Peter Fritz

Robert-Bosch Krankenhaus, Stuttgart, Baden-Württemberg, Germany

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Publications (221)709.93 Total impact

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    ABSTRACT: Peritoneal inflammation and fibrosis is a response to the uremic milieu and exposure to hyperosmolar dialysis fluids in patients on peritoneal dialysis. Cells respond to a high osmolarity via the transcription factor Nuclear Factor of Activated T Cells 5 (NFAT5). The response of human peritoneal fibroblasts (HPFBs) to glucose was analyzed in vitro. The expression levels of NFAT5 and chemokine (C-C motif) ligand 2 (CCL2) mRNA were quantified in peritoneal biopsies of five non-uremic controls, five uremic patients prior to PD (pPD), and 8 patients on PD (oPD) using real-time PCR. Biopsies from five controls, 25 pPD- and 25 oPD-patients were investigated using immunohistochemistry (IHC) to detect the expression of NFAT5, CCL2, nuclear factor-κB (NF-κB)p50, NF-κBp65, and CD68. High glucose concentrations led to an early, dose dependent induction of NFAT5 mRNA in HPFBs. CCL2 mRNA expression was up-regulated by high concentrations of glucose after 6 h, but most notably, a concentration dependent induction of CCL2 was present after 96 h. In human peritoneal biopsies NFAT5 mRNA levels were increased in uremic patients, when compared to non-uremic controls. No significant difference was found between the pPD-group and oPD-group. CCL2 mRNA expression was higher in the oPD-group. IHC analysis was consistent with the results of mRNA analysis. CD68 positive cells were significantly increased in the oPD-group. "Uremia" results in NFAT5 induction, which might promote early changes of the peritoneum. Up-regulation of NFAT5 in PD-patients is associated with NFκB induction, potentially resulting in the recruitment of macrophages. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 04/2015; 308(11):ajprenal.00617.2014. DOI:10.1152/ajprenal.00617.2014 · 4.42 Impact Factor
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    ABSTRACT: INTRODUCTION: Simple peritoneal fibrosis and encapsulating peritoneal sclerosis (EPS) are important lesions in the peritoneum of patients on peritoneal dialysis (PD). We have previously described a population of podoplanin-positive myofibroblasts in peritoneal biopsies from patients with EPS. Platelet-derived growth factor receptor-β (PDGFRβ) is a marker of pericytes, and PDGFs might be involved in the fibrotic response of the peritoneum. This study aimed to describe PDGFRβ in the human peritoneum. METHODS: In this retrospective analysis, we localized PDGFRβ in peritoneal biopsies from patients with EPS (n = 6) and patients on PD without signs of EPS (n = 5), and compared them with normal peritoneum (n = 4) and peritoneum from uremic patients (n = 5). Consecutive sections were stained for smooth-muscle actin (SMA) and podoplanin. Slides were scored semiquantitatively by 2 observers blinded to the diagnosis. RESULTS: PDGFRβ was expressed by cells of arterial walls in all biopsies. A prominent population of PDGFRβ-positive cells was present in the normal peritoneum, which were SMA negative on consecutive sections. In patients on PD, a high number of PDGFRβ were also positive for SMA. In EPS, the majority of podoplanin-positive cells were positive for PDGFRβ. In peritoneal biopsies from normal and uremic patients, the expression of SMA was mainly restricted to cells of arterial walls. Podoplanin expression was restricted to lymphatic vessels in normal peritoneum, in uremic patients, and in patients on PD without EPS. CONCLUSIONS: As podoplanin-positive myofibroblasts express PDGFRβ, these cells might be related to pericytes (rather than other sources of fibroblasts). PDGFRβ might turn out to be a therapeutic target in EPS. © 2014 S. Karger AG, Basel.
