[Histopathological differential diagnostics in context of joint implant allergic reactions]. / Histopathologische Differenzialdiagnostik bei gelenkimplantatallergischen Fragestellungen.

Total joint replacement has greatly increased over the last decades and so have endoprothesis-associated pathologies. European studies have shown a 10-year durability varying from 88% to 95%. By means of histopathology different pathogenetic synovial-like interface membrane (SLIM) patterns that lead to reduction of implant durability can be discerned, such as periprosthetic particles, bacterial infections and arthrofibrosis. Subsequently, SLIM types have been determined in a revised consensus classification including particle-induced type (type I) so-called non-septic loosening, infection type (type II) so-called septic loosening, combination type (type III) of bacterial and particle-induced types, indifferent type with mechanical and functional disorders (type IV), osseus pathologies (type V), arthrofibrotic type (type VI, endoprosthesis-associated arthrofibrosis) and allergic/immunological/toxic reactions to prosthesis material (type VII). Particles are characterized histopathologically according to the Krenn particle algorithm. In cases of severe lymphocyte/macrophage infiltration, necrosis, abrasion particle detection and granuloma formation, a toxic or allergic reaction to implant material should be considered. As a direct abrasion particle-induced toxicity cannot be differentiated from a particle-induced allergic type VII reaction to implant material, the histopathological diagnosis of toxic reaction to implant material or allergic reaction to implant material should be made with caution and only in association with immunological, allergic and clinical data. It is recommended that tissue samples should be arthroscopically taken from different regions: close to the prosthesis, distant from the prosthesis and from bone tissue. The pathologist should be given information concerning clinical, allergological and microbiological data.

[Revised consensus classification. Histopathological classification of diseases associated with joint endoprostheses]. / Erweiterte Konsensusklassifikation. Histopathologische Klassifikation von Gelenkendoprothesen-assoziierten Erkrankungen.

The revised classification of the periprosthetic membrane (synovial-like interface membrane SLIM) encompasses all pathological alterations which can occur as a result of endoprosthetic replacement of major joints and lead to a reduction in durability of prostheses. This also includes the established consensus classification of SLIM by which aseptic and septic prosthetic loosening can be subdivided into four histological types and histopathological criteria for additional pathologies: endoprosthesis-associated arthrofibrosis, immunological/allergic alterations and osseous pathologies. This revision represents the foundation for the histopathological diagnostics of the total spectrum of diseases associated with joint prostheses, is a suitable basis for a standardized diagnostic procedure and etiological clarification of endoprosthesis failure and also as a data standard for endprosthesis registers, in particular for registers based on routine data (e.g. German endoprosthesis register).

[Synovialitis of the arthrofibrotic type: criteria of a new synovialitis type for the diagnosis of arthrofibrosis]. / Synovialitis vom arthrofibrotischen Typ: Kriterien eines neuen Synovialitis-Typus für die Diagnose der Arthrofibrose.

After rheumatologic conservative medical therapy has been exhausted in degenerative and inflammatory joint diseases, arthroplastic operations are an important option to restore quality of life. Endoprosthesis-associated arthrofibrosis is a severe fibrosing disease of the synovial membrane after endoprosthetic operations. Neither the morphological substrate nor histopathological criteria have been described. The aim was to describe the histopathological substrate of arthrofibrosis and to define histological and immunohistochemical criteria of arthrofibrosis on the basis of tissue samples derived from revision. In histopathological analyses arthrofibrosis revealed a synovialitis with varying fibrosis, without detectable ossification and without minimal wear particle reaction (so-called synovialitis of arthrofibrotic type, SAT). A 3-stage grading was determined based on the cellular density of the fibrous tissue (fibroblast cellularity). In 191 cases with SAT, grade 1 was found in 24.1 % (n = 46), grade 2 was found in 51.8 % (n = 99) and grade 3 was found in 24.1 % (n = 46). The control group consisted of 29 cases with synovialitis of indifferent type (type IV membrane). If SAT grades 2 and 3 are summed together, i.e. the distance between the fibroblasts was less than two cell lengths, the difference of the fibroblast cellularity compared with the type IV membrane was significant (p < 0.001). Above SAT grade 2 the diagnosis of arthrofibrosis could be made with a sensitivity 0.7592 and specificity 0.8276. The SM-alpha-actin cytoplasmic positivity of fibroblasts indicates a myofibroblast phenotype and the ß-catenin positivity suggests a resemblance to fibromatosis or a keloid-like process. In the quantitative evaluation of the ß-catenin positive fibroblasts, there was a significant difference (p < 0.001) between type IV membrane and SAT. A threshold value of 20 beta-catenin positive cells per microscopic high power field (HPF) was determined, which represents in conjunction with the clinical information a new histopathological diagnosis component (sensitivity 0.720, specificity 0.867).

