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ABSTRACT: Lymph node involvement is a major feature in tumor spread of endometrial cancer and predicts prognosis. Therefore, evaluation of lymph vessel invasion (LVI) in tumor tissue as a predictor for lymph node metastasis is of great importance. Immunostaining of D2-40 (podoplanin), a specific marker for lymphatic endothelial cells, might be able to increase the detection rate of LVI compared with conventional hematoxylin-eosin (H-E) staining. The aim of this retrospective study was to analyze the eligibility of D2-40-based LVI evaluation for the prediction of lymph node metastases and patients' outcome.
Immunohistochemical staining with D2-40 monoclonal antibodies was performed on paraffin-embedded tissue sections of 182 patients with primary endometrioid adenocarcinoma treated in 1 gynecologic cancer center. Tumors were screened for the presence of LVI. Correlations with clinicopathological features and clinical outcome were assessed.
Immunostaining of D2-40 significantly increased the frequency LVI detection compared with conventional H-E staining. Lymph vessel invasion was identified by D2-40 in 53 (29.1%) of 182 tumors compared with 34 (18.3%) of 182 carcinomas by routine H-E staining (P = 0.001). D2-40 LVI was detectable in 81.0% (17/21) of nodal-positive tumors and significantly predicted lymph node metastasis (P = 0.001). Furthermore, D2-40 LVI was an independent prognostic factor for patients overall survival considering tumor stage, lymph node involvement, and tumor differentiation (P < 0.01). D2-40-negative tumors confined to the inner half of the myometrium showed an excellent outcome (5-year overall survival, 97.8%).
D2-40-based LVI assessment improves the histopathological detection of lymphovascular invasion in endometrial cancer. Furthermore, LVI is of prognostic value and predicts lymph node metastasis. D2-40 LVI detection might help to select endometrial cancer patients who will benefit from a lymphadenectomy.
International Journal of Gynecological Cancer 09/2012; 22(8):1442-8. · 1.65 Impact Factor
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Kirsten Kübler,
Carola tho Pesch,
Nadine Gehrke,
Soheila Riemann,
Juliane Dassler,
Christoph Coch,
Jennifer Landsberg,
Vera Wimmenauer, Martin Pölcher,
Christian Rudlowski,
Thomas Tüting,
Walther Kuhn,
Gunther Hartmann,
Winfried Barchet
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ABSTRACT: Owing to high rates of tumor relapse, ovarian cancer remains a fatal disease for which new therapeutic approaches are urgently needed. Accumulating evidence indicates that immune stimulation may delay or even prevent disease recurrence in ovarian cancer. In order to elicit proinflammatory signals that induce or amplify antitumor immune reactivity, we mimicked viral infection in ascites-derived ovarian cancer cells. By transfection or electroporation we targeted the synthetic double-stranded RNA poly(I:C) intracellularly in order to activate melanoma differentiation-associated gene-5 (MDA-5), a sensor of viral RNA in the cytosol of somatic cells. Cancer cells reacted with enhanced expression of HLA-class I, release of CXCL10, IL-6, and type I IFN as well as tumor cell apoptosis. Monocytes and monocyte-derived DCs (MoDCs) engulfed MDA-5-activated cancer cells, and subsequently upregulated HLA-class I/II and costimulatory molecules, and secreted CXCL10 and IFN-α. Further, this proinflammatory milieu promoted cytolytic activity and IFN-γ secretion of NK cells. Thus, our data suggest that the engagement of MDA-5 in a whole tumor cell vaccine is a promising approach for the immunotherapy of ovarian cancer.
European Journal of Immunology 07/2011; 41(10):3028-39. · 5.10 Impact Factor
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Philipp Harter,
Jalid Sehouli,
Alexander Reuss,
Annette Hasenburg,
Giovanni Scambia,
David Cibula,
Sven Mahner,
Ignace Vergote,
Alexander Reinthaller,
Alexander Burges,
Lars Hanker, Martin Pölcher,
Christian Kurzeder,
Ulrich Canzler,
Karl Ulrich Petry,
Andreas Obermair,
Edgar Petru,
Barbara Schmalfeldt,
Domenica Lorusso,
Andreas du Bois
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ABSTRACT: The DESKTOP I trial proposed a score for the prediction of complete cytoreduction in recurrent ovarian cancer. Resectability was assumed if 3 factors were present: (1) complete resection at first surgery, (2) good performance status, and (3) absence of ascites. The DESKTOP II trial was planned to verify this hypothesis prospectively in a multicenter setting.