    Nephron Clinical Practice 11/2014; DOI:10.1159/000368241 · 1.65 Impact Factor
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    ABSTRACT: Background. Puumala virus (PUUV) is the most common species of hantavirus in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute kidney injury (AKI) and thrombocytopenia. The major goals of this study were to provide a clear clinical phenotyping of AKI in patients with NE and to develop an easy prediction rule to identify patients, who are at lower risk to develop severe AKI. Methods. A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. Data were collected from medical records and prospectively at follow-up visit. Severe AKI was defined by standard criteria according to the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) classification. Fuller statistical models were developed and validated to estimate the probability for severe AKI. Results. During acute NE, 88% of the patients had AKI according to the RILFE criteria during acute NE. A risk index score for severe AKI was derived by using three independent risk factors in patients with normal kidney function at time of diagnosis: thrombocytopenia [two points; odds ratios (OR): 3.77; 95% confidence intervals (CI): 1.82, 8.03], elevated C-reactive protein levels (one point; OR: 3.02; 95% CI: 1.42, 6.58) and proteinuria (one point; OR: 3.92; 95% CI: 1.33, 13.35). On the basis of a point score of one or two, the probability of severe AKI was 0.18 and 0.28 with an area under the curve of 0.71. Conclusion. This clinical prediction rule provides a novel and diagnostically accurate strategy for the potential prevention and improved management of kidney complications in patients with NE and, ultimately, for a possible decrease in unnecessary hospitalization in a high number of patients.
    Nephrology Dialysis Transplantation 10/2014; 30(2). DOI:10.1093/ndt/gfu319 · 3.49 Impact Factor
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    ABSTRACT: Targeted chemotherapy for hepatocellular carcinoma (HCC) is impaired by intrinsic and/or acquired drug resistance. Since drugs used in HCC therapy (e.g. anthracyclines or the tyrosine kinase inhibitor sorafenib) are substrates of uptake and/or efflux transporters, variable expression of these transporters at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. In this study, the variability of expression of uptake (OCT1, OCT3) and efflux transporters (MDR1/P-glycoprotein, MRP1, MRP2, BCRP), selected for their implication in transporting drugs used in HCC therapy, was investigated. HCC and corresponding non-tumor tissue samples were collected from 24 Japanese patients at time of surgery. Protein expression was determined by immunohistochemistry. Expression data were correlated with clinicopathological characteristics and patients' outcome (median follow-up 53 months). Generally, expression was highly variable among individual tumor samples. Yet, median expression of OCT1, OCT3 and MDR1 in HCC was significantly lower (1.4-, 2.7- and 2-fold, respectively) than in non-tumor tissue, while expression of MRP2 persisted and BCRP showed a trend of increased levels in HCC. Patients with low BCRP expression had a significantly shorter overall and recurrence-free survival time. Results suggest different expression patterns of drug transporters in HCC, which are only in part associated with clinicopathological characteristics. Detailed information of expression of drug transporters in HCC may be promising for individualization and optimization of drug therapy of liver cancer.
    Drug metabolism and disposition: the biological fate of chemicals 09/2014; DOI:10.1124/dmd.114.059832 · 3.33 Impact Factor
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    ABSTRACT: Background Encapsulating peritoneal sclerosis (EPS) commonly presents after peritoneal dialysis has been stopped, either post-transplantation (PT-EPS) or after switching to hemodialysis (classical EPS, cEPS). The aim of the present study was to investigate whether PT-EPS and cEPS differ in morphology and clinical course. Methods In this European multicenter study we included fifty-six EPS patients, retrospectively paired-matched for peritoneal dialysis (PD) duration. Twenty-eight patients developed EPS after renal transplantation, whereas the other twenty-eight patients were classical EPS patients. Demographic data, PD details, and course of disease were documented. Peritoneal biopsies of all patients were investigated using histological criteria. Results Eighteen patients from the Netherlands and thirty-eight patients from Germany were included. Time on PD was 78(64–95) in the PT-EPS and 72(50–89) months in the cEPS group (p>0.05). There were no significant differences between the morphological findings of cEPS and PT-EPS. Podoplanin positive cells were a prominent feature in both groups, but with a similar distribution of the podoplanin patterns. Time between cessation of PD to the clinical diagnosis of EPS was significantly shorter in the PT-EPS group as compared to cEPS (4(2–9) months versus 23(7–24) months, p<0.001). Peritonitis rate was significantly higher in cEPS. Conclusions In peritoneal biopsies PT-EPS and cEPS are not distinguishable by histomorphology and immunohistochemistry, which argues against different entities. The critical phase for PT-EPS is during the first year after transplantation and therefore earlier after PD cessation then in cEPS.
