II. Medical Clinic

Augsburg, Germany

II. Medical Clinic

Augsburg, Germany
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Markl B.,Institute of Pathology | Renk I.,Institute of Laboratory Medicine | Oruzio D.V.,II. Medical Clinic | Jahnig H.,Institute of Pathology | And 3 more authors.
Journal of Surgical Oncology | Year: 2010

Aims: The proteases PAI-1 and uPA play a major role in extracellular matrix degradation, which facilitates tumour progression. Tumour budding is a histomorphological expression of enhanced tumour cell migration. Materials and Methods: To investigate their prognostic value for and correlation with colon cancer, a prospective study was performed. We analysed tissue levels of uPA and PAI-1 of 55 colon cancer tumours employing a commercially available enzyme-linked immunosorbent assay (ELISA). Tumour budding was analysed on cytokeratin-stained slides. Results: There was a strong correlation between uPA and tumour budding (R = 0.440; P < 0.001). uPA levels were increased in high grade tumours, whereas PAI-1 was elevated in cases with venous invasion (P = 0.004 and P = 0.028). PAI-1 values and tumour budding are associated significantly with the occurrence of distant metastases (P < 0.001 and P = 0.034, respectively). Tumour budding was significantly associated with lymph node metastases (P = 0.034). Multivariate analysis revealed PAI-1 and lymph node metastases to be independently predictive of distant metastases (P = 0.007 and P = 0.004, respectively). Conclusions: The results of our study show that tumour budding and the plasmin/plasminogen system are related. PAI-1 was independently predictive for the occurrence of distant metastasis. © 2010 Wiley-Liss, Inc.


Schindewolf M.,Goethe University Frankfurt | Steindl J.,Goethe University Frankfurt | Beyer-Westendorf J.,University Hospital Carl Gustav Carus Dresden | Schellong S.,Municipal Hospital Dresden Friedrichstadt | And 11 more authors.
Thrombosis Research | Year: 2014

Introduction In life-threatening immune heparin-induced thrombocytopenia (HIT), treatment with an approved non-heparin anticoagulant is essential. However, off-label use with fondaparinux has been reported in the literature. The study aim was to collect data on "real-life" management of patients with suspected acute HIT regarding diagnostic and therapeutic strategies. Patients and Methods In a national multi-centre registry study, patients with a 4 T's HIT-probability score of ≤ 4 points and treatment with at least one dose of (A)rgatroban, (L)epirudin, (D)anaparoid, or (F)ondaparinux were retrospectively evaluated. Results Of 195 patients, the 4 T's scores were 4/5/6/7/8 points in 46 (23.6%)/50 (25.6%)/74 (38.0%)/13 (6.7%)/7 (3.6%) patients, respectively. During heparin therapy, 47 (24.1%) thromboembolic events, 5 (2.6%) skin lesions, 1 (0.5%) amputation, 24 (12.3%) Hb-relevant bleedings, and 2 (1.0%) fatalities occurred. A functional heparin-induced platelet activation assay was performed in 96.9%, a platelet factor 4/heparin-dependent enzyme immunoassay in 89.2%, a particle gel immunoassay in 12.3%, and a serotonin-release assay in none of the patients. Argatroban was used in 16.4%, lepirudin in 2.1%, danaparoid in 23.6%, fondaparinux in 40.0% of the patients; the sequential therapy strata were: AF (5.6%), DA (5.6%), DF (2.6%), DL (2.1%), ADF (1.5%), and DFL (0.5%). Conclusions The current diagnostic laboratory strategy for suspected HIT is mostly (> 96%) based on the recommended 2-step strategy (immunoassay plus functional assay). However, there is a wide fondaparinux off-label use (up to 50.3%) for suspected HIT, even in those patients with a high clinical pretest probability. Efficacy and safety of fondaparinux for HIT-treatment require further evaluation. © 2014 Elsevier Ltd.