Participating centers prospectively enrolled all consecutive patients with platinum-sensitive first or second relapse. The score was applied to all patients, but centers were free to decide on therapy. All further therapies were documented, and the outcome of patients was analyzed. A 75% complete resection rate in 110 prospectively classified patients had to be achieved to confirm a positive predictive value of 2 or higher of 3 with 95% probability.
A total of 516 patients were screened within 19 months; of these, 261 patients (51%) were classified as score positive, and 129 patients with a positive score and first relapse were operated on. The rate of complete resection was 76%, thus confirming the validity of this score regarding positive prediction of complete resectability in 2 or more of 3 patients. Complication rates were moderate including second operations in 11% and perioperative mortality in 0.8%.
This score is the first prospectively validated instrument to positively predict surgical outcome in recurrent ovarian cancer. It can aid in the selection of patients who might benefit from secondary cytoreductive surgery and will be enrolled in the recently started randomized prospective DESKTOP III trial investigating the role of surgery in recurrent platinum-sensitive ovarian cancer.
International Journal of Gynecological Cancer 02/2011; 21(2):289-95. · 1.65 Impact Factor
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Manuel Debald, Martin Pölcher,
Uta Flucke,
Gisela Walgenbach-Brünagel,
Klaus-Jürgen Walgenbach,
Tobias Höller,
Matthias Wolfgarten,
Christian Rudlowski,
Reinhard Büttner,
Hans Schild,
Walther Kuhn,
Michael Braun
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ABSTRACT: Several international trials are currently investigating accelerated partial breast irradiation (APBI) for patients with early-stage breast cancer. According to existing guidelines, patients with lymphatic vessel invasion (LVI) do not qualify for APBI. D2-40 (podoplanin) significantly increases the frequency of LVI detection compared with conventional hematoxylin and eosin (HE) staining in early-stage breast cancer. Our purpose was to retrospectively assess the hypothetical change in management from APBI to whole breast radiotherapy with the application of D2-40.
Immunostaining with D2-40 was performed on 254 invasive breast tumors of 247 patients. The following criteria were used to determine the eligibility for APBI: invasive ductal adenocarcinoma of < or =3 cm, negative axillary node status (N0), and unifocal disease. Of the 247 patients, 74 with available information concerning LVI, as detected by D2-40 immunostaining and routine HE staining, formed our study population.
Using D2-40, our results demonstrated a significantly greater detection rate (p = .031) of LVI compared with routine HE staining. LVI was correctly identified by D2-40 (D2-40-positive LVI) in 10 (13.5%) of 74 tumors. On routine HE staining, 4 tumors (5.4%) were classified as HE-positive LVI. Doublestaining of these specimens with D2-40 unmasked false-positive LVI status in 2 (50%) of the 4 tumors. According to the current recommendations for APBI, immunostaining with D2-40 would have changed the clinical management from APBI to whole breast radiotherapy in 8 (10.8%) of 74 patients and from whole breast radiotherapy to APBI in 2 patients (2.7%).
These data support the implementation of D2-40 immunostaining in the routine workup to determine a patient's eligibility for APBI.
