Stephan Macher-Goeppinger

National Center for Tumor Diseases (NCT) Heidelberg, Heidelburg, Baden-Württemberg, Germany

Are you Stephan Macher-Goeppinger?

Claim your profile

Publications (57)200.42 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Presensitized kidney transplant recipients are at high-risk for early antibody-mediated rejection. We studied the impact of pre- and post-transplant donor-specific human leukocyte antigen (HLA) antibodies (DSA) and T-cell-activation on the occurrence of antibody-mediated rejection episodes (AMR) and graft loss (AMR-GL) in a unique cohort of 80 desensitized high-risk kidney transplant recipients. Patients with pre-transplant DSA demonstrated more AMR episodes than patients without DSA, but did not show a significantly increased rate of AMR-GL. The rates of AMR and AMR-GL were not significantly increased in patients with complement split product (C1q)-binding pre-transplant DSA. Pre-transplant C1q-DSA became undetectable post-transplant in 11 of 13 (85%) patients; 2 (18%) of these 11 patients showed AMR but no AMR-GL. In contrast, the post-transplant presence of C1q-DSA was associated with significantly higher rates of AMR (86 vs 33 vs 0%; P < 0.001) and AMR-GL (86 vs 0 vs 0%; log-rank P < 0.001) compared with post-transplant DSA without C1q-binding or the absence of DSA. Patients with both pre-transplant DSA and evidence of pre-transplant T-cell-activation as indicated by soluble CD30-positivity showed a significantly increased risk for AMR-GL [HR = 11.1, 95% confidence interval (CI) = 1.68-73.4; log-rank P = 0.013]. In these high-risk patients, AMR-GL was associated with total DSA in combination with T-cell-activation pre-transplant, and de novo or persistent C1q-binding DSA post-transplant.
    No preview · Article · Feb 2016
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Renal cell carcinoma (RCC) is characterized by a profound disruption of proapoptotic signaling networks leading to chemo- and radioresistance. A key mediator of DNA damage-induced apoptosis is the BH3-only protein PUMA. Given its central role in proapoptotic signaling, we analyzed a series of more than 600 precision-annotated primary RCC specimens for PUMA protein expression. We found a reduced expression of PUMA in 22.6% of RCCs analyzed. Unexpectedly, however, PUMA deficiency was not associated with more aggressive tumor characteristic as expected. Instead, a reduced PUMA expression was associated with a lower TNM stage, lower histopathologic grade, and more favorable cancer-specific patient survival. A direct correlation in a separate patient cohort revealed a profound disconnection between PUMA expression and apoptosis as exemplified by the fact that the tumor with the highest level of apoptotic cells was PUMA deficient. In a series of in vitro studies, we corroborated these results and discovered the highest propensity to undergo apoptosis in an RCC cell line with virtually undetectable PUMA expression. At the same time, PUMA expression was not necessarily associated with stronger apoptosis induction, which underscores the striking functional heterogeneity of PUMA expression and apoptosis in RCC. Collectively, our findings suggest that PUMA-independent mechanisms of cell death exist and may play an important role in suppressing malignant progression. They underscore the functional heterogeneity of RCCs and suggest that PUMA expression alone may not be a suitable predictive biomarker. A better understanding of alternative proapoptotic pathways, however, may help to design novel therapeutic strategies for patients with advanced RCC.
