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Background: The technique of compartment-based radical hysterectomy was originally described by M Höckel as total mesometrial resection (TMMR) for standard treatment of stage I and II cervical cancer. However, with regard to the ontogenetically-defined compartments of tumor development (Müllerian) and lymph drainage (Müllerian and mesonephric), compartments at risk may also be defined consistently in endometrial cancer. This is the first report in the literature on the compartment-based surgical approach to endometrial cancer. Peritoneal mesometrial resection (PMMR) with therapeutic lymphadenectomy (tLNE) as an ontogenetic, compartment-based oncologic surgery could be beneficial for patients in terms of surgical radicalness as well as complication rates; it can be standardized for compartment-confined tumors. Supported by M Höckel, PMMR was translated to robotic surgery (rPMMR) and described step-by-step in comparison to robotic TMMR (rTMMR)., Methods: Patients (n = 42) were treated by rPMMR (n = 39) or extrafascial simple hysterectomy (n = 3) with/without bilateral pelvic and/or periaortic robotic therapeutic lymphadenectomy (rtLNE) for stage I to III endometrial cancer, according to International Federation of Gynecology and Obstetrics (FIGO) classification. Tumors were classified as intermediate/high-risk in 22 out of 40 patients (55%) and low-risk in 18 out of 40 patients (45%), and two patients showed other uterine malignancies. In 11 patients, no adjuvant external radiotherapy was performed, but chemotherapy was applied., Results: No transition to open surgery was necessary. There were no intraoperative complications. The postoperative complication rate was 12% with venous thromboses, (n = 2), infected pelvic lymph cyst (n = 1), transient aphasia (n = 1) and transient dysfunction of micturition (n = 1). The mean difference in perioperative hemoglobin concentrations was 2.4 g/dL (± 1.2 g/dL) and one patient (2.4%) required transfusion. During follow-up (median 17 months), one patient experienced distant recurrence and one patient distant/regional recurrence of endometrial cancer (4.8%), but none developed isolated locoregional recurrence. There were two deaths from endometrial cancer during the observation period (4.8%)., Conclusions: We conclude that rPMMR and rtLNE are feasible and safe with regard to perioperative morbidity, thus, it seems promising for the treatment of intermediate/high-risk endometrial cancer in terms of surgical radicalness and complication rates. This could be particularly beneficial for morbidly obese and seriously ill patients.

Objective. To define compartment based therapeutic pelvic and periaortic lymphadenectomy in cervical and endometrial cancer. Compartment based oncologic surgery appears to be favorable for patients in terms of radicality as well as complication rates, and the same appears to be true for robotic surgery. We describe a method of robotically assisted compartment based lymphadenectomy step by step in uterine cancer and demonstrate feasibility data from 35 patients. Methods. Patients with the diagnosis of endometrial (n = 16) or cervical (n = 19) cancer were included. Patients were treated by rTMMR (robotic total mesometrial resection) or rPMMR (robotic peritoneal mesometrial resection) and pelvic or pelvic/periaortic rtLNE (robotic therapeutic lymphadenectomy) with cervical cancer FIGO IB-IIA or endometrial cancer FIGO I-III. Results. No transition to open surgery was necessary. Complication rates were 13% for endometrial cancer and 21% for cervical cancer. Within follow-up time median (22/20) month we noted 1 recurrence of cervical cancer and 2 endometrial cancer recurrences. Conclusions. We conclude that compartment based rtLNE is a feasible and safe technique for the treatment of uterine cancers and is favorable in aspects of radicality and complication rates. It should be analyzed in multicenter studies with extended followup on the basis of the described technique.