    PLoS ONE 08/2014; 9(8-8):e106511. DOI:10.1371/journal.pone.0106511 · 3.53 Impact Factor
  • Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis 07/2014; 34(5):561-565. DOI:10.3747/pdi.2013.00137 · 2.20 Impact Factor
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    ABSTRACT: Background: The well-characterized tubular-type of breast tumors is classified as low-risk breast cancer. Patients and Methods: We report on the results of a retrospective analysis on clinical and biological features of 248 tubular breast tumors including follow-up and treatment data from two German series of 21,065 breast cancer cases. The majority of tumors were stage I or stage II, ER- and PR-positive and c-erbB2-negative with a 5-year survival-rate of 96.3%. 51.3% of patients received hormonal treatment, 75.5% had post-operative radiotherapy and 11.8% were treated with a chemotherapeutical regimen. Conclusion: Our retrospective analysis showed no treatment benefit for either anti-hormonal or chemotherapeutical regimens. Post-operative radiotherapy, however, improved the survival rate of patients with tubular carcinoma (log-rank=5, p=0.025). Our data suggest that post-operative radiotherapy is an important treatment to prolong survival for patients suffering from tubular breast cancer.
    Anticancer research 07/2014; 34(7):3647-56. · 1.87 Impact Factor
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    ABSTRACT: Introduction and Aims: Despite obvious advantages of peritoneal dialysis (PD), glucose based PD solutions impair peritoneal health and contribute to relevant pathomechanisms, such as sterile inflammation, resulting in clinical complications such as deterioration of peritoneal dialysis membrane function and peritoneal infections. During PD, low glutamine levels in the peritoneum may contribute to these pathomechanisms. Supplementation of parenteral nutrition with alanyl-glutamine (AlaGln) dipeptide has been shown to counteract such pathological conditions and to improve clinical outcome in other models. Methods: Based on non-clinical data demonstrating beneficial effects of AlaGln in experimental PD, a clinical phase I/II trial (Eudract No. 2010-022804-29) was conducted at the Medical University of Vienna. A total of 20 stable patients (6 with a history of prior peritonitis) on PD underwent a single 4 h administration of standard PD solution (Dianeal® PD4 3.86%, Baxter Healthcare) or PD-protec™ (Dianeal® with added 8 mM AlaGln dipeptide (Dipeptiven®, Fresenius-Kabi) in an open label, randomized, two-period, cross-over designed trial. During a peritoneal equilibration test (PET) with either standard PD solution or with PD-protec™, the patients were closely clinically observed and blood and PD effluent was collected and tested for sterile inflammation, oxidative stress and reduced immunocompetence using routine laboratory techniques as well as transcriptomics and proteomics. Results: Safety of PD-protec™ was demonstrated by stable clinical and laboratory data and by absence of any drug-related adverse event. PD-protec™ also demonstrated efficacy in the sub-group of patients, which have previously suffered from peritonitis, with attenuated peritoneal levels of advanced oxidized protein products (AOPP) and significantly reduced interleukin 8 (IL-8) (treatment effect was 2.2 (CI 0.07 - 4.3; p=0.044)). Whereas the primary endpoint, Western blot analysis of expression of heat shock protein in peritoneal cells could not be measured due to scarce recovery of cells from the dialysate, highly sensitive fluorescent cyanine dyes and 2D difference gel electrophoresis enabled quantification of the oxidative stress proteome of cell pellets from PD. Combined transcriptomics and bioinformatics analysis indicated effects of glutamine supplementation. Ex-vivo assay exposure of PBMC to PD effluent from the PD-protec™ group significantly improved LPS-induced cytokine release, associated with significantly increased intracellular glutamine levels. Conclusions: Results from this trial demonstrated safety of PD-protec™ as reflected by stability of clinical and laboratory data and by the absence of any drug related adverse event, associated with increased peritoneal glutamine levels. Importantly, the obtained data clearly demonstrate the potential of PD-protec™ for improving the clinical course of PD by counteracting the PD related and uremic pathomechanism of sterile inflammation, at least in the highly relevant risk population post-peritonitis. In this sub-group treatment with AlaGln resulted in reduction of peritoneal IL-8 levels as marker of sterile inflammation. These results represent the basis for a trial investigating the effects of AlaGln in a larger number of PD patients following extended treatment.
