina per total volume of the epithelial phase was chosen as target parameter. It indicates the degree of glandular differentiation in adenocarcinomas and is estimated as a ratio-of-means statistic with variable denominator within cases. The confidence intervals of the volume fraction estimated by the bootstrap method were slightly narrower than the parametrically calculated confidence intervals for all data sets. The outcomes of significance tests based on the bootstrap technique were unchanged as compared with classical tests based on the assumptions of normality and homoscedasticity of the data. Special attention was paid to the reproducibility of the bootstrap technique in replicated trials on the same data.

Breast Neoplasms↗

PubMed2005

Explorative statistical analysis of planar point processes in microscopy.

Basic methods of explorative statistical analysis for stationary and isotropic planar point processes are briefly and informally reviewed. At the explorative level, planar point patterns may be characterized in terms of the intensity, the K-function and the pair correlation function. These second-order functions enable one to classify a given point process as completely random, clustering or repulsive. The repulsive behaviour may be quantified by an estimate of the hard-core distance. In the exploratory approach, the statistics are essentially free from model assumptions. Second-order spatial functions have been estimated to characterize genuine planar point processes in the macroscopic domain, for example in forestry, geography and epidemiology. For light microscopy and transmission electron microscopy, two situations are distinguished, which may be summarized as the genuine planar case and the stereological case. In the genuine planar case, a direct interpretation of the results of spatial statistics is feasible. Here, monolayers in cell culture, intramembranous particles on freeze fracture specimens and amacrine cells of the retina are mentioned as examples. In the stereological case, point patterns are generated by sections through 3D structures. Here the observed point patterns may arise as the centres of sectional profiles of particles, or as centres of sectional profiles of spatial fibre processes. In both situations, exploratory spatial point process statistics allow a quantitative characterization of sectional images for the purposes of group comparisons and classification. Moreover, for spatial fibre processes it has recently been shown that the observed pair correlation function of the centres of the fibre profiles is an estimate of the reduced pair correlation function of the fibre process in 3D. Hence for fibre processes a stereological interpretation of point process statistics obtained from sections is an additional option.

Data Interpretation, Statistical↗

PubMed2004

Prediction of the axillary lymph node status in mammary cancer on the basis of clinicopathological data and flow cytometry.

Axillary lymph node status is a major prognostic factor in mammary carcinoma. It is clinically desirable to predict the axillary lymph node status from data from the mammary cancer specimen. In the study, the axillary lymph node status, routine histological parameters and flow-cytometric data were retrospectively obtained from 1139 specimens of invasive mammary cancer. The ten variables: age, tumour type, tumour grade, tumour size, skin infiltration, lymphangiosis carcinomatosa, pT4 category, percentage of tumour cells in G2/M- and S-phases of the cell cycle, and ploidy index were considered as predictor variables, and the single variable lymph node metastasis pN (0 for pN0, or 1 for pN1 or pN2) was used as an output variable. A stepwise logistic regression analysis, with the axillary lymph node as a dependent variable, was used for feature selection. Only lymphangiosis carcinomatosa and tumour size proved to be significant as independent predictor variables; the other variables were non-contributory. Three paradigms with supervised learning rules (multilayer perceptron, learning vector quantisation and support vector machines) were used for the purpose of prediction. If any of these paradigms was used with the information from all ten input variables, 73% of cases could be correctly predicted, with specificity ranging from 82 to 84% and sensitivity ranging from 60 to 63%. If only the two significant input variables were used, lymphangiosis carcinomatosa and tumour diameter, the prediction accuracy was no worse. Nearly identical results were obtained by two different techniques of cross-validation (leave-one-out against ten-fold cross validation). It was concluded that: artificial neural networks can be used for risk stratification on the basis of routine data in individual cases of mammary cancer; and lymphangiosis carcinomatosa and tumour size are independent predictors of axillary lymph node metastasis in mammary cancer.