International journal of radiation oncology, biology, physics 07/2010; 77(4):1128-33. · 4.59 Impact Factor
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Kirsten Kübler,
Nadine Gehrke,
Soheila Riemann,
Volker Böhnert,
Thomas Zillinger,
Evelyn Hartmann, Martin Pölcher,
Christian Rudlowski,
Walther Kuhn,
Gunther Hartmann,
Winfried Barchet
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ABSTRACT: Most malignant cells are poorly immunogenic and fail to elicit an effective antitumor immune response. In contrast, viral infections of cells are promptly detected and eliminated by the immune system. Viral recognition critically hinges on cytosolic nucleic acid receptors that include the proinflammatory RNA helicase retinoic acid-inducible gene-I (RIG-I). Here, we show that targeted delivery of RIG-I agonists induced ovarian cancer cells to upregulate HLA class I and to secrete the proinflammatory cytokines CXCL10, CCL5, interleukin-6, tumor necrosis factor-alpha, and IFN-beta. Ovarian cancer cells stimulated via RIG-I became apoptotic and were readily phagocytosed by monocytes and monocyte-derived dendritic cells, which in turn upregulated HLA class I/II and costimulatory molecules and released CXCL10 and IFN-alpha. Our findings offer proof of principle that mimicking viral infection in ovarian cancer cells triggers an immunogenic form of tumor cell apoptosis that may enhance immunotherapy of ovarian cancer.
Cancer Research 07/2010; 70(13):5293-304. · 7.86 Impact Factor
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ABSTRACT: To determine serum levels of circulating cell-free DNA (cfDNA) throughout the stages of endometrial proliferation and apoptosis during the menstrual cycle.
cfDNA was measured in 176 blood samples from 17 healthy volunteers taken at three different time points (menstruation, follicular and secretory phase). Additionally, blood samples from 20 newly diagnosed breast cancer patients were analysed. Quantitative real-time PCR was performed in order to quantify cfDNA fragments of 106 bp.
In healthy individuals, levels of cfDNA did not differ significantly during the menstrual cycle. In breast cancer patients, the median cfDNA level was significantly higher compared to healthy individuals, irrespective of the cycle phase (p<0.001).
The female cycle does not influence cfDNA serum level measurements. Considering the diagnostic or prognostic value of cfDNA in cancer patients, different time points of blood sampling in premenopausal women seem to be negligible.
Anticancer research 06/2010; 30(6):2235-40. · 1.73 Impact Factor
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Martin Pölcher,
Michael Braun,
Nicolaus Friedrichs,
Christian Rudlowski,
Eva Bercht,
Rolf Fimmers,
Axel Sauerwald,
Mignon-Denise Keyver-Paik,
Kirsten Kübler,
Reinhard Büttner,
Walther C Kuhn,
Juan-José Hernando
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ABSTRACT: Preoperative neoadjuvant chemotherapy (NAC) can significantly reduce tumour burden in patients with primarily unresectable chemosensitive tumours, allowing a more complete cytoreduction during debulking surgery and facilitating evaluation of tumour chemosensitivity, identification of appropriate treatment options and improvement of intervention protocols. In this study, we investigate, using immunohistochemistry, the impact of platinum/taxane-based NAC (NAC) on tumour-infiltrating lymphocytes (TILs) in advanced epithelial ovarian cancer (EOC) and their relationship with clinical outcome. All patients had clinical response, as shown by ascites volume and CA125 levels compared to pre-treatment findings. NAC intervention significantly increased CD4(+), CD8(+) and granzyme B(+) infiltration while Foxp3(+) accumulation remained unaffected. TILs were prognostically neutral for both progression-free survival (PFS) and overall survival (OS) before NAC. In contrast, after NAC, elevated granzyme B(+) infiltration displayed a tendency for improved PFS (log-rank 0.064). Further, low Foxp3(+) cell density was associated with longer PFS, as compared with strong Foxp3(+) infiltration (median 20.94 vs. 11.24 months; log-rank 0.0001) and with improved OS (median 30.75 vs. 16.04 months, respectively; log-rank 0.056), demonstrating clear prognostic significance for PFS. In addition, high granzyme B(+)/Foxp3(+) ratio post-NAC strongly correlated with improved PFS compared to low granzyme B(+)/Foxp3(+) cell ratio (median 17.88 vs. 11.24 months, respectively), and showed to be a favourable prognostic factor for PFS (log-rank 0.014). Our findings indicate that NAC elicited an immunologic profile in which low immunosuppressive Foxp3(+) infiltration and elevated numbers of activated granzyme B(+) cells were significantly associated with EOC-specific PFS, suggesting a contribution of immunologic effects to improved clinical outcome.
