Gerald Gitsch

Uterosacral ligament in postmenopausal women with or without pelvic organ prolapse

The uterosacral ligaments are thought to contribute to pelvic support. The objective of this study was to compare the structural components of these ligaments in women with and without pelvic organ prolapse (POP). We characterized uterosacral ligaments of 25 postmenopausal women with POP and 16 controls histomorphologically and immunohistochemically by quantifying their content of collagen I, III, and smooth muscle using a computerized image analysis. In 84% the uterosacral ligaments were composed of more than 20% of smooth muscle cells. There was no difference in collagen I expression and smooth muscle cell amount between women with POP and those without. In contrast, the collagen III expression was significantly related to the presence of POP (p<0.001) rather than age or parity. Our findings suggest that the higher collagen III expression might be a typical characteristic of POP patients’ connective tissue. The considerable amount of smooth muscle cells in uterosacral ligaments may provide pelvic support.

Increased expression of matrix metalloproteinase 2 in uterosacral ligaments is associated with pelvic organ prolapse

The uterosacral ligaments are an important part of the pelvic support system and connective tissue alterations are thought to contribute to the development of pelvic organ prolapse (POP). The objective of this study was to compare the expression of matrix metalloproteinases (MMPs) 1 and 2 in these ligaments in women with and without POP. We analyzed the tissue samples obtained from left and/or right uterosacral ligaments of 17 women with POP and 18 controls by immunohistochemistry. There was no difference in MMP-1 expression between women with POP and those without. In contrast, the MMP-2 expression was significantly related to the presence of POP (p=0.004) rather than to age or parity. There was no difference in MMP-1 and MMP-2 expression between left and right uterosacral ligaments in women with POP compared to controls. Our findings strongly indicate that increased MMP-2 expression in uterosacral ligaments is associated with POP.

The MSKCC nomogram for prediction the likelihood of non-sentinel node involvement in a German breast cancer population.

Objective To assess whether the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram for prediction of NSLN metastasis is useful in a German breast cancer population and whether the characteristics of the breast tumor and the sentinel lymph node (SLN) are able to predict the likelihood of non-sentinel lymph node (NSLN) metastasis. Methods A total of 545 patients with primary breast cancer and SLN examination were evaluated. The MSKCC nomogram was applied to 98 patients with a positive SLN who subsequently had completion axillary lymph node dissection (ALND). Predictive accuracy was assessed by calculating the area under the receiver-operator characteristic (ROC) curve. The collective was evaluated by correlating the prevalence of NSLN and SLN metastasis to pathological features. Results The MSKCC nomogram achieved a ROC of 0.58 indicating a bad accuracy of the nomogram. Tumor size, histology, lymphovascular infiltration, multifocality, Her-2-neu positivity, and nuclear grade correlated with the probability of SLN metastasis. Histology and primary tumor localization correlated significantly with the probability of NSLN metastasis. Conclusions The MSKCC nomogram did not provide a reliable predictive model in our study population. However, the likelihood of SLN metastasis correlated with the presumed risk factors and no obvious differences between the MSKCC population and our population could be seen. In order to achieve interinstitutional reproducibility, standardization of surgical procedure and of the pathological assessment of the SLN is desirable.

Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes

Background:The aim of this study was to investigate the prognostic effect of tumour-infiltrating lymphocytes (TILs) in serous stage III ovarian carcinoma to determine TIL clonality and to correlate this to Her2/neu expression.Methods:Formalin-fixed and paraffin-embedded ovarian carcinomas were examined for CD20-, CD3-, CD4- and CD8-positive lymphocytes (n=100), and for Her2/neu-positive tumour cells (n=55/100) by immunohistochemistry. Clonality analysis was carried out by T-cell receptor γ (TCRγ) gene rearrangements (n=93/100). Statistical analyses included experimental and clinico-pathological variables, as well as disease-free (DFS) and overall (OS) survival.Results:CD20-positive B lymphocytes were present in 57.7% (stromal)/33.0% (intraepithelial) and CD3-positive T lymphocytes in 99.0% (stromal)/90.2% (intraepithelial) of ovarian carcinomas. Intraepithelial CD3-positive T lymphocytes were correlated with improved DFS in optimally debulked patients (P=0.0402). Intraepithelial CD8-positive T lymphocytes were correlated with improved OS in all optimally debulked patients (P=0.0201) and in those undergoing paclitaxel/carboplatin therapy (P=0.0092). Finally, rarified and clonal TCRγ gene rearrangements were detected in 37 out of 93 (39.8%) and 15 out of 93 (16.1%) cases, respectively. This was marginally associated with improved DFS (P=0.0873). Despite a significant correlation of HER2/neu status and intraepithelial CD8-positive lymphocytes (P=0.0264), this was non-directional (R=−0.257; P=0.0626).Conclusion:Improved survival of ovarian cancer patients is related to the infiltration, clonal selection and intraepithelial persistence of T lymphocytes.