    Nephrology Dialysis Transplantation 05/2014; 29(suppl 3):iii16-iii18. DOI:10.1093/ndt/gfu114 · 3.49 Impact Factor
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    ABSTRACT: The approved dual-color fluorescence in situ hybridization (FISH) test for the detection of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements in non-small-cell lung cancer (NSCLC) is complex and represents a low-throughput assay difficult to use in daily diagnostic practice. We devised a sensitive and robust routine diagnostic test for the detection of rearrangements and transcriptional up-regulation of ALK. We developed a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay adapted to RNA isolated from routine formalin-fixed, paraffin-embedded material and applied it to 652 NSCLC specimens. The reliability of this technique to detect ALK dysregulation was shown by comparison with FISH and immunohistochemistry. qRT-PCR analysis detected unbalanced ALK expression indicative of a gene rearrangement in 24 (4.6%) and full-length ALK transcript expression in six (1.1%) of 523 interpretable tumors. Among 182 tumors simultaneously analyzed by FISH and qRT-PCR, the latter accurately typed 97% of 19 rearranged and 158 nonrearranged tumors and identified ALK deregulation in two cases with insufficient FISH. Six tumors expressing full-length ALK transcripts did not show rearrangements of the gene. Immunohistochemistry detected ALK protein overexpression in tumors with gene fusions and transcriptional up-regulation, but did not distinguish between the two. One case with full-length ALK expression carried a heterozygous point mutation (S1220Y) within the kinase domain potentially interfering with kinase activity and/or inhibitor binding. Our qRT-PCR assay reliably identifies and distinguishes ALK rearrangements and full-length transcript expression in formalin-fixed, paraffin-embedded material. It is an easy-to-perform, cost-effective, and high-throughput tool for the diagnosis of ALK activation. The expression of full-length ALK transcripts may be relevant for ALK inhibitor therapy in NSCLC.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2014; DOI:10.1097/JTO.0000000000000068 · 5.80 Impact Factor
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    Dataset: mmc1
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    ABSTRACT: Millions of patients are treated with therapeutic monoclonal antibodies (Tmabs) for miscellaneous diseases. We investigated sera from six patients who received immune globulin, from one patient with refractory anti-neutrophil-cytoplasmic antibody (ANCA)-associated granulomatosis with polyangiitis (GPA) who developed two episodes of acute cholestatic liver disease, one after treatment with rituximab and a second after adalimumab and a healthy control group. Three sera from the patient and six sera from patients who received immune globulin were analyzed for antibodies to rituximab and adalimumab by ELISA. Additionally, sera from the patients and from nine healthy blood donors were coated with the Fab fragment of an unrelated humanized monoclonal antibody, with human Fc proteins as well as a mouse IgG globulin. Viral serology for hepatitis A, B, C and autoantibodies specific for autoimmune liver disorders were negative. In all three sera from the patient antibodies to rituximab could be detected, but also antibodies to adalimumab were present even at time points when the patient had not yet received adalimumab, indicating cross reactivity between both substances. Testing against an unrelated human Fab fragment revealed positive results, indicating that the patient had antibodies against human Fab fragments in general. The Fc proteins were negative, and patients' sera did also not react with mouse IgG globulins. Remarkably, 2 out of 5 patients which were treated with immune globulin had antibodies against human Fab fragments in general whereas in none of the samples from healthy controls antibodies to Fab fragment could be detected. This is the first study demonstrating cholestatic liver disease induced by two different Tmabs. Cross - reacting antibodies to Fab2 fragments in general are probably involved. Further studies must show if these Fab2 antibodies in general are related with drug-induced side effects and accelerated drug clearance in patients on Tmab therapy.
    PLoS ONE 11/2013; 8(11):e78856. DOI:10.1371/journal.pone.0078856 · 3.53 Impact Factor
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    ABSTRACT: Gastrointestinal (GI) involvement in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is rare. Medical charts of seven patients with GPA and MPA and GI involvement were reviewed regarding clinical presentation, outcome, diagnostic tools and therapy. Second, the cellular composition of the inflammatory infiltrate associated with the vascular lesions in histological samples (ileum, colon, rectum, duodenum) were investigated to identify possible treatment targets. Immunohistochemistry was done with antibodies against CD20, CD3 and CD34. Samples from a healthy control group (n = 15) were used for comparison. Mean age at onset of the first symptoms of vasculitis was 48 ± 21.3 years. At time of diagnosis GI symptoms were present in five out of seven patients (71%) and occurred during relapse of the vasculitis in two patients (29%). All patients had abdominal pain, four of seven (57%) had an acute kidney injury and three patients required renal replacement therapy. At the time of diagnosis five of seven patients (71%) required surgery and mean Birmingham Vasculitis Activity Score (BVAS) on admission was high (26.3 ± 7.7). Regarding outcome, one patient died due to gastrointestinal bleeding. Histological analysis showed significantly higher expression of CD3 in this patient compared to the control group (P = 0.02). Analysis of expression of CD20 and CD34 showed no statistically significant differences between patients with GPA and MPA with GI involvement compared to the control group. GI involvement in GPA and MPA is rare. Therapy directed at T cells might be an alternative treatment option.
