Background:Peritoneal dissemination and retroperitoneal lymph node involvement are main routes for tumour spread of epithelial ovarian cancer (EOC), possibly determined by the intercellular connecting protein E-Cadherin (E-Cad) and its fragments.Methods:Tumour tissue of 105 advanced EOC patients was evaluated for protein expression of E-Cad, β-Catenin and Calpain by western blotting and immunohistochemistry. Expression patterns were compared between tumours with solely intraperitoneal (pT3c, pN0; n=41) and tumours with retroperitoneal metastases (pT1a-3c, pN1; n=64). Lysates of the EOC cell line SKOV3 and tumour tissue from the intraperitoneal group were tested for E-Cad expression following Calpain treatment.Results:E-Cad full-length (E-Cad-FL, 120 kDa) and two major fragments at 85 kDa (E-Cad-85) and 23 kDa (E-Cad-23) were detected by western blotting. E-Cad-85 expression was significantly higher in tumours with solely intraperitoneal metastases and correlated strongly with E-Cad-23 and the protease Calpain. Calpain-mediated cleavage was identified as a potential mechanism to generate E-Cad-85 from E-Cad-FL by treating lysates from SKOV3 cells and tumour tissue with this enzyme. Increased cytoplasmic localisation of β-Catenin in tumours with high E-Cad-85 expression corroborates that E-Cad-85 loses the binding site for β-Catenin after fragmentation, enabling tumour cluster formation and peritoneal dissemination.Conclusions:Calpain-mediated E-Cad fragmentation appears to promote intraperitoneal EOC progression. Understanding these mechanisms might eventually lead to new tailored subtype-specific diagnostic and therapeutic interventions.

BackgroundPeritoneal dissemination and retroperitoneal lymph node involvement are main routes for progression of epithelial ovarian cancer (EOC). Vascular endothelial growth factor (VEGF) mediated angiogenesis has been identified as an important mechanism promoting tumour progression.MethodsTumour tissue of 100 patients with EOC was analysed for protein expression of vascular endothelial growth factor (VEGF)-A, -C, -D by Western Blot analysis. Expression patterns in patients with ‘extensive intraperitoneal’ metastases (pT3c pN1 and pT3b-pT3c pN0, n=80) were compared to patients with ‘predominantly retroperitoneal’ metastases (pT1a-pT3b, pN1, n=20). Overall and progression-free survival was analysed by Kaplan-Meier method.ResultsWhile no significant differences in expression levels among the different modes of metastases were noted for VEGF-A and -D, VEGF-C expression was significantly higher in the group of predominantly retroperitoneal metastases compared to the group with extensive intraperitoneal metastases. Patients with high VEGF-C expression had a significantly worse overall survival compared to patients with low expression levels.ConclusionsRetroperitoneal tumour progression in EOC patients is associated with high VEGF-C expression. VEGF-C may serve as a molecular marker to identify patients with assumed high risk for lymphatic metastases, who might benefit from specific treatment strategies.

Elderly patients are generally willing to participate in clinical studies, in our cohort regardless of their fitness. Benefits of participation seem to be unclear among a majority of potential study participants. Therefore, it might be decisive to provide more general information regarding benefits and safety for elderly patients in a clinical trial.

ObjectivesSuperficially invasive stage IA squamous vulvar cancer (VSCC) is defined as a single lesion measuring ≤2 cm with a depth of invasion of ≤1.0 mm (FIGO stage IA). This article examines the natural course and prognosis of superficially invasive VSCC.MethodsThis is a retrospective case series of 46 patients (median age 58 years) with superficially invasive stage IA VSCC receiving wide local excision between January 1996 and November 2014 in the University Medical Center Hamburg-Eppendorf.ResultsMedian tumor size was 4 mm. In 39/46 (84.8%) patients peri-tumoral high-grade intraepithelial neoplasia (HSIL) and/or lichen sclerosus (LS) of the vulva were histologically detected: 34 (74.0%) usual type high-grade vulvar intraepithelial neoplasia (uVIN, HSIL), 4 (8.7%) LS with simultaneous VIN (3 uVIN, 1 differentiated VIN (dVIN)), 1 (2.2%) with LS only. 37/46 (80.4%) patients had a R0 resection; in 2 (4.3%) a high-grade VIN was detected in the margin and in 7 (15.2%) the resection status was unknown. The mean follow-up was 58 (range 10–185) months. Four patients (8.7%) suffered from an invasive recurrence after 4, 17, 40, and 54 months, three in the vulva and one in the groin. All local recurrences occurred in women with LS in a combination with high-grade VIN (3 uVIN, 1 dVIN). Two were treated surgically again including inguino-femoral lymphadenectomy (ifLAE) (no regional lymph node metastasis histologically) as invasion depth exceeded 1 mm. The third patient refused treatment. Inguinal recurrence was treated with a bilateral ifLAE, revealing one positive lymph node, followed by adjuvant radiotherapy (groins, pelvis). None of these patients had experienced further recurrences at last follow-up.ConclusionsSuperficially invasive VSCC is characterized by having a very good prognosis. Sole surgical therapy is highly effective. Patients with LS might benefit additionally from intensified surveillance and adequate maintenance therapy in specialized centers.