[Indications for tissue biopsy. Diagnostic histopathology in rheumatological diseases]. / Biopsieindikationen. Histopathologische Diagnostik in der Rheumatologie.

The role of a standardized histopathological examination of tissue biopsies and of different tissue compartments (synovia, vascular tissue, bone) is discussed in order to stratify the therapy of different forms of arthritis and other rheumatological diseases. Furthermore the diagnostic steps for the histopathological diagnosis of metabolic osteopathic diseases are highlighted. The synovitis-score is described as a diagnostic device leading to the diagnosis of a low-grade synovitis, which is associated with degenerative and posttraumatic arthropathies, or of a high-grade synovitis which is associated with rheumatic diseases.

High STEAP1 expression is associated with improved outcome of Ewing's sarcoma patients.

BACKGROUND: Ewing's sarcoma (ES) is the second most common bone or soft-tissue sarcoma in childhood and adolescence and features a high propensity to metastasize. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a membrane-bound mesenchymal stem cell marker highly expressed in ES. Here, we investigated the role of STEAP1 as an immunohistological marker for outcome prediction in patients with ES. PATIENTS AND METHODS: Membranous STEAP1 immunoreactivity was analyzed using immunohistochemistry in 114 primary pre-chemotherapy ES of patients diagnosed from 1983 to 2010 and compared with clinical parameters and patient outcome. Median follow-up was 3.85 years (range 0.43-17.51). RESULTS: A total of 62.3% of the ES samples displayed detectable STEAP1 expression with predominant localization of the protein at the plasma membrane. High membranous STEAP1 immunoreactivity was found in 53.5%, which correlated with better overall survival (P=0.021). Accordingly, no or low membranous STEAP1 expression was identified as an independent risk factor in multivariate analysis (hazard ratio 2.65, P=0.036). CONCLUSION: High membranous STEAP1 expression predicts improved outcome and may help to define a specific subgroup of ES patients, who might benefit from adapted therapy regimens.

The psychosocial burden of essential tremor in an outpatient- and a community-based cohort.

BACKGROUND AND PURPOSE: To compare psychosocial burden in patients with essential tremor (ET) in an outpatient (OPC)- and a community-based cohort (CBC). METHODS: A sample of outpatients of a tertiary referral center (n = 180) and a community-based sample (n = 100) with ET were asked for study participation. Psychosocial aspects were assessed by a questionnaire on psychosocial aspects of ET, neuropsychological scales, quality of life, personality traits, and coping strategies. RESULTS: One hundred and seven patients of the OPC and 90 individuals of the CBC participated and their results are descriptively presented. Statistical analysis was restricted to 38 pairs of OPC and CBC individuals matched for age, sex, and tremor severity. One-third of these individuals reported a profound impairment in everyday or professional life. Neuropsychological scales showed a severe depression in 8% of the individuals and pathologic values for the general level of psychiatric symptoms in 26%. The main coping strategy was 'active problem-orientated coping'. Patients of the OPC perceived a more severe impact of ET on their life. Multivariate analysis revealed the Beck Depression Inventory score as the only predictive factor for the outcome variables, physical and mental component scores, of the SF-12 health survey. CONCLUSIONS: ET causes a significant psychosocial impairment, which does depend on symptom severity but also on mood with depression as the main driving factor and other so far undetermined factors.

[Histopathological degeneration score of fibrous cartilage. Low- and high-grade meniscal degeneration]. / Histopathologischer Degenerations-Score des Faserknorpels. Low-grade- und High-grade-Meniskusdegeneration.