Algorithms↗

PubMed2004

Incidental carcinoma of the prostate: clinicopathological, stereological and immunohistochemical findings studied with logistic regression and self-organizing feature maps.

OBJECTIVE: To identify significant predictive factors determining category T1a and T1b in incidental prostatic carcinoma with classical and neural multivariate data analysis methods. MATERIALS AND METHODS: Incidental prostatic carcinomas diagnosed in our department during 1990-99 (66 cases) were re-examined. Besides acquiring routine clinical and pathological data the tumours were assessed by scoring immunohistochemistry for proliferative activity and p53-overexpression. Tumour vascularization (angiogenesis) and epithelial texture variables were investigated by quantitative stereology. The data were evaluated by classical statistical methods (t-test, correlation analysis, logistic regression). Moreover, self-organizing feature maps (SOMs) were applied as an exploratory approach to unsupervised data analysis by artificial neural networks. RESULTS: The proliferative fraction, p53 overexpression of tumour cell nuclei, preoperative prostate-specific antigen value and density of capillary vascularization correlated with the Gleason score in incidental prostatic carcinoma. In a stepwise logistic regression analysis with the tumour categories T1a and T1b as dependent variables, the Gleason score and the volume fraction of epithelial cells were significant independent predictors of the tumour category. The cases could be grouped into clusters of different degrees of malignancy using SOMs. CONCLUSIONS: Texture variables of tumour cells are of central importance for the extent of propagation in the prostate in incidental prostatic adenocarcinomas. Gleason score and quantitative stereological estimates of the volume fraction of tumour cells are significant predictors of T1a and T1b categories of incidental prostatic carcinoma. Unsupervised clustering of T1 prostate carcinoma cases by SOMs correlates well with the dichotomous classification into T1a and T1b according to the UICC.

Aged↗

PubMed2002

Genetic changes in stage pT2N0 prostate cancer studied by comparative genomic hybridization.

OBJECTIVE: To identify chromosomal regions important for progression in clinically organ-confined prostate cancer, as the genetic changes underlying the development and progression of prostate cancer are poorly understood. MATERIALS AND METHODS: Comparative genomic hybridization (CGH) was used to search for DNA sequence copy-number changes in a series of 50 primary organ-confined prostate adenocarcinomas (pT2N0) removed by radical prostatectomy. RESULTS: CGH analysis indicated that 23 (46%) of the primary prostate adenocarcinomas showed chromosome alterations. The percentage of tumours with losses (38%) was higher than with gains (28%). Losses of 13q (24%), 8p (18%), 6q (10%), 16q (8%), 18q (6%) and 5q (6%) and gains of 17q (12%), 20q (12%), 9q (10%), 17p (8%) and 8q (6%) were the most frequent alterations. Amplifications were found at 8q24-qter. Minimal overlapping regions of loss, indicative of the presence of tumour-suppressor genes, were mapped to 13q21.1-q21.3 and 8p21.2, and minimal overlapping regions of gain, indicative of the presence of oncogenes, were found at 9q34.4-qter, 17q25-qter and 20q13.3-qter. There was a significant association between Gleason score and losses and gains (P = 0.003), and an association between chromosomal imbalance and high histological grade (P = 0.008). CONCLUSION: These results suggest that losses or gains of DNA in these regions are important for prostate cancer progression, and document the spectrum of chromosomal alterations in stage pT2N0 of clinically organ-confined prostate cancer.

Adenocarcinoma↗

PubMed2001

A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease.

This study describes a tumor progression model for ductal pancreatic cancer in mice overexpressing TGF-alpha. Activation of Ras and Erk causes induction of cyclin D1-Cdk4 without increase of cyclin E or PCNA in ductal lesions. Thus, TGF-alpha is able to promote progression throughout G1, but not S phase. Crossbreeding with p53 null mice accelerates tumor development in TGF-alpha transgenic mice dramatically. In tumors developing in these mice, biallelic deletion of Ink4a/Arf or LOH of the Smad4 locus is found suggesting that loci in addition to p53 are involved in antitumor activities. We conclude that these genetic events are critical for pancreatic tumor formation in mice. This model recapitulates pathomorphological features and genetic alterations of the human disease.