    International Journal of Rheumatic Diseases 10/2013; 17(4). DOI:10.1111/1756-185X.12203 · 1.77 Impact Factor
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    ABSTRACT: Adjuvant tamoxifen is a valid treatment option for women with oestrogen receptor (ER)-positive breast cancer. However, up to 40% of patients experience distant or local recurrence or die. MicroRNAs have been suggested to be important prognosticators in breast cancer. This study aims to identify microRNAs with the potential to predict tamoxifen response. We performed a global microRNA screen (1105 human microRNAs) in primary tumours of six matched pairs of postmenopausal, ER-positive breast cancer patients treated with tamoxifen, who were either recurrence free or had developed a recurrence (median follow up: 8.84years; range: 1.28-12.7years). Patients of this discovery set and the 81 patients of the validation set (median follow up: 8.64years; range: 0.21-19.85years) were treated at the Robert Bosch Hospital, Stuttgart, Germany, between 1986 and 2005. Out of the top 20 deregulated microRNAs (12 up-regulated, eight down-regulated) miR-126 (Hazard Ratio (HR)=0.56, 95% confidence interval (CI): 0.38-0.83; Holm-adj. P=0.022) and miR-10a (HR=0.53, 95% CI: 0.33-0.85; Holm-adj. P=0.031) were identified as significant predictors of tamoxifen outcome by multivariate Cox regression analysis in the independent validation set of 81 postmenopausal, ER-positive patients. Kaplan-Meier survival analyses based on cut-offs determined by receiver operating characteristics curves confirmed that a higher expression of miR-126 and miR-10a in the patients tumour was associated with longer relapse-free time (log-rank P=0.037, P<0.0001, respectively). Our data suggest that miR-126 and miR-10a are independent predictors for tumour relapse in early postmenopausal breast cancer patients treated with adjuvant tamoxifen.
    European journal of cancer (Oxford, England: 1990) 08/2013; 49(17). DOI:10.1016/j.ejca.2013.07.145 · 4.82 Impact Factor
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    ABSTRACT: Secondary hyperparathyroidism develops in nearly all patients with end-stage renal disease. Parathyroidectomy is often performed when medical therapy fails. The most common postoperative complication, hungry bone syndrome (HBS), requires early recognition and treatment. A total of 84 patients who underwent parathyroidectomy because of secondary hyperparathyroidism were investigated. Detailed analysis of laboratory parameters (calcium, phosphate, parathyroid hormone, hemoglobin, and urea levels) and baseline characteristics (age at time of surgery, duration of renal replacement therapy, and medication) was performed to detect preoperative predictors for the development of HBS. Average overall follow-up of the cohort was 4.7 years. Within this time frame, 13 of 84 patients had to undergo a second surgery because of recurrent disease, and HBS occurred in 51.2%. Only decreased preoperative calcium levels and younger age at time of surgery were significant predictors of HBS. Minimal levels of calcium were detected 3 weeks after surgery. Preoperative vitamin D therapy could not prevent HBS and could not shorten the duration of intravenous calcium supplementation. HBS is a very common complication after parathyroidectomy. Younger patients and patients with low preoperative calcium levels were at higher risk for the development of HBS. Remarkably, preoperative vitamin D therapy could not prevent HBS and had no impact on the length of intravenous calcium supplementation. Intensive monitoring of calcium levels must be performed for at least 3 weeks after surgery.
    International Journal of Nephrology and Renovascular Disease 07/2013; 6:131-7. DOI:10.2147/IJNRD.S47179
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    ABSTRACT: Multifunctional Y-box Binding Protein-1 (YB1) is correlated with a poor outcome in breast cancer. We found YB1 expression to be regulated by antiestrogens commonly used in the hormonal therapy of breast cancer and known as activators of Transforming Growth Factor-β (TGFβ). Thus, a putative influence of YB1 on TGFβ signaling should be investigated. The effect of YB1 on TGFβ signaling was monitored by expression analysis and reporter gene assays in breast cancer cells overexpressing YB1 and treated with antiestrogens. Antiestrogen-mediated inhibition of estrogen receptor-α led to a suppression of YB1 protein synthesis. On the other hand, YB1 was found to be an enhancer of TGFβ signaling. High levels of YB1 expression lead to a stimulation of TGFβ pathways, thereby counteracting antihormonal breast cancer therapy and representing a putative resistance mechanism.