Although histopathology of meniscal degeneration plays an important role, no criteria to assess severity of the degeneration are available to date. Our aim was to create a histopathological scoring system for meniscal degeneration with good interobserver variability, taking matrix degradation and cellularity in meniscal tissue into consideration. Degeneration is classified as follows: grade 1 (low), grade 2 (intermediate), grade 3 (high). The pattern of NITEGE deposits (G1 fragment of aggrecan) was assessed immunohistochemically (n=38) and compared with the grades of degeneration. In 48% of the patients with grade 2 or 3 degeneration extracellular NITEGE deposits (specificity 100%) were found, whereas grade 1 patients showed no deposits. Extracellular NITEGE deposits correlated positively with the grade of degeneration. In all, 30 cases (10 per grade) were assessed by three pathologists (A, B, C). Grading conformity was 70% for grade 1, 66% for grade 2 and 100% for grade 3. Cohen's Kappa coefficient was 0.6--0.7 between pairs of observers. Combining grade 1 and 2 to low-grade degeneration, compared to a grade-3 high-grade degeneration achieved Kappa coefficients of between 0.93 and 1.0. This reproducible degeneration score for fibrous cartilage could form the basis for the standardized assessment of meniscal degeneration.

[Analysis of the statistical value of various commercially available stool tests - a comparison of one stool sample in correlation to colonoscopy]. / Evaluierung der statistischen Kennwerte verschiedener kommerziell erhältlicher Stuhltests - Ein Quervergleich aus derselben Stuhlprobe in Korrelation zur Koloskopie.

INTRODUCTION: Guajac based fecal occult blood tests have proven to reduce mortality of colorectal cancer - despite their unsatisfactory statistical values. The potential of newer tests is yet inconclusive. We compared two guajac based, four immunochemical and the M2-PK test with colonoscopic and histological results as a reference. METHODS: In 1128 stool samples of patients undergoing (screening) colonoscopy the mentioned tests were performed. RESULTS: Positivity rate was 1.9 to 4.1 % for guajac based and immunochemical tests, M2-PK reached 11.6 %. In case of advanced neoplasias, no significant differences in sensitivity (7.3 - 20 %), specifity (96.6 - 98.4 %), positive predictive value (16.7 - 30.6 %) or accuracy (92.9 - 94.0 %) between guajac based and immunochemical tests were encountered. The slightly higher sensitivity of M2-PK (27.3 %) did not reach statistical significance - however the comparatively low specifity (89.2 %) and accuracy (86.2 %) were clearly lower compared to all other tests. Regarding all neoplasia, immunochemical tests performed better than conventional hemoccult, but the difference did not reach statistical significance. In this group, the sensitivity of M2-PK is clearly better, but specifity is clearly inferior to all other tests. DISCUSSION: Low sensitivity and low predictive values are explained by the study design with single test and low prevalence of neoplasia. Due to small numbers, there is only a trend, but no significant difference between the performance of conventional hemoccult compared with immunochemical and high senstitive guajac tests. Because of its low specificity, M2-PK is not an appropriate screening test for colorectal neoplasia.

[Cystic desmoplastic small round cell tumor: tumor development from cystic-"mesothelioblastic" areas?]. / Zystischer desmoplastischer klein- und rundzelliger Tumor: Tumorentwicklung aus zystisch-"mesothelioblastischen" Arealen?

A 7-cm cystic lesion in the upper left abdomen and additional smaller solid tumor nodules were diagnosed incidentally in a 15-year-old boy without tumor symptoms. The main tumorous cystic lesion showed a flattened single-cell tumor cell component in gradual transition to stratified, papillary and truly "invasive" typical desmoplastic areas of a desmoplastic small round-cell tumor (DSRCT). The Ki-67-proliferation index gradually increased within three histologic tumor patterns up to about 70% in the typical desmoplastic (infiltrating) component. Using microdissection techniques, EWS-WT1-gene fusion transcripts were detected in the cystic (single-cell-layered), the papillary and the solid tumor proliferations (exon 7 of EWS on chromosome 22 with exon 8 of WT1 on chromosome 11). The presented case illustrates a predominant cystic growth pattern of DSRCT, in which a stepwise development in the pathogenesis of DSRCT from cystic (-"mesothelioblastic") towards a more papillary proliferation and finally typical "infiltrative" desmoplastic tumor pattern might be discussed. The cystic pattern could represent an initial stage in the development of the neoplasia. The presence of specific EWS-WT1-gene fusion transcripts in all tumor growth patterns in this respect would indicate an early event in t(11;22)(p13;q12) translocation in the pathogenesis of DSRCT.