Animals↗

PubMed2001

Cluster analysis of comparative genomic hybridization (CGH) data using self-organizing maps: application to prostate carcinomas.

Comparative genomic hybridization (CGH) is a modern genetic method which enables a genome-wide survey of chromosomal imbalances. For each chromosome region, one obtains the information whether there is a loss or gain of genetic material, or whether there is no change at that region. Usually it is not possible to evaluate all 46 chromosomes of a metaphase, therefore several (up to 20 or more) metaphases are analyzed per individual, and expressed as average. Mostly one does not study one individual alone but groups of 20-30 individuals. Therefore, large amounts of data quickly accumulate which must be put into a logical order. In this paper we present the application of a self-organizing map (Genecluster) as a tool for cluster analysis of data from pT2N0 prostate cancer cases studied by CGH. Self-organizing maps are artificial neural networks with the capability to form clusters on the basis of an unsupervised learning rule, i.e., in our examples it gets the CGH data as only information (no clinical data). We studied a group of 40 recent cases without follow-up, an older group of 20 cases with follow-up, and the data set obtained by pooling both groups. In all groups good clusterings were found in the sense that clinically similar cases were placed into the same clusters on the basis of the genetic information only. The data indicate that losses on chromosome arms 6q, 8p and 13q are all frequent in pT2N0 prostatic cancer, but the loss on 8p has probably the largest prognostic importance.

Carcinoma↗

PubMed2001

Prediction of postoperative prostatic cancer stage on the basis of systematic biopsies using two types of artificial neural networks.

OBJECTIVE: The choice of therapy for prostatic cancer should depend on a rational preoperative estimate of tumor stage. Artificial neural networks were used to predict postoperative staging of prostatic cancer from sextant biopsies and routinely available preoperative data. METHODS: In group I (97 cases), nonorgan confinement (tumor stage > or =pT3a) was predicted on the basis of age and six histopathological variables from sextant biopsies. In group II (77 cases), nonorgan confinement and extraprostatic organ infiltration (tumor classification > or =pT3b) were predicted from age, four histopathological variables, the preoperative PSA level, and the total prostate volume estimated by preoperative ultrasonography. Learning vector quantization (LVQ) networks were applied for this purpose and compared to multilayer perceptrons (MLP) and linear discriminant analysis (LDA). RESULTS: Nonorgan confinement could be predicted correctly in 90% of newly presented cases from sextant biopsy histopathology alone. A similar accuracy of predicting nonorgan confinement (83%) was obtained by combining preoperative biopsy histology with clinical data. Extraprostatic organ infiltration could be predicted correctly in 82%. The best results were obtained by LVQ networks, followed by MLP networks and LDA. CONCLUSION: The postoperative tumor stage of prostatic cancer can be estimated with high accuracy, sensitivity and specificity from preoperative routine parameters using artificial neural networks, especially LVQ networks. The results suggest that this methodology should be evaluated in a larger prospective study.

Aged↗

PubMed2001

Ki-67 immunostaining in pancreatic cancer and chronic active pancreatitis: does in vivo FDG uptake correlate with proliferative activity?