    Full-text · Article · Dec 2015 · Translational oncology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inhibitors of the mTOR pathway, such as everolimus, are promising compounds to treat patients with renal cell carcinomas (RCCs). However, the precise mechanisms of action are far from clear, and biomarkers predicting the response to mTOR inhibitors are still missing. Here, we provide evidence that in RCCs the rpS6 protein is the major mediator of anti-tumoral effects exerted by everolimus. Inhibition of mTOR signaling results in substantially decreased clonogenicity and proliferation of RCC cells, but did not significantly induce apoptosis. Everolimus effectively blocked protein biosynthesis both in vitro and in a novel ex vivo tissue slice model using fresh vital human RCC tissue. Compared to other components of the mTOR pathway, phosphorylation of rpS6 was most effectively downregulated by everolimus. Importantly, siRNA-mediated downregulation of rpS6, but not of 4ebp1 or p27, abolished the inhibitory effects of everolimus on proliferation and protein synthesis. Moreover, we analyzed the tissue expression of phosphorylated rpS6 (p-rpS6) and non-phosphorylated rpS6 in a large collection of patients with RCCs (n=598 and n=548, respectively). Expression of both proteins qualified as independent negative prognostic markers with a substantially shorter survival of patients with RCCs exhibiting high levels of rpS6 and p-rpS6. Taken together, our functional studies identified rpS6 as a main mediator of the anti-tumoral activity of Everolimus. Therefore, further (pre-)clinical evaluations of rpS6 as a predictive marker for everolimus-based treatment for RCC patients are warranted. Finally, the combined detection of phosphorylated and non-phosphorylated rpS6 could represent a robust prognostic marker to identify patients with high risk RCCs.
    Full-text · Article · Oct 2015 · Oncotarget
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background In simultaneous pancreas-kidney transplantation (SPKT), monitoring of the pancreas allograft is more complex than the kidney allograft due to difficulties in obtaining pancreas histology and weak clinical evidence supporting the role of donor-specific antibodies (DSA). Methods We performed a single-center retrospective analysis of all 17 SPKT recipients who underwent a total of 22 pancreas allograft indication biopsies from October 2009 to September 2012. Fifteen patients had at least 2 DSA measurements: pretransplantation and at the time of biopsy. Results All 7 patients (100%) with post-transplantation DSA-positivity (de novo: n = 6; persistent: n = 1) at biopsy had at least 1 rejection episode either of the pancreas (n = 4) or the kidney (n = 3), with 3 antibody-mediated rejections (AMR). In contrast, only 4 of 8 patients (50%) without post-transplantation DSA had evidence of rejection, with 1 AMR. Findings during pancreas allograft biopsy procedures led to a change of immunosuppressive therapy in 11 of 15 (73%) patients. Patient survival, graft survival, and function were not adversely affected by the presence of post-transplantation DSA. One major and 2 minor procedure-related complications occurred during the pancreas biopsies. Conclusions In this small retrospective analysis, pancreas allograft histology provided the most therapeutically relevant information, rather than the kidney histology or DSA monitoring.
    No preview · Article · Oct 2015 · Transplantation Proceedings
  • S Macher-Göppinger
    [Show abstract] [Hide abstract]
    ABSTRACT: Due to advanced imaging techniques, renal cell carcinoma (RCC) is now identified earlier, often in localized stages. As a result, nephron-sparing surgical resection is possible in most cases. The development of new targeted therapies has changed the way metastatic RCC is treated. Despite this positive trend with improved survival rates and expanding treatment options, reliable biomarkers for better predicting disease course are lacking. These are urgently needed to enable personalized therapy based on the treatment-associated risks, the presence of comorbidities, and molecular tumor characteristics. We were able to show that proteins with a regulatory influence on apoptotic signal cascades represent not only promising prognostic markers, but also interesting targets for new therapeutic approaches. Furthermore, our data demonstrate that molecular tests are necessary to correctly classify a RCC with Xp11.2 translocation, since in addition to translocation, amplification can also result in TFE3 activation. Translational research with RCC biomarker identification and establishment, as well as molecular characterization and subtyping of RCCs is required to guide therapeutic decisions and enable personalized medicine in RCC patients.