Reexcision of soft tissue sarcoma: sufficient local control but increased rate of metastasis.

BACKGROUND: Assuming a benign tumor, soft tissue sarcomas are often treated by inadequate resection. The concept of reexcision in these patients is still under debate. Therefore, it was our goal to evaluate the results of this treatment with particular respect to residual tumor. METHODS: During a 14-year period, a total of 143 patients were referred to Heinrich-Heine-University Düsseldorf and the University of Hamburg [corrected] after unplanned excision. Reexcision was performed in 139 patients. The assessed endpoints were local recurrence-free survival, distant metastasis-free survival, and tumor-related mortality. Univariate and multivariate analyses were performed using a log-rank test and Cox's proportional-hazard models. RESULTS: Over a median observation period of 109 months, local recurrence appeared in 18 patients (12%) and distant metastasis in 46 patients (33%). Residual tumor was detected in 43 patients (31%) and was significantly associated with reduced relapse-free and overall survival. Local recurrence, however, was not affected. CONCLUSIONS: Despite an incomplete initial resection, reexcision enables local control similar to that in patients without residual tumor. Still, these patients have a worse prognosis owing to an increased rate of distant metastasis; therefore, patients with soft tissue masses of unknown identity should be transferred to centers that specialize in treating sarcomas for adequate initial resection.

Stable interference of EWS-FLI1 in an Ewing sarcoma cell line impairs IGF-1/IGF-1R signalling and reveals TOPK as a new target.

BACKGROUND: Ewing sarcoma is a paradigm of solid tumour -bearing chromosomal translocations resulting in fusion proteins that act as deregulated transcription factors. Ewing sarcoma translocations fuse the EWS gene with an ETS transcription factor, mainly FLI1. Most of the EWS-FLI1 target genes still remain unknown and many have been identified in heterologous model systems. METHODS: We have developed a stable RNA interference model knocking down EWS-FLI1 in the Ewing sarcoma cell line TC71. Gene expression analyses were performed to study the effect of RNA interference on the genetic signature of EWS-FLI1 and to identify genes that could contribute to tumourigenesis. RESULTS: EWS-FLI1 inhibition induced apoptosis, reduced cell migratory and tumourigenic capacities, and caused reduction in tumour growth. IGF-1 was downregulated and the IGF-1/IGF-1R signalling pathway was impaired. PBK/TOPK (T-LAK cell-originated protein kinase) expression was decreased because of EWS-FLI1 inhibition. We showed that TOPK is a new target gene of EWS-FLI1. TOPK inhibition prompted a decrease in the proliferation rate and a dramatic change in the cell's ability to grow in coalescence. CONCLUSION: This is the first report of TOPK activity in Ewing sarcoma and suggests a significant role of this MAPKK-like protein kinase in the Ewing sarcoma biology.

Survival after an antiangiogenetic therapy and surgery in a wide spread growing teratoma originating from a testicular mixed malignant germ cell tumor.

Growing teratoma is still an often unsolved problem especially in male with mixed malignant GCTs of the testis or the mediastinum. This specific situation with progressive tumor growth and simultaneous normalization of tumor markers during or after treatment of malignant GCTs with teratomatous elements is judged as a fatal situation if this situation can not be controlled by extensive surgery, as teratoma are not sensible to chemotherapy or irradiation. Here, we report the case history of a 17-year old male patient with a testicular malignant GCT and wide spread lymph node metastases, who developed a rapidly progressive growing teratoma within the lymph node metastases. Within the molecular profile of the tumor we could find a cytogenetic picture typically found in malignant adult GCTs. In view of the bulky abdominal, thoracic and cervical metastases and the uncontrolled tumor progression, the situation was considered incurable. However, following an individual treatment attempt, this patient was treated with a four-agent combination of drugs with antiangiogenetic potential as well as low-dose cyclic chemotherapy. This approach resulted in a sustained disease stabilization followed by extensive surgical resection of the metastases. We therefore would like to highlight this treatment approach in unresectable growing teratoma and would like to stimulate further research and collaboration to come to an optimized treatment suggestion for this group of poor prognostic patients.

Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM-01 trial.