Predictive Value of Aurora-A/STK15 Expression for Late Stage Epithelial Ovarian Cancer Patients Treated by Adjuvant Chemotherapy

Purpose: To investigate the expression and regulation of the centrosomal kinase Aurora-A/STK15 (AURKA) in epithelial ovarian cancers and to determine the prognostic and predictive value of this marker for patients with late stage epithelial ovarian cancer treated by distinct adjuvant chemotherapies. Experimental Design: Archival resection specimens of epithelial ovarian cancers (n = 115) and nonneoplastic ovaries (n = 28) were analyzed for AURKA mRNA and protein expression by microdissection and quantitative reverse transcriptase-PCR and immunohistochemistry. AURKA DNA copy numbers were measured by fluorescence in situ hybridization in 37 cases. Statistical evaluation was done with respect to clinicopathologic variables, disease-free survival, and overall survival. Results: AURKA mRNA expression was significantly elevated in cancers (P < 0.001) and correlated with AURKA protein expression (P = 0.0134). Overexpression of AURKA protein was detected in 68 of 107 (63.5%) cases and was linked with increased AURKA DNA copy numbers (P = 0.0141) and centromere 20 aneusomy (P = 0.0137). Moreover, AURKA overexpression was associated with improved overall survival in optimal debulked patients receiving taxol/carboplatin therapy (n = 43, P = 0.018). Finally, in an exploratory approach, patients receiving non–taxane-based therapy, AURKA overexpression was predictive for worse overall survival (n = 30, P = 0.049). Conclusions: AURKA overexpression is seen in the majority of late stage epithelial ovarian cancers, most likely due to increased AURKA DNA copy numbers and/or chromosome 20 aneusomy. Importantly, AURKA overexpression may differentially affect taxane and non–taxane-based adjuvant therapy responses. The study sheds new light on AURKA expression and regulation in epithelial cancers in vivo and specifically shows its value as a clinically relevant marker and as a potential therapeutic target per se.

Weak expression of focal adhesion kinase (pp125FAK) in patients with cervical cancer is associated with poor disease outcome.

Purpose: The pp125 focal adhesion kinase (FAK) plays a pivotal role in tumor cell signaling. FAK expression has been linked to tumor cell invasion and metastasis, but data on cervical cancer are inconclusive. Our goal was to investigate FAK expression in cervical cancer and to assess whether its expression correlates with prognosis. Experimental Design: FAK expression was examined using immunohistochemistry with sections from 162 resected cervical cancer specimens. Kaplan-Meier survival curves were used to determine the significance of FAK expression in the prognosis of cervical cancer patients. Results: Specific FAK expression was found in the tumor cells, whereas normal cervical epithelium showed barely any FAK expression. Of 162 invasive cervical cancer specimens, 55 (34%) revealed weak expression of FAK, whereas moderate and strong expression was found in 63 (39%) and 44 (27%) tumors, respectively. Patients with tumors expressing weak amounts of FAK were characterized by a significantly poorer overall survival compared with those with moderate and high intratumoral FAK expression (P = 0.002). Weak expression of FAK correlated with pelvic lymph node metastasis (P = 0.026) and recurrent disease (P = 0.013). Multivariate Cox regression analysis revealed decreased FAK expression and pelvic lymph node metastasis to be significant independent factors predictive of poor disease outcome (hazard ratio, 0.36; P = 0.005; hazard ratio, 2.38; P = 0.018, respectively). Conclusions: Weak expression of FAK in invasive cervical cancer is a strong independent predictor of poor patient outcome. Further studies are warranted to elucidate whether FAK expression analysis is a suitable tool identifying patients at high risk even at an early clinical stage.