Cancer Immunology and Immunotherapy 06/2010; 59(6):909-19. · 3.70 Impact Factor
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ABSTRACT: To evaluate changes in Ki-67 expression during neoadjuvant chemotherapy (NACT) in advanced ovarian cancer.
Patients with International Federation of Gynecology and Obstetrics stage IIIC or IV and large-volume ascites were treated with NACT within a phase 2 trial. The expression of Ki-67 was evaluated by immunohistochemistry on paraffin-embedded tissue samples and classified by percentage of stained cells. Survival curves were plotted using the Kaplan-Meier method.
Comparison of 40 individual paired results from pretreatment and posttreatment samples revealed a median difference of -0.11 in the Ki-67 index (95% confidence interval, -0.20 to -0.01; P = 0.005, signed rank test). Univariate analysis identified a high Ki-67 index as well as an increasing Ki-67 index after NACT as significant prognostic markers for progression-free survival (P = 0.004 and P = 0.001; log-rank test). Six of 12 patients with an increased Ki-67 index after NACT developed recurrence within 6 months after therapy.
Changes of the Ki-67 index during NACT are associated with progression-free survival. If confirmed in prospective trials, an increasing Ki-67 index during preoperative treatment may serve as an indicator for resistance to chemotherapy.
International Journal of Gynecological Cancer 05/2010; 20(4):555-60. · 1.65 Impact Factor
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ABSTRACT: The aim of our study was to analyze the effect of taxane-based chemotherapy on tumor angiogenesis in patients with advanced epithelial ovarian cancer.
Within a prospective phase II trial, 32 patients with stage IIIC and IV ovarian cancer were treated with either two or three cycles of neoadjuvant chemotherapy prior to cytoreductive surgery. Carboplatin (AUC5) and docetaxel (75 mg/m2) were administered intravenously in a 3-weekly schedule. Changes in intratumor microvessel density (MVD) were assessed with immunohistochemistry by staining pre- and posttreatment surgical tumor specimens with panendothelial, neovascular and lymphatic vessel markers.
Mean values of MVD defined by CD31, CD34, CD105 and D2-40 antibodies showed 12.3, 21.0, 2.7 and 3.1 vessels per high power field (HPF) before chemotherapy and increased after treatment to 15.3, 21.8, 4.8 and 3.6 per HPF, respectively. These changes were significant for CD31 (p = 0.04) and for CD105 (p = 0.02).
Taxane-based chemotherapy appears to promote tumor vascularization when administered every 3 weeks. A possible explanation is the secondary recovery of MVD in response to immediate cytotoxic and antiangiogenic effects of the chemotherapy. If confirmed prospectively, these findings favor shorter treatment intervals of taxane-based chemotherapy to counteract proangiogenic recovery.
BMC Cancer 04/2010; 10:137. · 3.01 Impact Factor
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ABSTRACT: Sorafenib is a novel oral anticancer agent targeting signal transduction and angiogenic pathways through inhibitory effects against MAP kinases and vascular endothelial growth factor receptor-2. The objectives of this neoadjuvant phase II-trial in patients with advanced epithelial ovarian cancer were to assess the activity and tolerability of the combination therapy of carboplatin/paclitaxel with multi-target tyrosine kinase inhibitor sorafenib.
Patients with histologically proven stage IIIC or IV disease and large volume ascites were eligible. Enrolled patients received 2 of 6 cycles carboplatin (area under the curve 5) and paclitaxel (175 mg/m(2)) preoperatively and concomitant sorafenib 400 mg twice daily. After four cycles of postoperative chemotherapy, a maintenance phase of single agent oral sorafenib through 1 year was planned. This phase II-study was planned with a sample size of 102 patients and progression-free survival as primary study endpoint.
Four patients were enrolled. After preoperative treatment and cytoreductive surgery, all patients were excluded from protocol due to severe toxicities. Three patients had life threatening events (cardiac output failure, myocardial infarction, anastomotic leak); two patients had primary progressive disease. The study was terminated on the basis of the recommendation of an independent data safety monitoring board.