BACKGROUND: This paper evaluates the prognostic and predictive impact of protein expression of various molecular markers in high-risk breast cancer (HRBC) patients with >9 involved lymph nodes, who received different chemotherapy dose-intensification strategies within a prospective randomized WSG AM-01 trial. MATERIALS AND METHODS: Paraffin-embedded tumors from 236 patients, who were randomly assigned to dose-dense conventional chemotherapy with four cycles of E(90)C(600) followed by three cycles of C(600)M(40)F(600) every 2 weeks (DD) or a rapidly cycled tandem high-dose regimen with two cycles of E(90)C(600) every 2 weeks followed by two cycles of E(90)C(3000)Thiotepa(400) every 3 weeks (HD), were available for retrospective central pathological review (116 HD/120 DD). Expression of estrogen receptor (ER), progesterone receptor (PR), MIB-1, epidermal growth factor receptor, and Her-2/neu was evaluated immunohistochemically using tissue microarrays. Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis). RESULTS: After a median follow-up of 61.7 months, 5-year event-free survival (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% versus 41% [hazard ratio (HR) = 0.60, 95% CI 0.43-0.85, P = 0.004]; OS: 76% versus 61% (HR = 0.58, 95% CI 0.39-0.87, P = 0.007). In multivariate analysis, HD, tumor size <3 cm, positive PR, negative MIB-1 staining, and grade 1/2 were associated with favorable outcome. Interaction analysis showed that regarding predictive effects, triple negative (ER/PR/Her-2/neu) and G3 tumors derived most benefit from HD. CONCLUSION: Tandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple-negative tumors and/or G3 with their poor prognostic marker profile.

Interdisciplinary treatment of primary hepatic angiosarcoma: emergency tumor embolization followed by elective surgery.

Among primary hepatic malignancies, sarcomas represent a minority of 2 %. Of those, primary hepatic angiosarcoma is the most common one. In the past its incidence has been related to the exposure of certain chemicals like thorotrast, vinyl-chloride or arsenic. - Patients suffering from this aggressive, highly vascular tumor have a poor prognosis in general. Without treatment most of them die after rapid tumor progression with multifocal dissemination. In case of tumor perforation, fatal abdominal hemorrhage has been observed. - We herein report the successful interdisciplinary treatment of an 81 year-old woman with a perforated primary hepatic angiosarcoma of the left hepatic lobe. Initially, tumor bleeding was stopped by emergency interventional coil embolization. After stabilization of the patient, we performed an elective tumor resection. The patient could eventually be discharged in a good clinical condition. - So far, no standard therapy has established for patients with primary hepatic angiosarcoma. Surgery seems to be the treatment of choice. In addition, preoperative interventional embolization of the tumor supplying vessels reduces the risk of pre- and intraoperative bleeding. The value of adjuvant chemotherapy is not yet clarified. - The outcome of most patients with primary hepatic angiosarcoma remains poor and there is a need for clinical studies.

Microsatellite instability in Ewing tumor is not associated with loss of mismatch repair protein expression.

Only few clinical factors predict the prognosis of patients with Ewing tumors. Unfavorable outcome is associated with primary metastatic disease, age > 15 years, tumor volume above 200 ml, and the histological response to chemotherapy. The aim of this study was to elucidate the prevalence and clinical impact of microsatellite instability (MSI) together with the relation between MSI and mismatch repair protein expression in Ewing tumors. DNA from 61 primary Ewing tumors and 11 Ewing tumor cell lines was extracted and microsatellite analysis for the detection of instability or loss of heterozygosity was performed for the five markers of the Bethesda panel BAT25, BAT26, D5S346, D2S123, and D17S250, which represents the established marker panel for the analysis of hereditary non-polyposis colorectal carcinoma (HNPCC) patients. In addition, single nucleotide repeat regions of the two tumor genes BAX and transforming growth factor receptor II (TGFBR2) were also included. All of the 61 samples were suitable for LOH analysis and 55 for the determination of MSI-status. LOH of these microsatellite markers was detected in 9 of the 61 patients (14.8%). Over all, genetic instability, i.e. MSI and/or LOH, was detected in 17 tumors (27.9%). One out of the 11 tumor cell lines (STA ET1) was characterized by instability of all the five Bethesda markers, while from primary tumor samples, only one showed MSI in more than one microsatellite marker (D5S346 and D17S250, MSI-high). Eight of the fifty-five patients (14.5%) showed instability of one microsatellite locus (MSI-low). No instability was detected in BAT26, D2S123, BAX and TGFBR2. There was no significant correlation between MSI and loss of expression of mismatch repair proteins MLH1, MSH2, or MSH6. The impairment of the p53 signaling pathway (expression of TP53 and/or MDM2 by immunohistochemistry) was significantly associated with reduced overall survival (15 of 49 patients (30.6%), P = 0.0410, log-rank test). We conclude that MSI is not prevalent in Ewing tumor and that the nature of instability differs from the form observed in colorectal carcinoma, the model tumor of MSI. This is documented by the different pattern of MSI (no BAT26 instability) in Ewing tumors and the lack of a strict correlation between MSI-high and loss of expression of MSH2, MSH6 and MLH1.