    Anticancer research 06/2013; 33(6):2473-80. · 1.87 Impact Factor
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    ABSTRACT: Adjuvant tamoxifen treatment provides benefit for millions of women with estrogen receptor positive breast cancer; however, up to 50% of patients experience distant or local recurrence or even die. Tamoxifen resistance is contributed to by host and tumor associated factors and the latter has been particularly attributed to adaptive changes of the tumor involving the regulation of cellular pathways associated with growth, proliferation and apoptosis. Recently, microRNA expression signatures have been appreciated as useful tools to improve the classification of tumors into subtypes and the assessment of tumor heterogeneity. However it is not clear to what extend microRNA signatures derived from the primary tumor can predict treatment outcome. Here we test the hypothesis that distinct microRNAs expressed in the primary tumor can predict the onset of local and distant recurrence following adjuvant tamoxifen. We investigated 115 patients diagnosed with ER positive breast cancer at the Robert Bosch Hospital,
    Cancer Research 04/2013; 73(8 Supplement):1938. DOI:10.1158/1538-7445.AM2013-1938 · 9.28 Impact Factor
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    ABSTRACT: Background/Aim: We report on survival data of 595 patients with stage I-III lung cancer with respect to TNM classification. We constructed a basic model consisting of stage and grade, and assessed the improvement of survival prediction after adding comorbidity data, spirometric data, clinical and laboratory parameters. Body mass index (BMI) and presence of a cardiac disease reached statistical significance for prediction of overall survival in a Cox regression model. In addition to BMI (<25 kg/m(2)) and the presence of cardiovascular disease, the spirometric variable (FEV1) predicted early death (less than five months postoperatively). When the survival random forest method was employed to predict disease outcome, creatinine levels and VO2 max became additional variables of interest for predicting survival. We propose that our lung cancer database may help to identify variables (aside from histomorphological variables) that are suitable for identifying patients at risk of death after surgical treatment of lung cancer.
    Anticancer research 04/2013; 33(4):1609-19. · 1.87 Impact Factor
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    ABSTRACT: Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD), characterized by marked inflammation and severe fibrosis of the peritoneum, and associated with high morbidity and mortality. EPS can occur years after termination of PD and, in severe cases, leads to intestinal obstruction and ileus requiring surgical intervention. Despite ongoing research, the pathogenesis of EPS remains unclear. We performed a global transcriptome analysis of peritoneal tissue specimens from EPS patients, PD patients without EPS, and uremic patients without history of PD or EPS (Uremic). Unsupervised and supervised bioinformatics analysis revealed distinct transcriptional patterns that discriminated these three clinical groups. The analysis identified a signature of 219 genes expressed differentially in EPS as compared to PD and Uremic groups. Canonical pathway analysis of differentially expressed genes showed enrichment in several pathways, including antigen presentation, dendritic cell maturation, B cell development, chemokine signaling and humoral and cellular immunity (P value<0.05). Further interactive network analysis depicted effects of EPS-associated genes on networks linked to inflammation, immunological response, and cell proliferation. Gene expression changes were confirmed by qRT-PCR for a subset of the differentially expressed genes. EPS patient tissues exhibited elevated expression of genes encoding sulfatase1, thrombospondin 1, fibronectin 1 and alpha smooth muscle actin, among many others, while in EPS and PD tissues mRNAs encoding leptin and retinol-binding protein 4 were markedly down-regulated, compared to Uremic group patients. Immunolocalization of Collagen 1 alpha 1 revealed that Col1a1 protein was predominantly expressed in the submesothelial compact zone of EPS patient peritoneal samples, whereas PD patient peritoneal samples exhibited homogenous Col1a1 staining throughout the tissue samples. The results are compatible with the hypothesis that encapsulating peritoneal sclerosis is a distinct pathological process from the simple peritoneal fibrosis that accompanies all PD treatment.
