Philip Kahl

University of Cologne, Köln, North Rhine-Westphalia, Germany

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Publications (63)230.37 Total impact

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    ABSTRACT: In this study, immunohistochemical staining pattern of cytochrome c oxidase subunit 1 (CCO1) was investigated in the differentiation of renal oncocytoma (RO) from eosinophilic (EoC) and classic chromophobe renal cell carcinoma (ChRCC). A feature found in ChRCC/EoC but not in RO is the predominance of a perinuclear halo when stained for CCO1. In a cohort of 103 mixed cases including 44 RO, 37 classic ChRCC and 22 EoC, the diagnosis based on this immunohistochemical feature alone was consistent with the previous routine diagnosis in 95.7%. We reached 100% specificity and 81.4% sensitivity of this pattern in ChRCC. Specificity for RO was 93.2% and sensitivity correspondingly 95.5%. We propose a novel and easily interpretable immunohistochemical method for the discrimination of benign RO from certain subtypes of malignant ChRCC. Because of strong similarity in morphology of the 2 entities the diagnosis often cannot be made based on standard histopathology alone. The study describes for the first time the formation of a perinuclear halo in CCO1 immunohistochemistry as a highly specific marker for the diagnosis of ChRCC. We think this method can be a strong amendment for routine diagnostics in renal cell carcinoma.
    Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 09/2014; 23(1). DOI:10.1097/PAI.0000000000000036 · 2.06 Impact Factor
  • The Open Prostate Cancer Journal 07/2014; 7(1):7-11. DOI:10.2174/1876822901407010007
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    ABSTRACT: We report a case of possible congenital tuberculosis in a 22+2 weeks, 460 g, vaginally delivered female infant born to a mother suffering from tuberculous endometritis, diagnosed soon after delivery. At 156 days of age, Mycobacterium tuberculosis was detected via PCR from the infant's gastric juice and was subsequently isolated. There was no evidence for horizontal transmission. Mother and child were treated successfully. This case illustrates the possibility of significant latency between infection and clinical manifestation in preterm infants and also emphasizes the need for urgent treatment of neonates in such situations. © 2013 S. Karger AG, Basel.
    Neonatology 11/2013; 105(2):91-94. DOI:10.1159/000355538 · 2.37 Impact Factor
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    ABSTRACT: Background: Postoperative ileus (POI) is an iatrogenic complication of abdominal surgery, mediated by a severe inflammation of the muscularis externa (ME). We demonstrated that orally applicated CPSI-2364 prevents POI in rodents by blockade of p38 MAPK pathway and abrogation of NO production in macrophages. In the present experimental swine study we compared the effect of orally and intravenously administered CPSI-2364 on POI and examined CPSI-2364 effect on anastomotic healing. Methods: CPSI-2364 was administered preoperatively via oral or intravenous route. POI was induced by intestinal manipulation of the small bowel. ME specimens were examined by quantitative PCR for CCL2 chemokine gene expression and myeloperoxidase activity. Functional analyzes included measurement of ileal smooth-muscle ex vivo contractility, in vivo intestinal and colonic transit. Furthermore, anastomotic healing of a rectorectostomy after CPSI-2364 treatment was assessed by perianastomotic hydroxyproline concentration, a histochemically evaluated healing score and anastomotic bursting pressure (ABP). Results: CPSI-2364 abolished inflammation of the ME and improved postoperative smooth muscle contractility and intestinal transit independently of its application route. Hydroxyproline concentration and ABP measurement revealed no wound healing disturbances after oral or intravenous CPSI-2364 treatment whereas histological scoring demonstrated delayed anastomotic healing after intravenous treatment. Conclusion: CPSI-2364 effectively prevents POI in swine independently of its application route. Impairment of anastomotic healing could be observed after intravenous but not oral preoperative CPSI-2364 treatment. Subsumed, an oral preoperative administration of CPSI-2364 appears to be a safe and efficient strategy for prophylaxis of POI. © 2013 S. Karger AG, Basel.