[Prognostic and predictive impact of protein expression profiling in high risk breast cancer patients treated with high-dose chemotherapy]. / Prognostische und prädiktive Bedeutung von Proteinexpressions-Profilen in einer Hochrisiko-Mammakarzinomsubgruppe aus der WSG AM01 phase III-Studie (Hochdosis-Chemotherapie versus konventionelle dosis-dichte Chemotherapie).

The prognostic and predictive impact of protein expression profiles was analyzed in high-risk breast cancer patients who had previously been shown to benefit from high-dose chemotherapy (HDCT) in comparison to dose-dense chemotherapy (DDCT). Using tissue microarrays, the expression of 34 protein markers was evaluated in 236 patients who had received either HDCT or DDCT (in the WSG AM01 trial). 1) 24 protein markers of the initial panel of 34 markers were sufficient to identify five profile clusters by K-means clustering: luminal A (27%), luminal B (12%), HER-2 (21%), basal-like (13%) cluster and a so called 'multiple marker negative'=MMN cluster (27%) characterized by the absence of specifying markers. 2) After DDCT, HER-2 and basal-like groups had significantly worse event-free survival (EFS) (HR 3.6 (95% CI, 1.65-8.18; p = 0.001) and HR 3.7 (95% CI, 1.68-8.48); p < 0.0001), respectively) when compared to both luminal groups. 3) After HDCT, the hazard ratio was 1.5 (95% CI, 0.76-3.05) for EFS in the HER-2 subgroups and 1.1 (95% CI, 0.37-3.32) in the basal-like subgroups which indicates a better outcome for patients in the HER-2 and basal-like subgroups who received HDCT. Protein expression profiling in high-risk breast cancers identified 5 subtypes, which differed with respect to survival and response to chemotherapy: In contrast to luminal A and B subtypes, HER-2 and basal-like subgroups had a significant predictive benefit from HDCT when compared to DDCT.

[Transient elastography for diagnosing liver cirrhosis]. / Transiente Elastografie zur Diagnose der Leberzirrhose.

BACKGROUND AND OBJECTIVE: Detection of liver cirrhosis has numerous implications because of the potential sequelae of cirrhosis. Transient elastography (Fibroscan), was evaluated as a novel, non-invasive means of assessing cirrhosis by measuring liver stiffness. METHODS: 147 consecutive patients with different forms of liver disease and histologically determined stages of liver fibrosis were prospectively studied by transient elastography. 48 patients had liver cirrhosis. RESULTS: The number of transient elastographic measurements per patient was 12+/-4 (range 6 - 30). Valid elastography measurements were available for 135 out of 147 patients (92 %). The results of transient elastography correlated positively with the histological score of liver fibrosis (r = 0.8; 95 % CI: 0.72 - 0.85; p < 0.001). Areas under the receiver operating characteristic curve (AUROC) were 0.91 for > or = F3 fibrosis (95 % CI: 0.85 - 0.96) and 0.94 for cirrhosis (95 % CI: 0.90 - 0.98). Using a cut-off value of 13 kPa for detection of liver cirrhosis a sensitivity of 90 %, a specificity of 82 %, a positive predictive value of 71 % and a negative predictive value of 95 % were obtained. CONCLUSIONS: Measuring liver stiffness by transient elastography proved to be an easy method to assess liver cirrhosis. In combination with clinical signs, ultrasound and biochemical markers noninvasive diagnosis of liver cirrhosis will be further improved.

Suppression of KCMF1 by constitutive high CD99 expression is involved in the migratory ability of Ewing's sarcoma cells.