The addition of sorafenib to carboplatin/paclitaxel chemotherapy was not feasible within this neoadjuvant regimen in primary advanced ovarian cancer. Although the occurrence of serious adverse events might have emerged at random, a detrimental effect of preoperative study medication could not be denied. Further evaluations of sorafenib in ovarian cancer are warranted.
Cancer Chemotherapy and Pharmacology 03/2010; 66(1):203-7. · 2.83 Impact Factor
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Sabine Classen,
Christine Muth,
Svenja Debey-Pascher,
Daniela Eggle,
Marc Beyer,
Michael R Mallmann,
Christian Rudlowski,
Thomas Zander, Martin Pölcher,
Walther Kuhn,
Michael Lahn,
Joachim L Schultze,
Andrea Staratschek-Jox
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ABSTRACT: The development of targeted drugs would greatly benefit from the simultaneous identification of biomarkers to determine the aspects of bioactivity, drug safety and efficacy, particularly when affecting receptor-signaling pathways. However, the establishment of appropriate systems to monitor drug-induced events requires an accessible surrogate tissue for functional read out.
Therefore we present a universal platform based upon T cell-based gene expression profiling for the identification of biomarkers using the antitransforming growth factor beta receptor inhibitor LY2109761 as an example.
Our initial screen revealed 12 candidate genes specifically regulated in T cells by the inhibitor. In subsequent in-vitro and in-vivo analyses, the combined monitoring of independent gene regulation of three genes was established in peripheral blood mononuclear cells as novel pharmacodynamic candidate biomarkers for antitransforming growth factor beta receptor based therapies.
Overall, the proposed concept of biomarker identification can be easily adapted towards other drug candidates for whom gene regulation can be established in cellular components of peripheral blood.
Pharmacogenetics and Genomics 03/2010; 20(3):147-56. · 3.48 Impact Factor
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Martin Pölcher,
Sven Mahner,
Olaf Ortmann,
Jörn Hilfrich,
Klaus Diedrich,
Georg-Peter Breitbach,
Cornelia Höss,
Claudia Leutner,
Michael Braun,
Volker Möbus,
Ina Karbe,
Patrick Stimmler,
Christian Rudlowski,
Jörg Schwarz,
Walther Kuhn
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ABSTRACT: Early response criteria and surgical outcome were evaluated in patients with advanced epithelial ovarian cancer treated with neoadjuvant chemotherapy. Patients with FIGO stage IIIC or IV ovarian cancer and an ascites volume of >or=500 ml were randomly assigned to receive preoperatively 3 (A1) or 2 (A2) of 6 cycles of carboplatin and docetaxel intravenously. Response was monitored by measuring target lesions, ascites volumes and serum CA 125 levels. The primary outcome measure was the preoperative reduction of ascites volume. Secondary outcome measures were the evaluation of residual tumor and perioperative morbidity and mortality. Eighty-three patients underwent cytoreductive surgery, 40 after 3 cycles and 43 patients after 2 cycles of neoadjuvant chemotherapy. 'Optimal debulking' (<or=1 cm) was achieved in 30 (A1) and 32 patients (A2). Eight (A1) and 6 patients (A2) had a persistent ascites volume>or=500 ml. A decrease of the CA 125 level from baseline of less than 50% was observed in 7 (A1) and 9 patients (A2). Computed tomography scan results showed progressive disease in 6 patients (3 A1; 3 A2). Any amount of residual disease after cytoreductive surgery, persistent ascites, and a less pronounced decrease of CA 125 were associated with poor progression-free survival rates. In conclusion, ascites volume reduction and CA 125 decline appear to be appropriate response criteria. A treatment schedule with two preoperative cycles is a reasonable option for neoadjuvant chemotherapy in advanced ovarian cancer. High surgical standards are mandatory, even after neoadjuvant chemotherapy.
Oncology Reports 09/2009; 22(3):605-13. · 1.84 Impact Factor
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Michael Braun, Martin Pölcher,
Simone Schrading,
Oliver Zivanovic,
Theresa Kowalski,
Uta Flucke,
Claudia Leutner,
Tong-Wong Park-Simon,
Christian Rudlowski,
Walther Kuhn,
Christiane K Kuhl
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ABSTRACT: Evaluation of the impact of preoperative magnetic resonance imaging (MRI) of the breast on the clinical management of patients with operable breast cancer (BC).