Markl B.,Institute of Pathology | Schaller T.,Institute of Pathology | Kokot Y.,IV. Medical Clinic | Endhardt K.,Institute of Pathology | And 4 more authors.
American Journal of Surgery | Year: 2015

Background: Stage migration is an accepted explanation for the association between lymph node (LN) yield and outcome in colon cancer. To investigate whether the alternative thesis of immune response is more likely, we performed a retrospective study. Methods: We enrolled 239 cases of node negative cancers, which were categorized according to the number of LNs with diameters larger than 5mm (LN5) into the groups LN5-very low (0 to 1 LN5), LN5-low (2 to 5 LN5), and LN5-high (≥6 LN5). Results: Significant differences were found in pT3/4 cancers with median survival times of 40, 57, and 71months (P = .022) in the LN5-very low, LN5-low, and LN5-high groups, respectively. Multivariable analysis revealed that LN5 number and infiltration type were independent prognostic factors. Conclusions: LN size is prognostic in node negative colon cancer. The correct explanation for outcome differences associated with LN harvest is probably the activation status of LNs. © 2015 Elsevier Inc.


Markl B.,Institute of Pathology | Arnholdt H.M.,Institute of Pathology | Jahnig H.,Institute of Pathology | Spatz H.,Klinikum Augsburg | And 3 more authors.
Annals of Surgical Oncology | Year: 2010

Background: We recently introduced ex vivo, intra-arterial methylene blue injection as a simple method to improve the lymph node (LN) harvest in gastrointestinal cancer. We now combined it with a novel ex vivo sentinel lymph node (evSLN) mapping technique. Methods: evSLN mapping was performed by subserosal (n = 20) or submucosal (n = 30) India ink injection. Subsequently, methylene blue was injected intra-arterially to enhance visibility of all LNs to improve the overall LN harvest. Manual LN dissection was carried out after fixing overnight. evSLNs nodes were identified by detecting carbon particles during histological examination. In primary node-negative cases, all detected LNs were step sectioned and immunohistochemically stained for pan-cytokeratin. Results: India ink injection was easy to perform. Methylene blue injection failed in 1 case. The mean lymph node harvest was 42 ± 18 LNs, and the SLN detection rate was 78%. The sensitivity for detecting metastases was 75%. The mean SLN number was 3 ± 1. LN metastases were found in 20 of 47 malignant cases (43%). Skip metastases occurred in 4 cases. Of these cases, 3 showed involvement of at least 1 entire LN. True upstaging (N0 → N1mi) was found in 1 of 23 cases (4%) within a SLN after advanced evaluation. Conclusions: Combination of methylene blue technique and ex vivo sentinel mapping is feasible, easy to perform, and cost effective. It guarantees an optimal LN harvest and has the potential to heighten the sensitivity of metastasis detection. © 2010 Society of Surgical Oncology.


Markl B.,Institute of Pathology | Moldovan A.I.,Institute of Pathology | Jahnig H.,Institute of Pathology | Cacchi C.,Institute of Pathology | And 5 more authors.
Annals of Surgical Oncology | Year: 2011

Background. Exact lymph node (LN) staging is crucial for prognosis estimation and treatment stratification in gastric cancer. Recently, a new concept for improving LN harvest and the accuracy of LN staging was introduced. It combines methylene blue-assisted lymph node dissection (MBLND) with a new ex vivo sentinel lymph node (evSLN) mapping technique. The purpose of this study was to investigate these techniques in a prospective and randomized manner. Methods. A total of 50 patients with proven or suspicious gastric cancer were enrolled. Twenty-five patients each were randomized to the conventional technique (Unstained) or MBLND (Methylene). In 46 cases, additional evSLN mapping with black ink as a marker dye was performed. Results. Methylene blue-assisted lymph node dissection was associated with a highly significantly improved LN harvest (36 ± 10 vs. 21 ± 10; P<0.001). The biggest differences were seen in LNs ≤ 6 mm. In contrast to the conventional technique, neither partial gastrectomy nor preoperative chemotherapy influenced LN harvest in the methylene group. The evSLN detection rate, sensitivity, and accuracy were 87, 81, and 93%, respectively. Isolated tumor cells were detected after immunohistochemical staining in 3 of 17 cases (18%). The probability of carrying a metastasis was two times higher in evSLNs compared to non-evSLNs (44 vs. 23%; P<0.001). Conclusions. Methylene blue-assisted lymph node dissection is a highly effective method of improving the LN harvest in gastric cancer. Further application of evSLN mapping is feasible and has the potential to heighten the sensitivity of metastasis detection. © Society of Surgical Oncology 2011.