Background: We evaluated the prognostic value of the new serum biomarkers mesothelin (cell surface glycoprotein and tumor differentiation antigen), L1 cell adhesion molecule (L1CAM) and afamin (vitamin D-binding protein) alone and in combination with cancer antigen 125 (CA125) in serum samples of 154 patients with first-diagnosis of primary ovarian cancer, before surgery and after platinum-based chemotherapy. We correlated these findings with clinical parameters and evaluated their prognostic value with regard to overall survival (OS)., Materials and Methods: Blood (9 ml) was obtained before surgery (n=154) and after chemotherapy (n=82) for the measurement of serum markers using commercial Enzyme Linked Immunosorbent Assay (ELISA) kits for mesothelin, L1CAM, afamin and CA125. Mesothelin positivity was defined as >2.0 nM, L1CAM as >10 ng/ml, afamin as <45 mg/l and CA125 as >35 U/ml, respectively., Results: Before surgery, mesothelin positivity significantly correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.002), residual postoperative tumor (p<0.0001), serous histological subtype (p<0.0001) and higher age (p=0.013). Elevated CA125 levels significantly correlated with advanced FIGO stage (p<0.0001) and grading (p=0.012). After chemotherapy, mesothelin as well as CA125 levels, were significantly associated with FIGO stage (p=0.041 and p=0.017) and residual tumor (p=0.022 and p=0.002) while L1CAM correlated with platinum sensitivity (p=0.041). In contrast, afamin at all determined time points showed no correlation with any of these parameters. The combination of markers did not add any significant power to their use., Conclusion: Mesothelin and L1CAM appear to correlate with clinical prognostic parameters and might be useful biomarkers for therapy monitoring and, thus, could serve as attractive targets for therapy of ovarian cancer.

Background: The aim of this study is to detect possible risk factors for development of short- and long-term local complications after inguinofemoral lymphadenectomy for vulval cancer., Methods: This retrospective cohort study included 34 vulval cancer patients that received inguinofemoral lymphadenectomy. The detected complications were wound cellulitis, wound seroma formation, wound breakdown, wound infection, and limb lymphoedema. Followup of the patient ran up to 84 months after surgery., Results: Within a total of 64 inguinofemoral lymphadenectomies, 24% of the inguinal wounds were affected with cellulitis, 13% developed a seroma, 10% suffered wound breakdown, 5% showed lower limb edema within a month of the operation, and 21.4% showed lower limb edema during the long-term followup. No significant correlation could be found between saphenous vein ligation and the development of any of the local complications. The 3-year survival rate in our cohort was 89.3%., Conclusions: Local complications after inguino-femoral lymphadenectomy are still very high, with no single pre-, intra-, or postoperative factor that could be incriminated. Saphenous vein sparing provided no significant difference in decreasing the rate of local complications. More trials should be done to study the sentinel lymph node detection technique.

Background: Breast cancer patients may experience disease relapse even 10-20 years after primary diagnosis. Recurrence is caused by dormant disseminated tumor cells (DTCs) in the bone marrow (BM). Whereas chemotherapy is unable to eradicate these non-proliferating cells, bisphosponates are currently being discussed as eliminating DTCs. The purpose of our study was to: i) analyze the presence of DTCs in the BM of breast cancer patients 2-10 years after first diagnosis of cancer, and ii) to study the effect of ibandronate on DTCs in those patients with DTC persistence., Patients and Methods: Bilateral BM aspirates of 54 individuals diagnosed 2-10 years ago with breast cancer, but currently disease free, were analyzed for DTCs by immunocytochemistry using pan-cytokeratin antibody A45-B/B3. Patients with DTC persistence received oral ibandronate treatment (50 mg per day) for six months and bilateral BM aspirates were analyzed for DTCs again after therapy., Results: DTCs were found in 18/54 (33%) of the patients, with a median number of 3 disseminated tumor cells (range 1-6 cells). These 18 patients received ibandronate orally for 6 months and 17/18 patients were analyzed for DTCs again after therapy. Only 3/17 (18%) patients remained DTC-positive, with the detection of 1 (n=2 patients) and 3 DTCs, respectively. These three DTC-positive patients continued their ibandronate intake for a further six months and re-examination of the BM resulted in no detection of DTCs in any of the three patients., Conclusion: Our pilot study indicates the potential effect of ibandronate on DTCs and further studies are needed to demonstrate these findings in a larger patient cohort.