    Cellular Physiology and Biochemistry 11/2013; 32(5):1362-1373. DOI:10.1159/000356575 · 3.55 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2013; 51(08). DOI:10.1055/s-0033-1353110 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2013; 51(08). DOI:10.1055/s-0033-1352731 · 1.67 Impact Factor
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    ABSTRACT: Epithelial-to-mesenchymal transition (EMT), the phenotypical change of cells from an epithelial to a mesenchymal type, is thought to be a key event in invasion and metastasis of adenocarcinomas. These changes involve loss of keratin expression as well as loss of cell polarity and adhesion. We here aimed to determine whether the loss of keratin expression itself drives increased invasion and metastasis in adenocarcinomas and whether keratin loss leads to the phenotypic changes associated with EMT. Therefore, we employed a recently described murine model in which conditional deletion of the Keratin cluster II by Cre-recombinase leads to the loss of the entire keratinmultiprotein family. These mice were crossed into a newly generated Cre-recombinase inducible KRAS-driven murine lung cancer model to examine the effect of keratin loss on morphology, invasion and metastasis as well as expression of EMT related genes in the resulting tumors. We here clearly show that loss of a functional keratin cytoskeleton did not significantly alter tumor morphology or biology in terms of invasion, metastasis, proliferation or tumor burden and did not lead to induction of EMT. Further, tumor cells did not induce synchronously expression of vimentin, which is often seen in EMT, to compensate for keratin loss. In summary, our data suggest that changes in cell shape and migration that underlie EMT are dependent on changes in signaling pathways that cause secondary changes in keratin expression and organization. Thus, we conclude that loss of the keratin cytoskeleton per se is not sufficient to causally drive EMT in this tumor model.
    PLoS ONE 03/2013; 8(3):e57996. DOI:10.1371/journal.pone.0057996 · 3.53 Impact Factor
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    ABSTRACT: Earlier studies indicate that epigenetics contribute to the pathogenesis of penile squamous cell carcinoma. Histone methylation patterns are frequently altered during carcinogenesis. Therefore, we investigated the methylation pattern of the histones H3K4, H3K9 and H3K27 in penile carcinoma and normal tissue.Materials and MethodsA tissue microarray was constructed with 65 penile carcinomas, 6 metastatic lesions and 30 control tissues. Global histone methylation was assessed using immunohistochemistry.ResultsGlobal levels of H3K4me1, H3K9me1, H3K9me2, H3K27me2 and H3K27me3 were decreased, whereas H3K9me3 was increased in penile carcinoma. Histone methylation levels defined an epigenetic entity that allowed accurate differentiation of cancer and normal samples. We observed no correlation of histone methylation levels with clinicopathological parameters or patient outcome.Conclusions The description of a definite epigenetic entity in penile carcinoma provides a rationale for testing epigenetic agents in patients with metastatic disease.