    No preview · Article · Sep 2015 · Der Pathologe
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: About 40% of clear-cell renal cell carcinomas (ccRCC) harbor mutations in Polybromo-1 (PBRM1), encoding the BAF180 subunit of a SWI/SNF chromatin remodeling complex. This qualifies PBRM1 as a major cancer gene in ccRCC. The PBRM1 protein alters chromatin structure and its known functions include transcriptional regulation by controlling the accessibility of DNA and influencing p53 transcriptional activity. Since little is known about regulation of PBRM1, we studied possible mechanisms and interaction partners involved in the regulation of PBRM1 expression. Activation of p53 in RCC cells resulted in a marked decrease of PBRM1 protein levels. This effect was abolished by siRNA-mediated down regulation of p53, and transcriptional activity was not crucial for p53-dependent PBRM1 regulation. Pulse-chase experiments determined post-translational protein degradation to be the underlying mechanism for p53-dependent PBRM1 regulation, which was accordingly inhibited by proteasome inhibitors. The effects of p53 activation on PBRM1 expression were confirmed in RCC tissue ex vivo. Our results demonstrate that PBRM1 is a target of p53-induced proteasomal protein degradation and provide further evidence for the influence of PBRM1 on p53 function in RCC tumor cells. Considering the paramount role of p53 in carcinogenesis and the presumptive impact of PBRM1 in RCC development, this novel regulation mechanism might be therapeutically exploited in the future. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2015 · The Journal of Pathology
  • [Show abstract] [Hide abstract]
    ABSTRACT: For desensitization of ABO-incompatible kidney transplant recipients we recently proposed nonantigen-specific immunoadsorption (IA) and rituximab. We now compared clinical outcomes of 34 ABO-incompatible living-donor kidney recipients who were transplanted using this protocol with that of 68 matched ABO-compatible patients. In addition, we analyzed efficacy and cost of nonantigen-specific as compared to blood group antigen-specific IA. Before desensitization, the median isoagglutinin titer of 34 ABO-incompatible patients was 1:64 (Coombs technique). Patients received a median of 7 preoperative IA treatments. Twenty-four patients had a median of 2 additional plasmapheresis treatments to reach the preoperative target isoagglutinin titer of 1:8 or less. After a median postoperative follow-up of 22 months, overall graft survival in the ABO-incompatible group was not significantly different from that in ABO-compatible patients (log-rank P = 0.20), whereas patient survival tended to be lower (log-rank P = 0.05). The incidence of rejection episodes was 15% in both groups. The ABO-incompatible kidney recipients had a higher incidence of BK virus replication (P = 0.04) and nephropathy (P = 0.01) and showed more often colonization with multidrug resistant bacteria (P = 0.02). In comparison to blood group antigen-specific IA, nonantigen-specific IA showed equal efficacy but was associated with reduction in cost. Clinical outcomes of ABO-incompatible patients desensitized with a nonantigen-specific IA device and rituximab do not differ from that of matched ABO-compatible patients although a trend toward reduced patient survival was noted. Special attention must be paid to the higher incidence of BK virus infection in recipients of ABO-incompatible grafts.
    No preview · Article · May 2015 · Transplantation
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute rejection following kidney transplantation (KTx) is still one of the challenging complications leading to chronic allograft failure. The aim of this study was to investigate the role of microdialysis (MD) in the early detection of acute graft rejection factor following KTx in porcine model. Sixteen pigs were randomized after KTx into case (n=8, without immunosuppressant) and control groups (n=8, with immunosuppressant). The rejection diagnosis in our groups was confirmed by histopathological evidences as "acute borderline rejection". Using MD, we monitored the interstitial concentrations of glucose, lactate, pyruvate, glutamate and glycerol in the transplanted grafts after reperfusion. In the early post-reperfusion phase the lactate level in our case group was significantly higher comparing to the control group and remained in higher levels until the end of monitoring. The lactate to pyruvate ratio showed a considerable increase in the case group during the post-reperfusion phase. The other metabolites (glucose, glycerol, glutamate) were nearly at the same levels at the end of our monitoring in both study groups. The increase in lactate and lactate to pyruvate ratios seems to be an indicator for early detection of acute rejection after KTx. Therefore, MD as a minimally invasive measurement tool may help to identify the need to immunosuppression adjustment in the early KTx phase before the clinical manifestation of the rejection. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Apr 2015 · International Journal of Surgery (London, England)