Markl B.,Institute of Pathology | Arnholdt H.M.,Institute of Pathology | Jahnig H.,Institute of Pathology | Schenkirsch G.,Clinical and population based cancer registry Augsburg | And 6 more authors.
Human Pathology | Year: 2010

Maspin has been characterized as a potent tumor suppressor in many in vitro and in vivo studies. In contrast, in stage III colon cancer, an association with shorter overall survival as well as sensitivity to chemotherapy was found for cases with nuclear maspin expression. Because 20% of node-negative colorectal cancer cases show a fatal clinical course, we hypothesized that immunohistochemical maspin expression could be of help to identify higher-risk cases. Therefore, we analyzed survival in a study employing 156 cases of stage I/II colorectal cases. Immunohistochemical cytoplasmic and/or nuclear maspin expression was found in 72% and 48% of the cases, respectively. Significant correlations between cytoplasmic expression and high tumor grade (P < .01) and between nuclear expression and tumor budding (P < .001) were shown. No differences concerning overall survival and immunohistochemical maspin expression were found when the complete collective was analyzed. However, evaluation of the pT3 cases revealed a highly significant worse mean overall survival of cases with a combination of nuclear expression and cytoplasmic loss of maspin compared to cases with the opposite expression pattern nuclear loss and cytoplasmic expression (mean overall survival 40 versus 63 months, respectively; P < .001). The other possible combinations (complete positive and complete negative) showed intermediate mean overall survival times with 54 and 49 months, respectively. Our findings suggest a compartment-dependent function of maspin in colorectal cancer, which can be useful in identifying stage II cases with a higher risk for fatal outcome with a possible benefit from adjuvant chemotherapy. © 2010 Elsevier Inc. All rights reserved.


PubMed | Klinikum Augsburg, Institute of Pathology, Clinical and Population Based Cancer Registry Augsburg, II Medical Clinic and IV Medical Clinic
Type: Journal Article | Journal: American journal of surgery | Year: 2015

Stage migration is an accepted explanation for the association between lymph node (LN) yield and outcome in colon cancer. To investigate whether the alternative thesis of immune response is more likely, we performed a retrospective study.We enrolled 239 cases of node negative cancers, which were categorized according to the number of LNs with diameters larger than 5mm (LN5) into the groups LN5-very low (0 to 1 LN5), LN5-low (2 to 5 LN5), and LN5-high (6 LN5).Significant differences were found in pT3/4 cancers with median survival times of 40, 57, and 71months (P = .022) in the LN5-very low, LN5-low, and LN5-high groups, respectively. Multivariable analysis revealed that LN5 number and infiltration type were independent prognostic factors.LN size is prognostic in node negative colon cancer. The correct explanation for outcome differences associated with LN harvest is probably the activation status of LNs.


Cacchi C.,Institute of Pathology | Cacchi C.,Institute For Pathologie | Arnholdt H.M.,Institute of Pathology | Jahnig H.,Institute of Pathology | And 4 more authors.
International Journal of Colorectal Disease | Year: 2012

Purpose The purpose of the present study is to characterise the lymphatic vessel density (LVD) in the T3 colorectal carcinoma and to correlate it with N status, grading and presence of tumour budding. Methods A total of 56 cases of T3 colorectal carcinoma were retrieved from the pathology's archive of Klinikum Augsburg. All slides were stained immunohistochemically with D2-40 (lymphatic endothelium) and with pancytokeratin to assess the tumour budding. Tumour budding and lymph vessel density were investigated independently by BM and CC. The highest density of lymphatic vessels was counted both in tumour centre (ILVD) and at the periphery of the tumour (PLVD) within an area of 0.24 mm2. Results Due to the strong intra-observer (BM and CC) difference in ILVD and PLVD, all cases were re-evaluated establishing a consensus that has been used for the further analyses. There was a significant difference between PLVD and ILVD (12±4 versus 6±3; P<0.001). Moreover, we found a non-significant trend towards high PLVD in the cases with nodal metastasis versus the negative one, 13±5/ hpf versus 11±4 (P=0.072). There was no association between tumour budding and ILVD and PLVD (P=0.249 and 0.38). Conclusion Colorectal carcinoma induces lymphangiogenesis. A higher PLVD could increase the capability of cancer cell to invade the lymphatic system. However, the obvious difficulties in immunohistochemical evaluation and the rather small differences between nodal positive and negative cases in T3 colorectal cancer seem to limit the clinical value of LVD evaluation. © Association of Clinical Biochemists of India 2012.