Quality of life and sexual functioning in endometrial cancer survivors

OBJECTIVE Recent evidence suggests equivalent efficacy in terms of local control for adjuvant vaginal brachytherapy (VBT) compared to external beam radiotherapy after surgery in patients with intermediate-high endometrial cancer. The objective of this study is to compare the quality of life (QoL) and sexual function of women with endometrial cancer that were treated with either surgery alone or surgery in combination with postoperative VBT. METHODS Women were interviewed at least 5 years after initial treatment for endometrial cancer. QoL was evaluated by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and the cervical cancer module, CX-24. Sexual function was evaluated by using the Female Sexual Function Index (FSFI). Eligible women had early stage disease, were currently disease-free, and had undergone surgery and adjuvant VBT, but neither external beam radiotherapy nor systemic treatment. This study group were then compared using univariate and multivariate analyses with an age-matched control group comprising of endometrial cancer patients without adjuvant VBT. RESULTS Fifty-five patients (29 surgery plus VBT and 26 surgical controls without VBT) were included for analysis. With respect to QoL including, e.g., physical, role, emotional and social functioning and likewise in terms of sexual function univariate and multivariate analyses did not show significant differences between patients with VBT and the controls without VBT of any of the outcome measures. CONCLUSION Adjuvant VBT after surgery does not seem to have a significant impact on quality of life and sexual function in endometrial cancer survivors.

Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prognostic and therapeutic implications

BackgroundCancer–testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY-BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors.MethodsThe reactivity pattern of various mAbs (6C1, MA454, M3H67, 57B, E978, GAGE #26 and NY-BR-1 #5) were assessed by immunohistochemistry in a tissue micro array series of 210 randomly selected primary invasive breast cancers in order to study the diversity of different CTAs (e.g. MAGE-A, NY-ESO-1, GAGE) and NY-BR-1. These expression data were correlated to clinico-pathological parameters and outcome data including disease-free and overall survival.ResultsExpression of at least one CTA was detectable in the cytoplasm of tumor cells in 37.2% of the cases. NY-BR-1 expression was found in 46.6% of tumors, respectively. Overall, CTA expression seemed to be linked to adverse prognosis and M3H67 immunoreactivity specifically was significantly correlated to shorter overall and disease-free survival (p=0.000 and 0.024, respectively).ConclusionsOur findings suggest that M3H67 immunoreactivity could serve as potential prognostic marker in primary breast cancer patients. The exclusive expression of CTAs in tumor tissues as well as the frequent expression of NY-BR-1 could define new targets for specific breast cancer therapies.

Good Prediction of the Likelihood for Sentinel Lymph Node Metastasis by Using the MSKCC Nomogram in a German Breast Cancer Population

BackgroundThe sentinel lymph node (SLN) procedure could be omitted in cases of accurate prediction of very high or very low probability of SLN metastasis in early breast cancer patients. We evaluated a breast cancer nomogram, an online tool provided by the Memorial Sloan–Kettering Cancer Center (MSKCC), that predicts the likelihood of a positive lymph node.MethodsData from 545 patients with successful SLN biopsy were collected, including 118 patients with a positive sentinel lymph node. Histopathological assessment of the SLN included hematoxylin and eosin staining and/or immunohistochemistry. Predictive accuracy was assessed by calculating the area under the receiver–operator characteristic (ROC) curve.ResultsIn our collective tumor size, histology, lymphovascular infiltration, multifocality, Her-2-neu positivity, and nuclear grade correlated with the probability of SLN metastasis. The ROC of the validated nomogram in our breast cancer population revealed a value of 0.78 compared with 0.75 in the original publication.ConclusionThe MSKCC nomogram is a useful tool in our population of breast cancer patients. However, variations in the pathological assessment of the SLN between breast cancer centers worldwide might be an impediment to widespread application of the nomogram.

Evidence of androgen receptor expression in lichen sclerosus: an immunohistochemical study.

Objective: While topical androgen administration is widely used in the treatment of lichen sclerosus of the vulva, localization and level of expression of androgen receptor (AR) have not been described previously. Methods: Thirty-nine paraffin-embedded punch biopsies of patients with lichen sclerosus of the vulva were examined. Androgen receptor, estrogen receptor (ER), and progesterone receptor (PR) expression in lichen sclerosus and in normal vulvar skin were investigated by immunohistochemistry. Results: Five tissue specimens (12.8%) of lichen sclerosus showed nuclear staining with anti-AR in the parabasal cell layers of the epidermis. Median age of patients with positive nuclear staining for AR versus women without AR expression was 71 (range, 63-78) and 66.5 (range, 38-91) years, respectively. Estrogen receptor expression was present in only one patient. Nuclear staining reaction for PR expression was absent in all cases. Four of the five AR-positive women reported no complaints and therefore received no topical testosterone therapy. Conclusion: Our results suggest a lack of complaints in AR-positive lichen sclerosus patients. Our findings could justify a larger study comparing symptoms of patients with and without AR expression.