Retrospective analysis of 160 patients with operable breast cancer (stages Tis through T4), treated from 2002 through 2004. All patients underwent a full mammographic assessment, high frequency breast ultrasound, and breast MRI. The impact of preoperative MRI was evaluated for each patient with regard to changes in the therapeutic procedure. Patient and tumor characteristics were analyzed to identify possible patient subgroups that predominantly would benefit from preoperative MRI.
Preoperative MRI affected the clinical management in 44 of 160 patients (27.5%). In 30 cases (18.75%) additional in situ or invasive cancers or a more widespread tumor extent were diagnosed correctly which went undetected by clinical palpation, mammography, and breast ultrasound. In 14 cases (8.75%) additional surgical procedures were performed based on suspicious MRI findings that turned out to be benign in final pathology. Age, menopausal status, breast density, tumor characteristics (type, tumor size, grading), ER-, PR- and HER2-receptor features did not significantly differ between patients in which breast MRI affected the clinical management and patients that experienced no additional information from MRI.
Preoperative breast MRI changes surgical management of patients with operable breast cancer. MRI detects additional invasive carcinoma and proves to be a powerful supplement to the conventional work-up in the clinical management of breast cancer. This advantage is independent from patients- and tumor-specific characteristics.
Breast Cancer Research and Treatment 10/2008; 111(1):179-87. · 4.43 Impact Factor
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Michael Braun,
Uta Flucke,
Manuel Debald,
Gisela Walgenbach-Bruenagel,
Klaus-Jürgen Walgenbach,
Tobias Höller, Martin Pölcher,
Matthias Wolfgarten,
Axel Sauerwald,
Mignon Keyver-Paik,
Marietta Kühr,
Reinhard Büttner,
Walther Kuhn
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ABSTRACT: The aim of this study was to investigate the use of D2-40 for the detection of lymphovascular invasion (LVI) in node positive and negative early breast cancer. LVI is associated with axillary lymph node metastases (ALNM) and a long-term prognostic factor. A precise identification of LVI would have a strong clinical impact for breast cancer patients.
Immunohistochemical staining with D2-40 and CD34 was performed on formalin-fixed, paraffin-embedded tissue sections of 254 invasive breast tumors of 247 patients with node negative and node positive early breast cancer. All slides were screened for the presence of LVI. Correlation with clinico-pathological factors including LVI as retrieved by routine haematoxylin and eosin (H.E.) stained sections and the eligibility for the prediction of ALNM was assessed.
Using the D2-40 antibody for immunostaining, our results demonstrate a significant higher detection (P < 0.001) of LVI as compared with routine H.E.-staining in early breast cancer. LVI was correctly identified by D2-40 (D2-40+) in 70 out of 254 tumors (28%) as compared to 40 tumors (16%) by routine HE staining (HE+). There was a significant correlation between D2-40 + LVI and age, t-stage, nodal status, grading and hormonreceptor-status. Correlation between D2-40 + LVI and menopausal-status, HER2-status and histological type was not significant, while there was a significant correlation of D2-40 and so called "triple negative" tumors (ER/PR and HER2neu-negative). In a multivariate analysis D2-40+ was the strongest predictor for ALNM with an odds ratio of 3.489 and a P-value of P = 0.0003, followed only by T-stage and grading with odds ratios of 3.167 and 1.953 and P-values P = 0.0003 and P = 0.0352.
Immunostaining with D2-40 significantly increased the frequency of detection of lymphatic invasion compared to conventional H.E.-staining in early breast cancer. As LVI is a strong predictive and prognostic marker, the monoclonal antibody D2-40 has the potential to play a significant role in pathological routine workup of breast tumors. Further prospective studies are needed to prove the clinical impact of D2-40.
Breast Cancer Research and Treatment 12/2007; 112(3):503-11. · 4.43 Impact Factor
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The Lancet Oncology 06/2007; 8(5):451-4. · 22.59 Impact Factor