    PLoS ONE 02/2013; 8(2):e56389. DOI:10.1371/journal.pone.0056389 · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Periostin is a matricellular protein involved in tissue remodeling through the promotion of adhesion, cell survival, cellular dedifferentiation, and fibrogenesis. It can be induced by transforming growth factor beta and high glucose concentrations. We hypothesized that this protein might be expressed in the peritoneal cavity of patients on peritoneal dialysis (PD) and even more in patients with signs of encapsulating peritoneal sclerosis (EPS). Method: In this retrospective study, we included peritoneal biopsies from patients on PD with EPS (n = 7) and without signs of EPS (n = 10), and we compared them with biopsies taken during hernia repair from patients not on PD (n = 11) and during various procedures from uremic patients not on PD (n = 6). Periostin was localized by immunohistochemistry, scored semiquantitatively, and quantified by morphometry. Periostin protein concentrations were measured by ELISA in dialysates from 15 patients. Periostin messenger RNA was quantified in vitro in peritoneal fibroblasts. RESULTS: In control biopsies, periostin was present in the walls of larger arteries and focally in extracellular matrix in the submesothelial zone. Patients on PD demonstrated interstitial periostin in variable amounts depending on the severity of submesothelial fibrosis. In EPS, periostin expression was very prominent in the sclerosis layer. The area of periostin was significantly larger in EPS biopsies than in control biopsies, and the percentage of periostin-positive area correlated with the thickness of the submesothelial fibrosis zone. Periostin concentrations in dialysate increased significantly with time on PD in patients without signs of EPS; in patients with EPS, periostin concentrations in dialysate were low and demonstrated the smallest increase with time. In vitro, periostin was found to be strongly expressed by peritoneal fibroblasts. CONCLUSION: Periostin is strongly expressed by fibroblasts and deposited in the peritoneal cavity of patients with EPS and with simple peritoneal fibrosis on PD. This protein might play a role in the progression of peritoneal injury, and low levels of periostin after prolonged time on PD might be a marker of EPS.
    02/2013; DOI:10.3747/pdi.2010.00259
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    ABSTRACT: BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal dialysis (PD), with clinical signs of abdominal pain, bowel obstruction, and weight loss in late stages. METHODS: We retrospectively analyzed all patients who were diagnosed with EPS between March 1998 and October 2011 in our department of nephrology. We focused on the 24 EPS patients who underwent surgery because of symptomatic late-stage EPS. We identified 3 different macroscopic phenotypes of EPS that we categorized as types I - III. We correlated histologic findings with those macroscopic phenotypes of EPS. The postoperative and long-term outcomes were evaluated by macroscopic phenotype. RESULTS: Duration of PD was longer in type III than in types I and II EPS (p = 0.05). We observed no other statistically significant differences between the groups in baseline characteristics, except for operation time, which was longer in the type I than in the type III group (p = 0.02). Furthermore, we observed no statistically significant difference between the groups with respect to the onset of complaints before surgery (7.8 ± 5.9 months vs 7.0 ± 7.0 months vs 6.5 ± 5.3 months). Concerning patient outcomes, there was no evidence that any of the macroscopic EPS types was associated with more major or minor complications after surgery. For all study patients, follow-up was at least 3 years, with 19 patients still being alive, and 16 having no or very mild complaints. The typical histologic findings of EPS were present in all macroscopic types; only fibrin deposits were more prominent in type II than in type III. CONCLUSIONS: We describe 3 subtypes of EPS based on macroscopic findings. Postoperative treatment should probably not be influenced by the macroscopic EPS phenotype. Whether the different phenotypes represent different pathophysiologic processes remains unclear and has to be further evaluated.
    02/2013; DOI:10.3747/pdi.2012.00019

Publication Stats

6k Citations
709.93 Total Impact Points


  • 1982–2015
    • Robert-Bosch Krankenhaus
      Stuttgart, Baden-Württemberg, Germany
  • 1998–2014
    • Institut für klinische Pharmakologie
      Stuttgart, Baden-Württemberg, Germany
  • 2008–2013
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 2000–2013
    • University of Greifswald
      • • Department of Urology
      • • Institute of Pharmacology
      Greifswald, Mecklenburg-Vorpommern, Germany
    • Technische Universität Dresden
      • Institute of Clinical Pharmacology
      Dresden, Saxony, Germany
  • 2011
    • HELIOS Klinikum Erfurt
      Erfurt, Thuringia, Germany
  • 2002
    • Universität Heidelberg
      • Department of Urology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 1992
    • Pathologisches Institut Bremerhaven
      Bremerhaven, Bremen, Germany