  • V Schwenger · V Hankel · J Seckinger · S Macher-Göppinger · C Morath · M Zeisbrich · M Zeier · L P Kihm
    [Show abstract] [Hide abstract]
    ABSTRACT: Real-time contrast-enhanced sonography (CES) can assess microvascular tissue perfusion using gas-filled microbubbles. The purpose of the study was to evaluate the feasibility of early CES in predicting long-term kidney allograft function in comparison to color Doppler ultrasonography (CDUS). We prospectively studied 68 consecutive kidney transplant recipients using CES and conventional CDUS investigation 1 week after transplantation. Transplant tissue perfusion imaging was performed by low-power imaging during intravenous administration of the sonocontrast SonoVue. Renal tissue perfusion was assessed quantitatively using flash replenishment kinetics of microbubbles to estimate renal blood flow (RBF). The obtained sonography values were correlated with clinical data 1 week up to 1 year after transplantation. In contrast with conventional CDUS resistive indices, RBF estimated by CES 1 week posttransplantation significantly correlated with kidney function after 1 year (r = 0.67; P < .001). Determination of RBF by CES revealed a significant correlation with donor age but not recipient age, whereas conventional CDUS resistive index was significantly correlated to recipient age (r = 0.54; P < .001) but not donor age. Furthermore RBF was associated with vascular fibrosis and intimal thickening of the engraftment biopsies. This is the first prospective study demonstrating the prognostic value of CES early after kidney transplantation. In contrast with CDUS, CES reveals information about kidney allograft perfusion independent of recipient vascular compliance. Copyright © 2014 Elsevier Inc. All rights reserved.
    No preview · Article · Dec 2014 · Transplantation Proceedings
  • Source
    Dataset: CEM-2012
    Obul R Bandapalli · Stephan Macher-Goeppinger · Peter Schirmacher · Karsten Brand

    Full-text · Dataset · Sep 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives To evaluate CD24/CD44/CD47 cancer stem cell marker expressions in bladder cancer (BCa) and provide data on their prognostic significance for clinical outcome in patients undergoing radical cystectomy (RC). Material and methods Primary BCa tissue was used for xenograft studies. A tissue microarray was prepared using specimens from a cohort of 132 patients. All patients underwent RC for urothelial BCa between 2001 and 2010. Expression of CD24, CD44, and CD47 was examined in primary samples and xenografts by fluorescence-activated cell sorting. Populations of CD24low- and CD24high- expressing cells were sorted and evaluated for tumorigenicity in vivo. Tissue microarray was analyzed for CD24/CD44 staining intensity and tumor-specific vs. stromal cell staining. Associations with BCa survival, BCa stage, and lymph node status were evaluated by univariate and multivariate analyses. Results CD24 and CD44/CD47 expressions mark distinct cell populations within the normal urothelium as well as in BCa. CD24high/low expression was not sufficient to characterize CD24 as a BCa-initiating marker in in vivo primary xenotransplants. CD24 and CD44 expressions correlated with lower cancer-specific survival in patients. However, multivariate analyses of CD24 or CD44 did not demonstrate significantly increased hazards for cancer-specific death if analyzed together with stage, grade, and nodal status of patients. Conclusions Cancer stem cell markers CD24/CD44/CD47 are differentially expressed in cells of urothelial BCa in patients undergoing RC and influence cancer-specific survival of patients. Further evaluation of CD24/CD44/CD47 protein expression could be of high therapeutic value in BCa. However, both CD24 and CD44 expressions cannot be regarded as independent prognostic parameters for patients undergoing RC.