Disseminated tumor cells (DTC) in the bone marrow (BM) are present in about 35% of ovarian cancers before surgery and after chemotherapy and are associated with worse prognosis. A molecular biomarker in the primary tumor predicting tumor cell spread would be highly desirable. The purpose of the study was to investigate loss of heterozygosity (LOH) in primary ovarian tumors at four ovarian cancer-relevant chromosomal loci involved in apoptosis, platinum sensitivity, or DNA-repair, to assess the prognostic value of LOH and to correlate LOH with DTC occurrence before surgery and after chemotherapy. Primary tumor DNA of 88 patients was analyzed for LOH at four polymorphic microsatellite markers using PCR-based fluorescence microsatellite analysis. BM aspirates were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. LOH at the entire marker set correlated with tumor grading (P = 0.0001) and histology (P = 0.004). LOH at marker D10S1765 correlated with FIGO stage (P = 0.046) and grading (P = 0.05), whereas LOH at D17S855 significantly associated with grading (P = 0.023) and histology (P = 0.012), respectively. DTC were detected in 49% of patients before surgery and in 50% of patients after chemotherapy. Interestingly, LOH proximal to D6S1581 significantly correlated with DTC presence before surgery (P = 0.05) and after chemotherapy (P = 0.022). Conclusively, our data suggest that allelic loss at D6S1581 (proximal to M6P/IGF2R locus) serves as a molecular biomarker for the presence of DTC in the BM before and after chemotherapy., (Copyright © 2011 Wiley-Liss, Inc.)

Objectives: Disseminated tumor cells (DTCs) in the bone marrow (BM) were shown to be of prognostic significance in gynecological cancers. Bone marrow aspiration is less accepted by patients compared with blood drawing. In this pilot study, we applied the AdnaTest BreastCancer based on immunomagnetic enrichment, targeting common antigens on epithelial gynecological cancers, followed by multiplex reverse transcriptase-polymerase chain reaction for selection and detection of circulating tumor cells (CTCs) in the blood of 122 ovarian cancer patients at primary diagnosis and/or after platinum-based chemotherapy. Results were compared with detection of DTC in BM., Methods: Ten-milliliter blood was obtained before surgery (n=86) and/or after chemotherapy (n=70) and analyzed for CTC with the AdnaTest BreastCancer for the detection of EpCAM-, MUC-1-, and HER-2-transcripts. CA 125 was assessed in an additional single-plex reverse transcriptase-polymerase chain reaction. Bone marrow aspirates were analyzed in duplicate by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3., Results: Before surgery, CTCs were detected in 19% of patients, expressing EpCAM (31%), MUC-1 (50%), HER-2 (31%), and CA 125 (50%), respectively. After chemotherapy, the overall detection rate for CTC was 27%, thereof EpCAM (68%), MUC-1 (47%), HER2 (21%), and CA 125 (37%). The overall detection rate for DTC in the BM was 35% before surgery and 31% after therapy. A comparison between DTC and CTC resulted in a concordance rate of 59% before surgery and 56% after chemotherapy. CTC positivity significantly correlated with shorter overall survival before surgery (P=0.0054) and after chemotherapy (P=0.047)., Conclusions: This methodological approach might help to identify molecular targets for specific biological therapies. Blood analysis could give additional information complimentary to that obtained by DTC.

Background: Recent data suggest a role of the ubiquitin-proteasome system in various malignancies. In patients with neoplasms, increased extracellular concentrations of circulating 20S proteasome (c-proteasome) have been detected in blood plasma. We tested the hypothesis that the plasma c-proteasome concentration is a biomarker associated with tumor stage and nodal status in patients with the primary diagnosis of non-metastatic breast cancer., Patients and Methods: Venous plasma concentration of 20S proteasome was measured by ELISA technique in 224 non-metastatic breast cancer patients and in 50 healthy volunteers. To assess the relation of proteasome expression to c-proteasome concentration, tumor specimens from 32 patients were immunohistochemically stained for 20S proteasome using an antibody directed against the core subunits of the catalytic domain of the 20S proteasome., Results: The median c-proteasome concentration was higher (p<0.0001) in breast cancer patients (397.5 ng/ml, range: 200-50,000 ng/ml) than in healthy controls (305 ng/ml, range: 140-425 ng/ml). There was no significant correlation between c-proteasome concentration and strength of proteasomal staining in tumor specimens. Neither tumor size, nor nodal status, nor any other prognostically important clinical parameter, including the presence of disseminated tumor cells in the bone marrow, correlated with high c-proteasome concentrations., Conclusion: Circulating proteasome concentrations appear to be higher in patients presenting with primary breast cancer than in healthy controls. Thus, the ubiquitin-proteasome system might represent a potential target in breast cancer treatment.