Thomaidis T.,Johannes Gutenberg University Mainz | Maderer A.,Johannes Gutenberg University Mainz | Al-Batran S.-E.,UCT | Kany J.,Johannes Gutenberg University Mainz | And 8 more authors.
BMC Cancer | Year: 2014

Background: Combination of fluoropyrimidines and a platinum derivative are currently standards for systemic chemotherapy in advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Nevertheless, individual likelihood for response to these therapeutic regimes remains uncertain. Even more, no predictive markers are available to determine which patients may benefit more from oxaliplatin versus cisplatin or vice versa. The new invasion and stem cell markers VEGFR-3 and CXCR4 have been linked prognostically with more aggressive esophagogastric cancer types. Thus, we aimed to assess correlations of VEGFR-3 and CXCR4 expression levels with clinical outcome in a randomized phase III study of patients with oxaliplatin/leucovorin/5-FU (FLO) versus cisplatin/leucovorin/5-FU (FLP).Methods: The patients data examined in this study (n = 72) were from the collective of the FLO vs. FLP phase III AIO trial. Tumour tissues were stained via immunohistochemistry for VEGFR-3 and CXCR4 expression and results were evaluated by two independent, blinded investigators.Outcome parameter: Survival analysis was calculated for patients receiving FLO vs. FLP in relation to VEGFR-3 and CXCR4 expression.Results: 54% and 36% of the examined tumour tissues showed strong positive expression of VEGFR-3 and CXCR4 respectively. No superiority of each regime was detected in terms of overall survival (OS) in the whole population. Patients with strong expression of CXCR4 on their tumour tissues profited more in terms of OS under the treatment of FLP (mOS: 28 vs 15 months, p = 0.05 respectively). Patients with negative VEGFR-3 and CXCR4 expression had a trend to live longer when FLO regime was applied (mOS: 22 vs. 9 months, p = 0.099 and 20 vs. 10 months, p = 0.073 respectively). In an exploratory analysis of patients older than 60 years at diagnosis, we observed a significant benefit in overall survival for VEGFR-3 and CXCR4-positive patients when treated with FLP (p = 0.002, p = 0.021 respectively).Conclusions: CXCR4 positive patients profited in terms of OS from FLP, whereas FLO proved to be more effective in CXCR4 and VEGFR-3 negative patients. Our results suggest, despite the limited size of the study, a predictive value of these biomarkers concerning chemotherapy with FLP or FLO in advanced esophagogastric cancer. © 2014 Thomaidis et al.; licensee BioMed Central Ltd.


Rupprecht H.-J.,II. Medical Clinic | Blank R.,II. Medical Clinic
Drugs | Year: 2010

The limitations of conventional anticoagulants have stimulated the development of new anticoagulants. The central position of factor Xa (FXa) at the junction of the intrinsic and extrinsic pathways in the coagulation cascade means that direct and indirect FXa inhibitors have increasingly changed antithrombotic strategies. FXa inhibitors potently and selectively inhibit thrombin formation rather than thrombin activity. Direct FXa inhibitors may directly bind to FXa, whereas indirect inhibitors are dependent on antithrombin. Direct inhibitors may bind free FXa and, in contrast to indirect inhibitors, FXa within the prothrombinase complex or within clots as well.Fondaparinux is the prototype indirect FXa inhibitor and has been extensively studied in the prevention and treatment of thromboembolic diseases, including acute coronary syndromes. Due to a favourable efficacy and safety profile and convenient once-daily dosing without the need for monitoring, fondaparinux is preferentially recommended in recent guidelines dealing with antithrombotic treatment.A number of small-molecule direct FXa inhibitors are currently at different stages of clinical development. After an extensive clinical trial programme demonstrating superior efficacy without a significant increase in major bleeds compared with enoxaparin, rivaroxaban is now available for the prevention of thromboembolic events in patients undergoing orthopaedic surgery. Rivaroxaban also offers the convenience of oral once-daily dosing without the need for monitoring. Whereas most direct FXa inhibitors are orally active, otamixaban is administered intravenously, offering rapid on-off anticoagulant activity. Other compounds under development may offer additional options for tailored antithrombotic strategies according to differing indications, clinical situations and patient variables. © 2010 Adis Data Information BV. All rights reserved.

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