UNLABELLED: PET with 18F-FDG has been shown to be useful in the detection and staging of pancreatic cancer. However, whether FDG uptake is dependent on proliferative activity is still unclear. The aim of this prospective study was to evaluate a probable correlation between FDG uptake and proliferative activity in benign and malignant pancreatic tumors. METHODS: Our series consisted of 23 patients with pancreatic cancer and 9 patients with chronic active pancreatitis (CAP). FDG PET was performed within 2 wk before surgery, and standardized uptake values (SUVs) were calculated for benign and malignant pancreatic tumors. Patients were selected when focally increased FDG uptake in previously known pancreatic tumors was present. Proliferation fraction was measured in tissue specimens using the anti-Ki-67 antibody MIB-1. A computer-assisted imaging system was used for quantification of nuclear Ki-67 immunostaining. Immunohistochemical findings were correlated to SUVS: RESULTS: Pancreatic cancer showed both intense nuclear staining of Ki-67 (39% +/- 16%) and high FDG uptake (SUV = 3.6 +/- 1.6). However, no significant correlation was found between in vivo FDG uptake and Ki-67 immunoreactivity (P = 0.65). By contrast, Ki-67 nuclear staining was significantly lower (3.8% +/- 2.7%, P < 0.05) in CAP, whereas FDG uptake was in the same range as for pancreatic cancer (SUV = 3.5 +/- 1.8). CONCLUSION: FDG uptake did not correlate with proliferative activity in pancreatic cancer. Proliferative activity was tenfold higher in malignant pancreatic tumors than in benign tumors associated with CAP, whereas FDG uptake in vivo did not differ significantly. Thus, a PET tracer indicating cellular proliferation should better differentiate between cancer and inflammatory lesions than do metabolic markers such as FDG.

Adenocarcinoma↗

PubMed2001

Leiomyosarcoma of the ethmoidal cells.

Leiomyosarcomas of the paranasal sinuses are rare malignant tumors. A case of a 68-year-old female with leiomyosarcoma of the ethmoidal cells is presented. Since half a year she had a stuffed nose on both sides. Preoperatively, several attacks of epistaxis on the right side occurred. CT scans showed a tumor of the ethmoidal cells on the right side. The tumor was completely removed via a functional endoscopic endonasal approach and right sphenoethmoidectomy and maxillary sinus surgery. The operation was followed by a radiotherapy with 72 Gy. Up to 29 months after the operation local recurrence could not be observed. Endonasal tumor resection followed by radiotherapy in a case of leiomyosarcoma without invasion of orbit and skull base can allow tumor control.

Aged↗

PubMed2000

Duodenum-preserving pancreatic head resection in patients with benign and borderline tumors of the pancreatic head.

BACKGROUND: Benign tumors of the pancreas are rare, accounting for only 1-2% of primary pancreatic lesions. Up to now, partial duodenopancreatectomy is still one of the established forms of treatment of benign tumors of the pancreas. We applied duodenum-preserving pancreatic head resection in 12 patients with benign pancreatic tumors to evaluate the feasibility, morbidity and recurrence rates after this less aggressive method. METHODS: Between April 1984 and December 1999, 12 patients with benign and borderline tumors of the pancreatic head were operated on by duodenum-preserving pancreatic head resection. RESULTS: All five patients with serous cystadenoma are free of recurrence 4.4 years after primary resection. One of two patients with mucinous cystadenoma and one of three patients with intraductal papillary mucinous tumor developed recurrent tumor within the former pancreatic head 5 years and 6 years, respectively, after the primary operation. Both patients were resected a second time. One of two patients with gastrinoma still has elevated serum gastrin levels. There was no hospital or long-term mortality. CONCLUSION: For a symptomatic serous cystadenoma, duodenum-preserving pancreatic head resection is a good alternative to partial duodenopancreatectomy. In borderline tumors with malignant potential, we would rather suggest a more radical duodenum-preserving segmental resection. A video clip (3 min) is attached demonstrating the basic steps of duodenum-preserving pancreatic head resection.

Adult↗

PubMed2000

Classification of spatial textures in benign and cancerous glandular tissues by stereology and stochastic geometry using artificial neural networks.