    The Journal of urology 03/2013; 189(3-3):1117-1122. DOI:10.1016/j.juro.2012.08.221 · 3.75 Impact Factor
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    ABSTRACT: We investigated circumscribed cell proliferations in healthy livers in comparison to non-cirrhotic livers bearing hepatocellular carcinoma. Using histochemical staining for cytochrome c oxidase, the fourth complex of the respiratory chain, we visualized patch-forming descendents of regeneratively active liver cells. The clonal nature of these patches was verified by laser-capture microdissection and Sanger sequencing of the enzyme's core subunits in patches carrying marker mutations on the mtDNA. We demonstrate a highly significant increase of the patch size and also a highly significant increase in the number of patches carrying marker mutations between hepatocellular carcinoma-free and -bearing livers. Thus, the carcinoma-bearing livers accumulated more genetic damage on mtDNA than the control group. Furthermore, for the first time, we present evidence in hepatocellular carcinoma-bearing non-cirrhotic livers of a significantly reduced pool of regeneratively active liver cells that are genetically and functionally altered. The analogy to ageing-related changes is suggestive of premature ageing of stem cells in non-cirrhotic hepatocellular carcinoma-bearing liver as an early step to hepatocarcinogenesis. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    The Journal of Pathology 11/2012; 228(3):333-40. DOI:10.1002/path.4060 · 7.33 Impact Factor
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    ABSTRACT: Recent studies have underlined the role of nuclear receptors in the involvement of prostate cancer signalling pathways. A total of 84 benign prostate hyperplasia (BPH), 84 low risk prostate cancer (LPC) and 64 advanced disease (APC) cases were sampled on a tissue microarray (TMA) and stained for retinoic acid receptor (RAR)-α, retionoid X receptor (RXR)-α, liver X receptor (LXR)-α, farnesoid X receptor (FXR) and proliferate-activated receptor gamma (PPAR)-γ and the (pro)-inflammatory molecules cyclooxygenase 2 (COX2), tumor necrosis factor (TNF)-α and inducible Nitric oxide synthase (iNOS) immunohistochemically. PPAR-γ expression in APC tissues was found to be significantly higher than that in LPC and BPH specimens (p<0.001). In contrast, RXR-a expression was significantly lower (p<0.001). COX2 staining demonstrated a trend towards overexpression in APC (p=0.025). No significant differences were found for RAR-α, iNOS and TNF-α expression. Staining of FXR and LXR was seen diffusely in the cytoplasm as well as in the nucleus, preventing sufficient evaluation by definition. This study provides the basis for applying PPAR-γ ligands clinically in treatment of APC.
    Anticancer research 08/2012; 32(8):3479-83. · 1.87 Impact Factor
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    ABSTRACT: Prostate cancer is routinely graded according to the Gleason grading scheme. This scheme is predominantly based on the textural appearance of aberrant glandular structures. Gleason grade is difficult to standardize and often leads to discussion due to interrater and intrarater disagreement. Thus, we investigated whether digital image based automated quantitative histomorphometry could be used to achieve a more standardized, reproducible classification outcome. In a proof of principle study we developed a method to evaluate digitized histological images of single prostate cancer regions in hematoxylin and eosin stained sections. Preprocessed color images were subjected to color deconvolution, followed by the binarization of obtained hematoxylin related image channels. Highlighted neoplastic epithelial gland related objects were morphometrically assessed by a classifier based on 2 calculated quantitative and objective geometric measures, that is inverse solidity and inverse compactness. The procedure was then applied to the prostate cancer probes of 125 patients. Each probe was independently classified for Gleason grade 3, 4 or 5 by an experienced pathologist blinded to image analysis outcome. Together inverse compactness and inverse solidity were adequate discriminatory features for a powerful classifier that distinguished Gleason grade 3 from grade 4/5 histology. The classifier was robust on sensitivity analysis. Results suggest that quantitative and interpretable measures can be obtained from image based analysis, permitting algorithmic differentiation of prostate Gleason grades. The method must be validated in a large independent series of specimens.
    The Journal of urology 03/2012; 187(5):1867-75. DOI:10.1016/j.juro.2011.12.054 · 3.75 Impact Factor
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    ABSTRACT: Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3) at different stages of prostate cancer (PCA) carcinogenesis. Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113), non-malignant prostate disease (n = 27), metastatic hormone-naive PCA (mPCA, n = 30) and castration-resistant PCA (CRPC, n = 34). Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.