    No preview · Article · Jul 2014 · Urologic Oncology
  • T. Höfner · S. Macher-Goeppinger · C. Klein · T. Rigo-Watermeier · C. Eisen · S. Pahernik · M. Sprick · A. Trumpp

    No preview · Article · Apr 2014 · European Urology Supplements
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Overexpression of Decoy Receptor 3 (DcR3), a soluble member of the tumor necrosis factor receptor superfamily, is a common event in several types of cancer. In renal cell carcinoma (RCC), DcR3 overexpression is associated with lymph node and distant metastasis as well as a poor prognosis. However, the functional role and regulation of DcR3 expression in RCC is so far unknown. Modulation of DcR3 expression by siRNA and ectopic gene expression, respectively, was performed in ACHN and 769-P RCC cell lines. Functional effects of a modulated DcR3 expression were analyzed with regard to migration, invasion, adhesion, clonogenicity, and proliferation. Furthermore, quantitative RT-PCR and immunoblot analyses were performed to evaluate the expression of downstream mediators of DcR3. In further experiments, luciferase assays, quantitative RT-PCR and immunoblot analyses were applied to study the regulation of DcR3 expression in RCC. Additionally an ex vivo tissue slice culture technique combined with immunohistochemistry was used to study the regulation of DcR3 expression in human RCC specimen. Here, we show that DcR3 promotes adhesion, migration and invasiveness of RCC cells. The DcR3-dependent increase in cellular invasiveness is accompanied with an up-regulation of integrin alpha 4, matrixmetalloproteinase 7 and urokinase plasminogen activator (uPA). Further, we identified a signaling pathway regulating DcR3 expression in RCC. Using in vitro experiments as well as an ex vivo RCC tissue slice culture model, we demonstrate that expression of DcR3 is regulated in a PI3K/AKT-dependent manner involving the transcription factor nuclear factor of activated T-cells (NFAT). Taken together, our results identify DcR3 as a key driver of tumor cell dissemination and suggest DcR3 as a promising target for rational therapy of RCC.
    Preview · Article · Oct 2013 · Molecular Cancer
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene cause hereditary and sporadic renal cell carcinomas (RCCs). The best characterized function of VHL protein is suppression of the α subunit of hypoxia inducible factor (HIF). Additional VHL functions have been reported, including induction of senescence upon loss of VHL mediated by downregulation of the chromatin remodeling factor p400. Induction of senescence either by oncogene activation or inactivation of tumor suppressors is considered a critical feature of mammalian cells by which to suppress tumorigenesis. In the present study, we investigated the relationship between the expression of p400 and patient survival following RCC diagnosis taking advantage of a large and well-documented series of RCC patients with long-term follow-up information. The expression of p400 was measured by immunohistochemistry using a tissue microarray containing tumor tissue samples from 868 RCC patients. Chi-squared tests, Kaplan-Meier curves, Cox regression models and Spearman's rank correlation estimates were used to investigate the possible relationship between p400 expression and Ki-67 proliferative index, clinical and pathological characteristics and patient survival. Complete loss of p400 expression was detected in 64% of all tumor specimens, and decreased p400 expression was associated with advanced tumor stage, higher grade of malignancy and regional lymph node metastasis. Among well-differentiated RCCs, high proliferation (Ki-67 index >10) was found in 12% of carcinomas with an increased p400 expression, compared to 5% of RCCs with decreased p400 expression. Multiple Cox regression indicated that patients with low proliferative tumors and increased p400 expression had a 60% lower cancer-specific mortality risk compared to those affected by low proliferative RCCs with decreased p400 expression. In summary, patients affected by highly proliferative tumors with decreased p400 expression exhibit a poor prognosis by multiple Cox regression. Our data suggest that the highly proliferative, decreased-p400 subgroup of RCCs represents tumors that are characterized by a loss of the tumor-suppressive mechanism of senescence.