Stereology and stochastic geometry can be used as auxiliary tools for diagnostic purposes in tumour pathology. Whether first-order parameters or stochastic-geometric functions are more important for the classification of the texture of biological tissues is not known. In the present study, volume and surface area per unit reference volume, the pair correlation function and the centred quadratic contact density function of epithelium were estimated in three case series of benign and malignant lesions of glandular tissues. The information provided by the latter functions was summarized by the total absolute areas between the estimated curves and their horizontal reference lines. These areas are considered as indicators of deviation of the tissue texture from a completely uncorrelated volume process and from the Boolean model with convex grains, respectively. We used both areas and the first-order parameters for the classification of cases using artificial neural networks (ANNs). Learning vector quantization and multilayer feedforward networks with backpropagation were applied as neural paradigms. Applications included distinction between mastopathy and mammary cancer (40 cases), between benign prostatic hyperplasia and prostatic cancer (70 cases) and between chronic pancreatitis and pancreatic cancer (60 cases). The same data sets were also classified with linear discriminant analysis. The stereological estimates in combination with ANNs or discriminant analysis provided high accuracy in the classification of individual cases. The question of which category of estimator is the most informative cannot be answered globally, but must be explored empirically for each specific data set. Using learning vector quantization, better results could often be obtained than by multilayer feedforward networks with backpropagation.

Breast↗

PubMed2000

Improved estimation of the pair correlation function of random sets.

The texture of binary spatial structures can be characterized by second-order methods of spatial statistics. The pair correlation function, which describes the structure in terms of spatial correlation as a function of distance, is of central importance in this context. Conventionally, the pair correlation function of stationary and isotropic random sets is estimated as the ratio of the covariance to the square of volume fraction of the phase of interest. In the present paper, an improved estimator of the pair correlation function is presented, where the covariance is divided by the square of a distance-adapted estimator of volume fraction. The new estimator is explained mathematically and applied to simulated images of the Boolean model and to microscopic images from neoplastic and non-neoplastic human glandular tissues. It leads to a considerable reduction of bias and variance of estimated pair correlation functions, in particular for large distances.

Animals↗

PubMed1999

Molecular mediators of tumor angiogenesis: enhanced expression and activation of vascular endothelial growth factor receptor KDR in primary breast cancer.

The progression of breast cancer growth and its ability to metastasize are associated with the process of angiogenesis. In this study, we examined the protein expression of vascular endothelial growth factor (VEGF) and its specific and functional receptor KDR in human breast tissue. We investigated a total of 13 mammary carcinomas, 3 fibroadenomas, 5 specimens with fibrocystic breast disease as well as normal (adjacent to malignant) breast tissue using immunohistochemistry and Western blot analysis. In all carcinomas examined, functional KDR protein was present independent of tumor type, tumor stage and histological grade as demonstrated by tyrosine phosphorylation analysis of KDR. When malignant tissues were compared with their neighboring non-neoplastic regions, activated KDR was found to be expressed to a much higher extent within the malignant tissue samples. In fibroadenomas, KDR was barely detectable, whereas in fibrocystic breast disease KDR expression was variable. Immunostaining of KDR was localized to endothelium and epithelium of mammary ducts in malignant and benign breast tissue, while VEGF immunoreactivity was primarily found in the endothelium and also in tumor cells and macrophages. Our data demonstrate that KDR activation is enhanced in breast cancer in vivo and emphasize the functional role of VEGF and KDR in the development of malignant breast disease.

Breast Neoplasms↗

PubMed1999

Detailed marker chromosome analysis in cell line U-BLC1, established from transitional-cell carcinoma of the bladder.

A permanent cell line, U-BLC1, was established from a primary transitional-cell carcinoma, TCC, of the urinary bladder. Karyotype analysis showed the line to be highly aberrant, with a near-triploid chromosome number of 68 to 73. Comparative genomic hybridization revealed some distinct differences between the primary tumor and the established cell line. Karyotype analysis showed 3 marker chromosomes with homogeneously staining regions, HSRs, in the cell line. The HSRs were isolated by microdissection and the microdissection probes were hybridized to normal metaphase chromosomes. The HSRs contain sequences known to be frequently involved in amplification in transitional-cell carcinoma of the bladder, 6p22, 7p11-p12, 9p23-pter, and one region not yet reported to be amplified in primary TCC of the bladder, 1p31-p32. A candidate-gene approach showed that in the region 7p11-p12 the EGFR locus is amplified and highly expressed.

Aged↗