    BMC Urology 03/2012; 12:5. DOI:10.1186/1471-2490-12-5 · 1.94 Impact Factor
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    ABSTRACT: To determine the role of global histone H3K9 and H4K20 methylation levels as prognostic parameters in patients with renal cell cancer (RCC). Global histone methylation levels were investigated in 193 RCC (including 142 clear cell (cc), 31 papillary (p), 10 chromophobe (ch) and 10 sarcomatoid (s) RCC), 10 oncocytomas and 30 benign renal specimens. Histone modifications were mostly similar in the different histological subtypes (p>0.05); significant differences were observed for ccRCC vs. pRCC and pRCC vs. sRCC. Comparing the global H3K9 methylation levels of benign renal tissue with RCC H3K9me1 (histone H3 lysine 9 mono-methylation) (p<0.001), H3K9me2 (histone H3 lysine 9 di-methylation) (p=0.001) and H3K9me3 (histone H3 lysine 9 tri-methylation) (p<0.001) was significantly over-expressed in benign renal tissue. H3K9 and H4K20 methylation levels were positively correlated to pT-stage (p<0.005) and grading (p<0.05). In localized RCC (n=144), H3K9me1 levels showed a significant correlation with progression-free survival in the univariate model (p=0.034). Global histone methylation levels may help to identify RCC patients with poor prognosis.
    Anticancer research 03/2012; 32(3):879-86. · 1.87 Impact Factor
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    ABSTRACT: In 25% aller Kolonkarzinome besteht eine familiäre Häufung. Das hereditäre Non-Polyposis-assoziierte Kolorektalkarzinom (HNPCC)/Lynch-Syndrom ist eine autosomal-dominant vererbte Erkrankung, welche einen Anteil von 2–3% aller kolorektalen Karzinome ausmacht. Da der Übergang von gutartigen Vorstufen zu bösartigen Tumoren und das Tumorwachstum im Vergleich zu sporadisch auftretendem Darmkrebs deutlich beschleunigt abläuft, ist ein gründlicher diagnostischer Nachweis von malignen Neoplasien und deren Vorstufen sowie die standardisierte Überwachung der betroffenen Patienten und ihrer Familien notwendig. Um dies zu leisten, wurde 1999 das deutsche HNPCC Konsortium als ein multizentrisches und interdisziplinäres Netzwerk von 7 Universitäten mit kooperierenden Gastroenterologen, Chirurgen, Humangenetikern, Pathologen und Epidemiologen gegründet. Die Pathologie liefert die histologische Diagnose und überprüft die Mikrosatelliteninstabilität (MSI) und die Expression der Mismatch-Reparatur-Proteine im Tumorgewebe. Die Diagnose HNPCC gilt als gesichert, wenn bei MSI-Tumoren die Amsterdam-II-Kriterien erfüllt sind oder wenn eine pathogene Keimbahnmutation in den Mismatch-Reparatur-Genen entdeckt wird. Ebenso gilt die Diagnose HNPCC als bestätigt, wenn eine Mutation fehlt, aber Bethesda-Kriterien erfüllt sind und ein Tumor mit MSI oder Verlust der Mismatch-Reparatur-Proteine gefunden wird. Die Ziele des HNPCC-Konsortiums bestehen in einer verbesserten Überwachung der Indexpatienten und ihrer Familien durch Definition optimaler diagnostischer Intervalle, in der Verbesserung der angewendeten Methoden, in der Entwicklung therapeutischer Ansätze sowie in der Detektion valider prognostischer Marker. Darüber hinaus wird die Integration des HNPCC-Programms in die allgemeine Gesundheitsversorgung angestrebt. Abstract In 25% of all colon cancers there is a familial aggregation. Hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome is an autosomal dominant disease which accounts for a proportion of 2–3% of all colorectal carcinomas. This syndrome shows various, often metachronously occurring tumors in the colon, rectum, stomach, endometrium, small intestine, ovaries, skin and ureter. As the transition from benign precursors to malignant tumors and tumor growth is significantly accelerated in comparison with sporadic colorectal cancer, a thorough diagnostic detection of malignant neoplasms and their precursors and standardized monitoring of affected patients and their families are necessary. To accomplish this, the German HNPCC Consortium was founded in 1999 as a multicentric and interdisciplinary network of seven universities cooperating with gastroenterologists, surgeons, human geneticists, pathologists and epidemiologists. Surgical pathology is an integral part of this network providing the histological diagnosis of tissue taken from patients, analyzing microsatellite instability and expression of DNA mismatch repair proteins in tumor tissue indicating the presence of HNPCC. The diagnosis of HNPCC is considered valid if microsatellite-unstable tumors fulfill the Amsterdam II criteria or if a pathogenic germline mutation is detected in the DNA mismatch repair genes. Similarly, the diagnosis of HNPCC is confirmed when a mutation is missing but Bethesda criteria are met and a tumor with microsatellite instability or loss of DNA mismatch repair proteins is found. The objectives of the German HNPCC Consortium are: better monitoring of the index patients and their families by defining optimal diagnostic intervals in the improvement of the methods used in the development of therapeutic approaches and in the detection of valid prognostic markers. Moreover, another aim of the consortium is the integration of the HNPCC program into general health care.