EpCAM is a tumor-associated antigen, which is frequently expressed in ovarian cancer. Recently, autoantibodies against EpCAM have been identified in patients with ovarian cancer. It is not clear whether these autoantibodies are of prognostic importance. We evaluated whether EpCAM-autoantibodies have an impact on the clinical course of patients with ovarian cancer. EpCAM-autoantibodies were determined in sera of 28 healthy voluntary age-matched women and 84 patients with primary epithelial ovarian cancer before and after platinum-based chemotherapy using a recombinant EpCAM-protein for antibody detection by ELISA technique. The median follow-up time was 18 months. Samples exceeding the mean antibody titer of healthy controls plus 2 standard deviations were considered positive. The antibody titer of healthy controls was 0.061 ± 0.015. Using a cut-off value of 0.091, we found 3/84 (4%) patients before and 12/61 (20%) patients with ovarian cancer to be positive for EpCAM-autoantibodies after first-line treatment. Using the paired T-Test, we noted a significant post-therapeutic increase of AABs (P < 0.0001). Notably, AAB-levels after first-line therapy were found to be correlated with the tumor resection status in primary surgery. Analysis of progression-free survival, FIGO stage, grading, age and sensitivity to platinum-based chemotherapy did not reveal significant associations with EpCAM-AAB titers. We observed an increase in AAB-levels during the first-line treatment of patients with ovarian cancer. EpCAM-AAB-levels after first-line treatment appear to correlate with macroscopic tumor residuals after initial surgery.

Background: Intracellularly, the ubiquitin-proteasome system participates in crucial functions such as cell cycling, differentiation, proliferation, gene transcription, and apoptosis. However, in malignancies including ovarian cancer increased extracellular concentrations of circulating 20S proteasomes (c-proteasomes) have been detected in blood. We tested the hypothesis that the c-proteasome plasma concentration is a biomarker associated with the clinical course of ovarian cancer patients., Methods: 20S-proteasome venous plasma concentration was measured by ELISA in patients presenting with ovarian cancer before (n=120) and after (n=68) primary treatment, and in healthy volunteers (n=55). The median follow-up time was 19 months. To assess the relation of proteasome expression with c-proteasome concentration, tumor specimens from 27 patients were immunohistochemically stained for 20S proteasome using an antibody directed against the core subunits of the catalytic domain of the 20S proteasome., Results: Median c-proteasome concentration was higher (p<0.0001) in untreated ovarian cancer patients (457.5 ng/ml, range: 200-12540 ng/ml) than in healthy controls 290 ng/ml, range: 140-425 ng/ml). Following completion of primary treatment, the median c-proteasome concentration increased (p=0.003) relative to baseline (595 ng/ml, range: 200-20000 ng/ml) and concentrations positively correlated (p=0.031) with residual disease left at primary surgery. Patients with post-treatment c-proteasome concentrations exceeding the cohort's median showed a diminished survival (p=0.045). We found no correlation between c-proteasome concentration and strength of proteasomal staining in tumor specimens., Conclusions: Circulating proteasome concentrations correlate with residual tumor mass and might be a prognostic variable in ovarian cancer following primary therapy., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The role of estrogens in ovarian carcinogenesis and progression of ovarian cancer is unclear. Cytochrome P450 is involved in estrogen metabolism, and polymorphisms have been associated with functional changes and risk for ovarian cancer. In this study, we investigated the impact of the CYP1A1 Ile462Val polymorphism upon tumor risk and disease progression in ovarian cancer patients. One hundred and eleven ovarian cancer patients who had been treated at the University Hospital of Essen between 1999 and 2007 and 119 age-matched healthy female controls were enrolled in this study. Genotyping was performed using PCR-RFLP. The distribution of genotypes was statistically significant different between ovarian cancer patients and healthy controls. We observed a significant association of the Ile allele with ovarian cancer (OR 2.6, 95% CI 1.5-4.7, p = 0.001). Clinical parameters such as overall survival, FIGO stage, grading, and age at diagnosis did not differ significantly. We observed a statistically significant association between the 462Val allele and platinum resistance, which was defined as a time interval < 6 months to disease progression after administration of a platinum-based primary chemotherapy (OR 5.9, 95% CI 1.5-23.2, p = 0.005). We observed a significant association between the presence of the 462Ile allele with ovarian cancer. While there is uncertainty about the potential involvement of CYP1A1 in the metabolism of platinum-containing agents, our findings suggest an association between the 462Val allele and the development of platinum resistance in ovarian tumors. If confirmed in a larger, independent collective, our findings would have important relevance with respect to the clinical consequences for the primary chemotherapy of ovarian cancer patients.

