Course of cervical intraepithelial neoplasia diagnosed during pregnancy.

PURPOSE: Management of high-grade cervical intraepithelial neoplasia [CIN grade 2 or 3 (CIN2-3)] diagnosed during pregnancy is controversial. Monitoring with colposcopy and cytology every 8-12 weeks is advised by the most current guidelines. STUDY DESIGN: This study analyzes the course of disease in pregnant women with abnormal cytologies or clinically suspicious cervixes. RESULTS: In total, 139 pregnant women, at a median age of 31 years (range 19-49), treated at the Colposcopy Unit of the University Medical Center Hamburg-Eppendorf between 2011 and 2017 were identified. During pregnancy, at least one biopsy was performed on 70.5% of patients. In 84.7% of cases, CIN2-3 (CIN2 n = 14 (14.3%), CIN3 n = 69 (70.4%)) was detected, 7.1% (n = 7) of women were diagnosed with CIN1, while no dysplasia was found in 8.2% (n = 8) of cases. No interventions were necessary during pregnancy. Despite explicit invitation, only 72.3% of women with CIN2-3 attended postpartal consultations. While 61.7% showed persistent lesions, 5% were diagnosed with CIN1 and 33.3% with complete remission. During pregnancy, 68.7% of women with prepartal CIN2-3 were tested for HPV infection. Later, 49.1% were followed up postpartally by means of HPV testing and histology. HPV clearance was observed in 36.4% of women with complete histological remission. Postpartum conization was performed on 44.6% of patients with prepartal CIN2-3 diagnosis. CIN2-3 was histologically confirmed in 97.3% cases. Progression from persistent CIN3 to microinvasive carcinoma was observed in a single case. CONCLUSIONS: High-grade CIN lesions, diagnosed during pregnancy, show a high rate of regression postpartum; whereas, progression to carcinoma is rare. Close and continuous monitoring rarely has any therapeutic consequences. Compliance for postpartal follow-up needs to be improved.

Superficially invasive stage IA vulvar squamous cell carcinoma-therapy and prognosis.

OBJECTIVES: Superficially 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. METHODS: This 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. RESULTS: Median 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. CONCLUSIONS: Superficially 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.

Participation of elderly gynecological cancer patients in clinical trials.

BACKGROUND: Elderly patients are underrepresented in clinical trials in gynecological cancer, even though they are disproportionally often affected. This study aimed to evaluate the disposition and apprehension of elderly patients toward study participation. METHODS: 112 elderly gynecological cancer patients (median age 70) were surveyed in a multicenter cross-sectional study. Besides fitness, state of disease, education and domestic situation, questions aimed at the general willingness to participate in a clinical trial. Personal reasons for refusal and anticipated advantages/disadvantages that might evolve from participation were inquired. RESULTS: Willingness to participate in a clinical study was generally high (72%, 74/102). Reasons for potential study participation were: 'better monitoring of the disease' (67.1%), 'better medical care' (46.1%), 'to help medical research' (44.7%), 'better medication' (35.5%) and 'because of my doctor's recommendation' (22.4%). Reasons for potential refusal were: 'too time consuming' (24.4%), 'fear of side effects' (21.8%), 'misuse as experimental animal' (18%), 'long distance to clinic' (14.1%) and 'too little or unclear information' (10.3%). 37.2% (29/78) of the patients stated that they had 'no objection' at all against study participation. The question if patients anticipated having a longer life due to study participation was answered with 'yes' or 'rather yes' in 42% (38/90); 28.9% answered 'no' or 'rather no' (29% undecided). No statistical significant relation between willingness to participate in a study and general fitness (p = 0.133), education (p = 0.122), age (p = 0.474) or domestic situation (p = 0.123) could be observed in a multivariate logistic regression model. CONCLUSIONS: 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.

E-Cadherin fragments as potential mediators for peritoneal metastasis in advanced epithelial ovarian cancer.

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, ß-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 ß-Catenin in tumours with high E-Cad-85 expression corroborates that E-Cad-85 loses the binding site for ß-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.

Ang-2 is a potential molecular marker for lymphatic metastasis and better response to bevacizumab therapy in ovarian cancer.