    No preview · Article · Aug 2013 · Oncology Reports
  • [Show abstract] [Hide abstract]
    ABSTRACT: For rare cancers such as neuroendocrine bladder cancer (NEBC) treatment options are limited, partly due to lack of pre-clinical models. Techniques to amplify rare primary NEBC cells could provide novel tools for the discovery of drug- and diagnostic targets. We aimed to develop preclinical experimental models for NEBC. Fresh tumor tissue from two NEBC patients was used to establish in vitro and in vivo models. Additional archived tissues from NEBC-patients were analyzed from the National Center of Tumor Diseases tissue bank. Primary tumor samples were collected during radical cystectomy. For inhibition of MET in animal models and cell culture PHA-665752 was used. Expression of markers and drug targets on NEBC were determined by flow cytometry. Growth of NEBC in vitro was determined by counting live cells. Tumor growth in mice was assessed by measuring tumor volume. Comparison between groups was done using non-parametric Kruskal-Wallis tests. Xenograft models and serum-free cultures of NEBC cells allowed screening for cell surface markers and drug targets. We found expression of the HGF-receptor MET on NEBC cultures, xenograft models and in primary patient sections. Growth of NEBC spheroids in vitro critically depended on HGF. Treatment of NEBC-bearing mice with a MET-inhibitor significantly decreased tumor growth compared to control-treated mice. Establishment of NEBC xenografts and serum-free cultures provided suitable models to identify diagnostic markers and therapeutic targets. Using such a model we can demonstrate HGF dependent growth of human NEBC and identify MET as a new treatment target for NEBC.
    No preview · Article · Jun 2013 · The Journal of urology
  • Christian Morath · Changli Wei · Stephan Macher-Goeppinger · Vedat Schwenger · Martin Zeier · Jochen Reiser
    [Show abstract] [Hide abstract]
    ABSTRACT: Circulating soluble urokinase receptor (suPAR) was recently identified as one of the causes responsible for native and recurrent focal segmental glomerulosclerosis (FSGS) through overactivation of podocyte β3 integrin. Here, we discuss the management of a patient with very high suPAR serum levels and FSGS recurrence. The suPAR reduction using plasmapheresis and immunoadsorption allowed for lowering of suPAR and reduced podocyte β3 integrin activation and proteinuria. The patient is successfully weaned to bimonthly suPAR removal treatments with improved renal parameters. In summary, we provide an approach for the successful management of severe recurrent FSGS using available therapies with biomarker guidance.
    No preview · Article · Mar 2013 · American journal of therapeutics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Due to increasing waiting times for deceased donor kidneys, living donor kidney transplantation is increasingly performed in the presence of donor-specific antibodies (DSA). Twenty-three patients with Luminex-detected DSA were successfully desensitized by anti-CD20 therapy and immunoadsorption (N = 19) or plasmapheresis (N = 4) and received a kidney transplant from a living donor. Twelve of the 23 patients (52%) had a positive CDC and/or ELISA crossmatch result before desensitization. Six patients were negative in CDC as well as ELISA screening but positive in Luminex for DSA. The 23 patients received a median of 8 apheresis treatments before and 5 treatments after transplantation. Induction therapy was performed with either thymoglobulin (N = 11) or basiliximab (N = 12). The 2-year graft survival rate was 100%. At last follow up, a median of 12 months after transplantation, median serum creatinine was 1.42 mg/dL, median MDRD-GFR 59.5 mL/min/1.73 m(2), and median urinary protein-to-creatinine ratio 0.12. Ten out of fourteen patients (71%) who had completed the first year after transplantation by the time of analysis had no DSA by day 360. Acute T-cell mediated rejection was diagnosed in one patient (4%), and antibody-mediated changes were found in 5 patients (22%). Four out of these 5 patients showed evidence of persistent (N = 2) or reemerging plus/minus de novo DSA (N = 2) on day 360, and the 2 patients with persistent DSA lost their allograft subsequently on days 750 and 810, respectively. Infectious complications were infrequent. Our previously described treatment algorithm for desensitization of living donor kidney transplant recipients with DSA results in good graft outcomes with a low rate of side effects.