Background: Bcl-2 plays a key role in the regulation of apoptosis. Recently, a novel regulatory single nucleotide polymorphism (-938C>A) in the inhibitory P2 BCL2 promoter was described. In this study we investigated its potential association with survival in epithelial ovarian cancer., Experimental Design: Patients (n=110) with primary epithelial ovarian cancer were retrospectively genotyped by pyrosequencing., Results: Genotype distribution was not significantly different between 110 ovarian cancer patients and 120 healthy controls, suggesting that genotypes of this polymorphism do not increase the susceptibility to ovarian cancer. Kaplan-Meier curves showed a significant association of the AA genotype with increased survival (p=0.002). Multivariate analysis revealed that the BCL2-938AC/CC genotype (hazard ratio 4.5; p=0.003) was an independent prognostic factor compared to other prognostic factors such as age, histological grade or tumor stage., Conclusion: The results suggest a role for the BCL2-938C>A polymorphism as a marker for survival in patients with epithelial ovarian cancer.

Background: Recent studies proposed L1CAM (L1 cell adhesion molecule) expression as a negative prognostic marker in epithelial ovarian cancer (EOC). The gene L1C was screened for single nucleotide polymorphisms (SNPs) which could impact upon EOC risk or disease progression., Patients and Methods: Overlapping DNA fragments, including the promoter region, intron 1 and all the exons of 10 healthy volunteers were analyzed to detect SNPs. EOC patients (n=103) and age-matched controls (n=104) were subsequently genotyped by restriction fragment length polymorphism (RFLP). Quantitative real-time PCR was carried out to detect potential associations of SNPs with L1C mRNA expression., Results: One SNP was found in intron 1 (L1C G842A). Genotyping of the EOC patients and age-matched controls revealed an association of EOC with the homozygous AA genotype (OR 7.4, CI 1.6-33.5; p=0.003). The L1C mRNA expression levels and clinical parameters did not differ significantly between the L1C G842A genotypes., Conclusion: The L1C 842 AA genotype may be a predisposing factor for EOC.