High CD99 expression levels and rearrangements of the EWS gene with ETS transcription factor genes characterize the Ewing's sarcoma family of tumors (ESFT). CD99 is a cell surface glycoprotein whose engagement has been implicated in cell proliferation as well as upregulation and transport of several transmembrane proteins in hematopoietic cells. In ESFT, antibody ligation of CD99 induces fast homotypic cell aggregation and cell death although its functional role in these processes remains largely unknown. Here, using an RNAi approach, we studied for the first time the consequences of modulated CD99 expression in six different ESFT cell lines, representing the most frequent variant forms of EWS gene rearrangement. CD99 suppression resulted in growth inhibition and reduced migration of ESFT cells. Among genes whose expression changes in response to CD99 modulation, the potassium-channel modulatory factor KCMF1 was consistently upregulated. In a series of 22 primary ESFT, KCMF1 expression levels inversely correlated with CD99 abundancy. Cells forced to express ectopic KCMF1 showed a similar reduction in migratory ability as CD99 silenced ESFT cells. Our results suggest that in ESFT, high CD99 expression levels contribute to the malignant properties of ESFT by promoting growth and migration of tumor cells and identify KCMF1 as a potential metastasis suppressor gene downregulated by high constitutive CD99 expression in ESFT.

[Soft tissue sarcomas: the role of histology and molecular pathology for differential diagnosis]. / Diagnostik und Differentialdiagnostik der Weichteilsarkome: Histologie und Molekularpathologie.

Soft tissue sarcomas include a wide spectrum of different entities. The so-called small round blue cell tumors and spindle cell tumors are difficult to classify based solely on conventional histology. To identify different subtypes of tumors special histochemical and immunohistochemical techniques are necessary. Analysis of protein expression by immunohistochemistry provides a helpful tool to investigate the histogenesis of tumors. A basic spectrum of antibodies should be included to study these tumors: Desmin and myogenin (or MyoD1) for skeletal differentiation; S-100, NSE, CD56, and synaptophysin for neural/neuroendocrine differentiation; CD3, CD20, and CD79 alpha for malignant lymphomas; CD34, sm-actin, and beta-catenin for spindle cell tumors; additional antigens, e. g. Ki-67 and p 53, for estimation of proliferation and tumor suppressor gene malfunctions. Nevertheless, the molecular analysis of soft tissue sarcomas is necessary for demonstration of specific translocations or gene defects to specify and proof a diagnosis. For this purpose, RT-PCR for RNA expression analysis of gene fusion transcripts and multi-color FISH for analysis of chromosomal rearrangements are used. Further investigations, using DNA microrrays may help to subclassify such tumors, with respect to prognosis or prediction of therapeutic response.

C-kit expression in high-risk breast cancer subgroup treated with high-dose or conventional dose-dense chemotherapy.

The proto-oncogene c-kit is known to be expressed in poorly differentiated breast cancer. In this study, we retrospectively evaluated the prognostic and predictive impact of c-kit in a high risk subgroup of breast cancer patients (>9 axillary node metastases) who received high-dose (HDCT) or dose-dense (DDCT) conventional chemotherapy and correlated these findings with the expression of the basal-type markers CK5 and CK 17, estrogen (ER) and progesterone (PR) receptor, Her-2/neu and MIB 1. C-kit, CK5, CK17, ER, PR, Her-2/neu and MIBI expression was evaluated immunohistochemically using tissue microarrays containing breast cancer samples from 236 patients who were randomized to the WSG AM01 trial (median follow-up of 60 months). There was a significant overall survival (OS) benefit for patients receiving HDCT compared to DDCT (p = 0.027). C-KIT expression was found in 12 % of all breast cancers and correlated with a poorer OS in multivariate analysis (p = 0.051). Furthermore, c-kit correlated with high grade (p = 0.019), CK5- and CK17-positivity (p <0.0001 and p = 0.001, respectively) and ER- and PR-negativity (p = 0.04 and p = 0.008, respectively). In contrast to CK5 and CK17, patients with c-kit positive breast cancers revealed no benefit from high-dose chemotherapy. These findings underline that c-kit expression represents an independent negative prognostic marker in high-risk breast cancer. Correlation with CK5 +/CK17+ and ER-/PR-suggests that c-kit positive carcinomas are at least partly of basal-type.