    02/2012; 27(1):42-46. DOI:10.1007/s12312-011-0724-1
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    ABSTRACT: Global histone modification patterns have been shown to be a predictive factor of recurrence in various cancers. We analyzed global histone-3-lysine-27 (H3K27) methylation in prostate cancer (PCA) tissues. H3K27 mono-, di-, and tri-methylation patterns were different in nonmalignant prostate tissue, localized PCA, metastatic PCA, and castration-resistant PCA. H3K27 mono-methylation was correlated with pT-stage, capsular penetration, seminal vesicle infiltration, and Gleason score in localized PCA and may therefore indicate adverse prognosis.
    Cancer Investigation 12/2011; 30(2):92-7. DOI:10.3109/07357907.2011.636117 · 2.06 Impact Factor
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    ABSTRACT: Lynch syndrome (Hereditary non-polyposis colorectal cancer/HNPCC) is a cancer susceptibility syndrome which is caused by germline mutations in DNA mismatch repair (MMR) genes, in particular MLH1 and MSH2. A pathogenic germline mutation in the respective MMR gene is suggested by the finding of a loss of a mismatch repair protein in tumor tissue on immunohistochemical staining combined with an early age of onset and/or the familial occurrence of colorectal cancer. Pathogenic germline mutations are identifiable in around 60% of patients suspected of Lynch syndrome, depending on the familial occurrence. The aim of the present study was to identify novel susceptibility genes for Lynch syndrome. 64 Healthy controls and 64 Lynch syndrome patients with no pathogenic MSH2 mutation but a loss of MSH2 expression in their tumor tissue were screened for rare and disease causing germline mutations in the functional candidate genes ESR1, ESR2, MAX, PCNA, and KAT2A. Thirty variants were identified, and these were then genotyped in an independent sample of 36 mutation negative Lynch syndrome patients and 234 controls. Since a trend towards association was observed for KAT2A, an additional set of 21 tagging SNPs was analyzed at this locus in a final case-control sample of 142 mutation negative Lynch syndrome patients and 298 controls. The mutation analysis failed to reveal any rare disease-causing mutations. No association was found at the single-marker or haplotypic level for any common disease-modifying variant. The present results suggest that neither rare nor common genetic variants in ESR1, ESR2, MAX, PCNA, or KAT2A contribute to the development of Lynch syndrome.