Besides known prognostic factors in breast cancer, disseminated tumor cells are regarded as a surrogate marker for minimal residual disease in breast cancer. Their prognostic significance is comparable to that of lymph node status. However, the mechanism by which the primary tumor directs cells to disseminate into lymph nodes or into blood vessels is unclear. Aquaporins (AQPs) are small integral membrane proteins that provide a major pathway for water transport throughout several organs, and have been shown to be of potential importance in various types of cancer. Here, we analyzed the single nucleotide polymorphism (SNP) A(-1364)C in AQP5 in 107 patients with early stage breast cancer in order to test the hypothesis that this polymorphism is associated with lymphogenous and hematogenous tumor cell dissemination and overall survival. Paraffin-embedded tumor tissue was dewaxed, and DNA was extracted from tumor tissues using the QIAamp Blood DNA Mini Kit. The quantification and quality of the extracted DNA were determined spectrophotometrically. Genotyping of the -1364A>C polymorphism was performed by Pyrosequencing. Cytokeratin-positive (CK+) bone marrow (BM) cells were isolated by density gradient centrifugation followed by immunocytochemistry, applying the pan CK antibody A45-B/B3. There was no evidence of an association between the AQP5C>A genotypes and an increased risk of developing breast cancer, nor between the genotypes and tumor size, lymph node involvement, distant metastasis, grade, histopathology, expression of estrogen receptor and HER2, or the dissemination of tumor cells to BM. In contrast, when comparing C-allele carriers with patients carrying the AA genotype, expression of the progesterone receptor differed significantly between these genotype groups (mean AA genotype 51%, mean AC and CC genotype 73%; p=0.039). Additionally, a significant correlation was found between progesterone receptor expression and adjuvant chemotherapy (p=0.021) and adjuvant endocrine therapy (p=0.017), respectively. SNPs in AQP5 are not associated with hematogenous or lymphogenous tumor cell spread. However, we observed for the first time an association between SNPs in AQP5 and progesterone receptor positivity, which might have implications for future adjuvant treatment. Further investigations must include more than one AQP as well as factors promoting angiogenesis to elucidate the different modes of tumor cell dissemination.

The trifunctional antibody catumaxomab with bispecificity for the epithelial cell adhesion molecule EpCAM and the T-cell antigen CD3, is a new therapeutic strategy for ovarian cancer patients with symptomatic malignant ascites. Whether or not intraperitoneal (i.p.) catumaxomab-therapy has influence on disseminated and circulating tumor cells was investigated by analyzing cytokeratin-positive (CK+) cells in bone marrow (BM) and peripheral blood (PB). Fourteen ovarian cancer patients with symptomatic ascites were treated with catumaxomab (up to 5 i.p.-infusions; increasing dosages (10-200 microg)). CK+-cells were isolated before and after antibody-therapy by density gradient centrifugation and immunocytochemistry (anti-CK antibody A45-B/B3). Catumaxomab-treatment resulted in the sustained reduction of ascites flow and arrested ascites reaccumulation. The mean overall survival was 8 months. CK+-cells in the BM were found in 70% before and 83% after therapy (in the PB 57% and 42%, respectively). A marked reduction of CK+-cells occurred in the BM in 2 and in the PB in 4 patients. Catumaxomab shows a strong intraperitoneal effect and possibly also systemic effects on tumor cells in the BM and PB.

Objectives: The precise role of gonadotropins in the carcinogenesis of epithelial ovarian cancer remains uncertain. Recently, the haplotype of two single nucleotide polymorphisms, Thr307Ala (rs6165) and Asn680Ser (rs6166), has been described as a risk factor for ovarian cancer in Chinese women. In this study we investigated the impact of this haplotype regarding the risk to develop ovarian cancer as well as possible effects upon the clinical course in a Caucasian patient sample., Subjects and Methods: Determination of genotypes in 115 patients with primary epithelial ovarian cancer and 115 age-matched controls was performed by Pyrosequencing for Thr307Ala and by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique for Asn680Ser., Results: Analysis of the genotypes revealed almost complete linkage disequilibrium of both SNPs. The distribution of genotypes was not statistically significant different between ovarian cancer patients and age-matched controls. Clinical parameters such as overall survival, CA12-5 elevation at primary diagnosis, age at diagnosis, FIGO stage, grading, and platinum resistance were not statistically significantly different regarding genotypes., Conclusions: We could not confirm the FSHR Ala307-Ser680 haplotype as a risk factor for epithelial ovarian cancer in Caucasian women. Hence, the modification of tumor risk may be affected by the ethnology of the patient collective. We could not find any associations of clinical parameters or course of the disease with the different genotypes.