PURPOSE: In ovarian cancer, there are two main routes of metastasis, namely intraperitoneal and retroperitoneal. Their biologic background is poorly understood. Identifying molecular markers involved might enable the development of tailored therapy regimens. Moreover, no reliable markers for response to anti-angiogenic treatment with bevacizumab are yet established. Angiopoietin-2 (Ang-2) is an angiogenic growth factor, involved in lymphatic activation and is associated with tumor progression. Here, we assessed the potential of Ang-2 as a molecular marker in metastasis and treatment of ovarian cancer. METHODS: In our study, quantitative and qualitative protein Ang-2 expression in tumor tissue of ovarian cancer patients was analyzed by Western blot (n = 138) and immunohistochemistry (n = 58). Further, Ang-2 levels in blood samples were quantified in enzyme-linked immunosorbent assay (n = 38). Expression levels of different tumor spread patterns were evaluated, and survival analyses were made. RESULTS: We observed that Ang-2 expression is significantly higher in tumors with retroperitoneal dissemination (pT1a-pT3b, pN1) compared to those showing intraperitoneal tumor growth (pT3c, pN0). In addition, patients with high Ang-2 expression have significantly longer overall survival compared to patients with low Ang-2 expression. Patients with high Ang-2 expression benefit significantly from therapy with bevacizumab. CONCLUSION: All in all, Ang-2 may serve as a molecular marker for patients with tumors prone to spread to lymph nodes and for patients who might benefit from bevacizumab therapy.

VEGF-C serum level is associated with response to bevacizumab maintenance therapy in primary ovarian cancer patients.

OBJECTIVE: At present, maintenance therapy with the antiangiogenic agent bevacizumab or with PARP-inhibitors represent two options for BRCA-wildtype ovarian cancer patients, after platinum-based first line chemotherapy. The identification of molecular markers to predict patient response to different maintenance therapies remains a major challenge. In the present study we analyzed the predictive potential of vascular endothelial growth factor C (VEGF-C) to identify ovarian cancer patients that might benefit from an antiangiogenic therapy. METHODS: 101 patients with primary epithelial ovarian cancer were analyzed for serum levels of VEGF-A,-C and CA-125 by ELISA. Serum levels were compared between patients with low pT-stage (pT1a-pT2c n = 11), healthy individuals (n = 27) and patients with higher pT-stage (> = pT3 n = 90). Adjusted ROC curves and an adjusted logistic regression model were carried out to evaluate the potential impact of VEGF-A and -C, as well as CA-125 serum level concentration on bevacizumab-therapy response, under consideration of covariates such as FIGO, pM, pN and residual tumor after surgery. RESULTS: A patient which has in comparison twice the VEGF-C concentration in serum, has a significant increased chance of response to bevacizumab by a factor of 2.79. Further, only VEGF-C serum levels were significantly higher in the group of patients with lower pT-stage compared to healthy individuals, whereas VEGF-A or CA-125 serum levels could not discriminate between healthy individuals and patients with ovarian cancer at low pT-stages. CONCLUSION: VEGF-C serum level might serve as as a biomarker to evaluate treatment response under bevacizumab.

Targeted Therapeutic Approaches in Vulvar Squamous Cell Cancer (VSCC): Case Series and Review of the Literature.

Therapeutic options in recurrent or metastasized vulvar squamous cell cancer (VSCC) not amenable to radiotherapy or radical surgery are limited. Evidence for the use of targeted therapies is sparse. All patients with VSCC treated at the Gynecological Cancer Center Hamburg-Eppendorf 20132019 were retrospectively evaluated for targeted therapeutic approaches. Furthermore, a MEDLINE, EMBASE, Web of Science, Scopus, and OVID database search was performed using the terms: vulvar cancer AND targeted therapy, erlotinib, EGFR, bevacizumab, VEGF, pembrolizumab, or immunotherapy. Twelve of 291 patients (4.1%) with VSCC received at least one targeted therapy at our institution. Previously, one or more platinum-based chemotherapy was applied to all patients [median 3.5 previous lines (range 25)]. In the erlotinib subgroup, two of five patients (40%) achieved stable disease (SD), while two patients (2/5, 40%) experienced partial response (PR). Treatment was given as monotherapy in second/third line for a median of 3.4 months (range 26 months). Bevacizumab (n=9) was given as maintenance therapy after platinum-based first-line chemotherapy (9/9); best response was complete response (CR) (n=2/9 22.2%). Median duration of treatment was 7 months (range 413 months) with two patients still under ongoing treatment. Best response in the pembrolizumab (n=3) subset was SD (n=1/3 33%). Treatment was given as monotherapy in second/third line for a median of 3.3 months (range 34 months). Nine of 12 patients (75%) experienced treatment-related adverse events (TRAEs), most commonly grade 1/2. Rapidly evolving antibody treatments have proven clinical benefit especially in HPV-driven tumor entities; however, clinical investigations in VSCC are still limited. These reported cases provide evidence for the clinical utility and feasibility while ensuring an acceptable safety profile.

VEGF-C expression attributes the risk for lymphatic metastases to ovarian cancer patients.

BACKGROUND: Peritoneal 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. METHODS: Tumour 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. RESULTS: While 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. CONCLUSIONS: Retroperitoneal 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.