    Familial Cancer 11/2011; 11(1):19-26. DOI:10.1007/s10689-011-9489-z · 1.62 Impact Factor
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    ABSTRACT: Molecular markers predictive of prostate cancer prognosis are urgently needed. Overexpression of the antiapoptotic protein, Bcl-2, has repeatedly been shown to be associated with adverse outcome in this malignancy. We hypothesized that a regulatory BCL2 -938C>A promoter polymorphism, which significantly affects promoter activity and Bcl-2 expression in different malignancies, may influence survival. Reporter assays and electrophoretic mobility shift assays reveled that the -938C>A BCL2 promoter polymorphism significantly affects promoter activity and transcription factor binding in prostate cancer cells. Significantly higher BCL2 mRNA expression was observed in primary prostate carcinomas derived from patients with the AA, compared to CC, genotype. Survival analysis showed that the -938AA genotype was an independent, unfavorable prognostic factor for relapse-free survival in a primary cohort of 142 patients and in an independent replication cohort of 148 patients, with hazard ratios (HR) of 4.4 (95% CI, 1.3-15.1; p = 0.018) and 4.6 (95% CI, 1.5-14.2; p = 0.009). Furthermore, the -938AA genotype was independently associated with worse overall survival in the replication series, with a HR of 10.9 (95% CI, 1.2-99.3; p = 0.034). We conclude that the BCL2 -938C>A polymorphism is an independent predictor of relapse-free and overall survival in patients with prostate cancer. The BCL2 -938C>A polymorphism should be evaluated prospectively and may also have promise in assisting optimal patient choice for treatment with BCL2-targeted drugs already in evaluation for prostate cancer treatment.
    International Journal of Cancer 11/2011; 129(10):2390-9. DOI:10.1002/ijc.25904 · 5.01 Impact Factor
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    ABSTRACT: Four and a half LIM domain protein-2 (FHL2) is a component of the focal adhesion structures and has been suggested to have an important role in cancer progression. This study analyses the role of FHL2 in peritumoural fibroblasts of sporadic and hereditary non-polyposis colorectal cancer (HNPCC). Tissue specimens of 48 sporadic and 49 hereditary colon cancers, respectively, were stained immunohistochemically for FHL2, transforming growth factor (TGF)-β1 ligand and α-SMA. Myofibroblasts at the tumour invasion front co-expressed α-SMA and FHL2. Sporadic colon cancer but not HNPCC cases showed a correlation between TGF-β1 expression of the invading tumour cells and FHL2 staining of peritumoural myofibroblasts. Overexpression of FHL2 in peritumoural myofibroblasts correlated to lymphatic metastasis in sporadic colon cancer but not in HNPCC. In cultured mouse fibroblasts, TGF-β1 treatment induced myofibroblast differentiation, stimulated FHL2 protein expression and elevated number of migratory cells in transwell motility assays, suggesting that FHL2 is regulated downstream of TGF-β. Physical contact of colon cancer cells and myofibroblasts via FHL2-positive focal adhesions was detected in human colon carcinoma tissue and in co-culture assays using sporadic as well as HNPCC-derived tumour cell lines. Our data provide strong evidence for an important role of FHL2 in the progression of colon cancers. Tumour-secreted TGF-β1 stimulates FHL2 protein expression in peritumoural fibroblasts, probably facilitating the invasion of tumour glands into the surrounding tissue by enhanced myofibroblast migration and tight connection of fibroblasts to tumour cells via focal adhesions. These findings are absent in HNPCC-associated colon cancers in vivo and may contribute to a less invasive and more protruding tumour margin of microsatellite instable carcinomas.