    No preview · Article · Jan 2013 · Atherosclerosis. Supplements
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: The B-cell translocation gene 2 (BTG2) is considered to act as a tumour-suppressor gene because of its antiproliferative and antimigratory activities. Higher levels of BTG2 expression in tumour cells have been linked to a better clinical outcome for several cancer entities. Here, we investigated the expression and function of BTG2 in bladder cancer. Methods: The expression of BTG2 in bladder cancer cells was silenced by RNA interference. Cell motility was investigated by wound healing and Boyden chamber assays. The protein expression of BTG2 in bladder cancer was studied by immunohistochemistry. Results: We observed that targeted suppression of BTG2 by RNA interference did not result in growth stimulation but led to a substantial inhibition of bladder cancer cell motility. Tissue microarray analyses of bladder cancer cystectomy specimens revealed that higher BTG2 expression levels within the tumours correlated strongly with a decreased cancer-specific survival for bladder cancer patients. Conclusion: These results indicate that endogenous BTG2 expression contributes to the migratory potential of bladder cancer cells. Moreover, high levels of BTG2 in bladder cancers are linked to decreased cancer-specific survival. These findings question the conception that BTG2 generally acts as a tumour suppressor and typically represents a favourable clinical marker for cancer patients.
    Preview · Article · Jan 2013 · British Journal of Cancer
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The aim of this study was to evaluate the prognostic relevance of melanoma-associated antigen (MAGE) A9 in renal cell carcinoma (RCC). Material and methods: Immunohistochemical staining for MAGE A9 was evaluated in a tissue microarray containing 587 RCC tumour tissue samples. Nuclear MAGE A9 expression was reviewed using a semiquantitative score. Follow-up has been surveyed since 1990 in a prospectively conducted tumour database. The effect of MAGE A9 expression on cancer-specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses. Subgroup analyses were performed for non-metastatic and metastatic disease. Results: Median age in all patients was 63.2 years, 354 patients were male and 233 female, and 108 patients had metastatic disease. Median follow-up was 5.6 years for all patients and 9.0 years for patients still alive (range 0-19.9 years). High nuclear MAGE A9 expression was present in 326 tumour specimens (55.5%). In multivariate analyses high nuclear MAGE A9 expression was associated with poor CSS (p = 0.0027). Furthermore, tumour stage, lymph-node and distant metastasis, Fuhrman grade G3/4, Karnofsky index < 80% and male gender were associated with poor CSS. In subgroup analyses, results were concordant for patients with non-metastatic disease. In patients with metastatic disease, only Karnofsky index > 80% was a significant predictor for CSS; MAGE A9 expression could not be shown to be associated with CSS (p = 0.161). Conclusions: High nuclear MAGE A9 expression is independently associated with poor CSS in patients with non-metastatic RCC. The assessment of MAGE A9 expression can provide additional prognostic information and should be used in decision-making regarding adjuvant therapy in patients with non-metastatic disease.
    No preview · Article · Nov 2012 · Scandinavian Journal of Urology and Nephrology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: During kidney transplantation (KTx), the length of cold ischemia time (CIT) and the subsequent changes in energy metabolism may lead to variations in interstitial metabolites. Using microdialysis (MD), we evaluated the effects of a short and long CIT on changes of these metabolites. Methods: Sixteen pigs were randomized in two identical groups, one with a short CIT and the other one with a long CIT. Using MD in the transplanted grafts, we evaluated the parenchyma concentrations of glucose, lactate, pyruvate, glutamate and glycerol in different stages. Results: We noted that during the warm ischemia time (WIT) and in the early post-reperfusion phase glucose levels increased more significantly in the long CIT group and remained high until the end of monitoring. At the end of CIT and during WIT, the long CIT group had a significantly higher glycerol level, but the level dropped gradually in the late post-reperfusion phase and reached a steady state in both groups. Conclusions: The extended CIT clearly results in considerably impaired graft metabolism. The high interstitial glucose levels within hours after KTx could be considered as a marker of primary delayed function of the graft. Furthermore, the glycerol value could reflect the extent of graft injury during the ischemia time or in case of acute impairment of graft perfusion.
    No preview · Article · Oct 2012 · Langenbeck s Archives of Surgery

Publication Stats

768 Citations
200.42 Total Impact Points

Institutions

  • 2015
    • National Center for Tumor Diseases (NCT) Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 2009-2015
    • Universität Heidelberg
      • • Department of Pathology
      • • Institute of Papyrology
      Heidelburg, Baden-Württemberg, Germany