    Laboratory Investigation 08/2011; 91(12):1695-705. DOI:10.1038/labinvest.2011.109 · 3.83 Impact Factor
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    ABSTRACT: To evaluate if histone H3 lysine 27 (H3K27) methylation plays a role in renal cell carcinoma (RCC) tissue and whether its expression is a predictor of cancer recurrence in RCC. A tissue microarray (TMA) with 193 RCC specimens (comprising 142 clear-cell, 31 papillary, 10 chromophobe and 10 sarcomatoid RCC), 10 oncocytoma tissue specimens and a TMA with 30 benign renal tissue samples were stained with antibodies against H3K27-monomethyl (H3K27me1), H3K27-dimethyl (H3K27me2) and H3K27-trimethyl (H3K27me3). Sections were scored according to staining intensity and the proportion of epithelial cells showing nuclear staining. H3K27 methylation levels were correlated with established clinical-pathological variables (tumour-node-metastasis [TNM] stage, Fuhrman grade) and progression-free/cancer-specific survival. H3K27me1/-me2/-me3 staining was significantly more intense in papillary RCC then in clear-cell RCC. H3K27me3 levels were higher in oncocytoma than in RCC. H3K27me1/-me2/-me3 methylation levels were inversely correlated with Fuhrman grading and pT-stage. Global H3K27me1/-me2/-me3 methylation levels were always higher in benign renal tissue than in RCC with tumour relapse (H3K27me1 P < 0.001, H3K27me2 P= 0.032, H3K27me3 P= 0.004). Progression-free survival was shorter in patients with lower levels of H3K27me1 and H3K27me3 in the univariate analysis. The newly created H3K27me score (combining the staining levels of the single modifications) was a significant and independent predictor of RCC progression-free survival. The present study on H3K27-methylation supports the hypothesis that global histone modifications are potential markers of cancer prognosis in RCC. One reason could be that decreased H3K27 indicates transcriptional activation and therefore predicts cancer activation.
    BJU International 08/2011; 109(3):459-65. DOI:10.1111/j.1464-410X.2011.10278.x · 3.13 Impact Factor
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    ABSTRACT: Prevention of perioperative activation of intestinal muscularis macrophages is a promising intervention to avoid post-traumatic gastrointestinal tract dysfunction. However, impaired macrophage function could have deleterious consequences on anastomotic healing, especially in complications aggravating the healing process itself, such as infectious problems either as preexisting local inflammation or infection (e.g., complicated diverticulitis) or endotoxemia due to early postoperative infections (e.g., pneumonia). Aim of this study was to investigate colonic anastomotic healing in macrophage-depleted mice in the presence of endotoxemia. Colonic anastomoses were performed, and mice were randomized into six groups (wild type; wild type with endotoxemia; pharmacological depletion of macrophages; pharmacological depletion with endotoxemia; genetically conditioned within the gut muscularis macrophage-deficient osteopetrotic mice; osteopetrotic mice with endotoxemia). Anastomotic tissues were removed 2, 5, and 10 days after surgery and used for functional, histological, biochemical, and molecular investigations. After pharmacological pretreatment, an almost complete depletion of macrophages was found in the muscularis up to 24 h postoperatively. Bursting pressure was significantly lower than 10 days after anastomotic procedure in osteopetrotic mice during endotoxemia, in marked contrast to transient pharmacologically macrophage-depleted mice. Pharmacological depletion during endotoxemia did not affect hydroxyproline concentration. Finally, in osteopetrotic mice during endotoxemia, collagen-3 expression was significantly lower compared to controls. In our current model, we demonstrate that perioperative pharmacological macrophage depletion and inactivation transiently diminishes muscularis macrophages and does not affect intestinal anastomotic healing in the presence of endotoxemia. However, a long-lasting macrophage absence or dysfunction impairs anastomotic healing and could be a risk factor for postoperative anastomotic leakage.
    International Journal of Colorectal Disease 03/2011; 26(6):737-46. DOI:10.1007/s00384-011-1171-2 · 2.42 Impact Factor

Publication Stats

1k Citations
230.37 Total Impact Points

Institutions

  • 2012–2014
    • University of Cologne
      • Institute of Pathology
      Köln, North Rhine-Westphalia, Germany
  • 2011–2012
    • Institute for Pathology, Cologne
      Köln, North Rhine-Westphalia, Germany
  • 2007–2011
    • University of Bonn
      • Institute of Pathology
      Bonn, North Rhine-Westphalia, Germany
  • 2010
    • Medical University of Varna
      Odessos, Varna, Bulgaria
  • 2007–2010
    • University of Bonn - Medical Center
      • Institute for Clinical Chemistry and Clinical Pharmacology
      Bonn, North Rhine-Westphalia, Germany