GPER-1 acts as a tumor suppressor in ovarian cancer

Background: It is known that the new membrane-bound estrogen receptor GPER-1 acts suppressive in breast cancer cells and its expression decreases during disease progression. This study was conducted to evaluate the GPER-1 expression in ovarian cancer and its correlation with progression. Its function was tested in vitro in ovarian cancer cells. PATIENTS AND METHODS: GPER-1 expression was analyzed by immunohistochemistry in 35 benign ovarian tumors, 35 tumors of low-malignant potential and in 124 ovarian cancers. GPER-1 expression was correlated to the prospectively evaluated disease-free survival of ovarian cancer patients. We also tested GPER-1 expression in ovarian cancer cells and the effect of GPER-1 stimulation on cell growth. RESULTS: GPER-1 expression was significantly lower in ovarian cancer tissue than in benign and low-malignant ovarian tumors. GPER-1 expression was observed in 83.1% of malignant tumors and was higher in early stage cancers and tumors with high histological differentiation. GPER-1 expression was associated with favourable clinical outcome. The difference in 2-year disease-free survival by GPER-1 expression was significant, 28.6% for GPER-1 negative and 59.2% for GPER-1 positive cases (p = 0.002). GPER-1 expression was observed in SKOV-3 and OVCAR-3 ovarian cancer cell lines. G-1, a selective GPER-1 agonist, suppressed proliferation of the two cell types via inhibition of cell cycle progression in G2/M phase and stimulation of caspase-dependent apoptosis. The blockade in G2/M phase was associated with increased expression of cyclin B1 and Cdc2 and phosphorylation of histone 3. CONCLUSION: GPER-1 emerges as a new tumor suppressor with unsuspected therapeutic potential for ovarian cancer

Contralateral lymph node metastases in patients with vulvar cancer and unilateral sentinel lymph node metastases

Introduction The risk of contralateral lymph node metastases following unilateral sentinel lymph node (SLN) metastases in patients with vulvar cancer(s) remains to be systematically assessed. Material and methods We performed a multicenter, retrospective registry-based study of 476 patients with vulvar cancer. The primary outcome measure was the rate of contralateral non-SLN metastases in the case of positive unilateral SLN. Results Out of 476 patients with primary vulvar cancer, 202 received SLN biopsy: 58 unilateral and 144 bilateral. Out of 66 patients with unilateral metastatic SLN, 62 (93.9%) received contralateral lymphadenectomy—18 after unilateral and 44 after bilateral SLN biopsy. In the study group, 132 SLN were assessed with a median number of 2 (range 1–4) per patient and 76 of these were positive. Lymph node-positivity was associated with advanced tumor stage, as well as lymph and vascular space invasion. In the group of patients with bilateral inguino-femoral lymphadenectomy, 1004 lymph nodes were resected with a median number of 15 (range 10–29) per patient. After full dissection of the inguino-femoral lymph nodes, no contralateral non-SLN metastases were found. Conclusions The risk of contralateral non-SLN metastases in patients with unilateral SLN metastases was low. Therefore, the impact of contralateral lymphadenectomy on patient survival should be investigated in further studies

Coulomb dissociation of N 20,21

Neutron-rich light nuclei and their reactions play an important role in the creation of chemical elements. Here, data from a Coulomb dissociation experiment on N20,21 are reported. Relativistic N20,21 ions impinged on a lead target and the Coulomb dissociation cross section was determined in a kinematically complete experiment. Using the detailed balance theorem, the N19(n,γ)N20 and N20(n,γ)N21 excitation functions and thermonuclear reaction rates have been determined. The N19(n,γ)N20 rate is up to a factor of 5 higher at

Loss of HER2 after HER2-targeted treatment

PurposeHER2 expression has been reported to be discordant between primary tumor and metastatic tissue.Patients and methodsHER2 discordance and relation to HER2-targeted treatment was investigated in 227 patients with primary breast cancer.ResultsHER2 discordance between primary biopsy and second biopsy after neoadjuvant or adjuvant treatment was observed in 20.7%. This discordance was related only to the use of HER2-targeted treatment: 30 of 33 (90.9%) women with downgraded HER2 expression underwent a HER2-targeted therapy, whereas in the group of patients with concordant HER2 expression, only 32 of 180 (17.8%) received HER2-targeted treatment (p<0.0001). HER2 discordance was associated with reduced disease-free survival but not overall survival. In a second cohort, including patients with HER2 overexpressing tumors, trastuzumab treatment was associated with change of HER2 expression from positive to negative in 47.3% of cases. Addition of pertuzumab increased the rate of HER2 loss up to 63.2%. Notably, the interval between last HER2-targeted treatment and the time of surgical excision of the tumor after neoadjuvant chemotherapy (NACT) or the biopsy of the metachronous metastasis was associated with a significant change in HER2 expression. The median time between NACT and the time of surgical excision was 23 days (range 5-81 days) for tumors with decreased HER2 expression and 51 days (range 10-179 days) for tumors with concordant HER2 expression. Furthermore, median time between the end of adjuvant treatment and second histology of the metachronous metastases accounted for 15 days (range 2-165 days) and 478 days (range 7-2739 days) was observed in the group of patients with decreased or unchanged HER2 expression, respectively.ConclusionThe interval between anti-HER2 treatment and the determination of HER2 in second histology is strongly associated with HER2 expression

GPER-1 expression is associated with a decreased response rate to primary tamoxifen therapy of breast cancer patients

Purpose Endocrine therapies using tamoxifen and/or aromatase inhibitors are important therapeutic options for the targeted treatment of hormone-responsive breast cancer. In addition to nuclear estrogen receptors ER alpha and beta, G-protein-coupled estrogen receptor GPER-1 is a third receptor-mediating estrogen effects in breast cancer cells. The aim of this study was to examine to what extent GPER-1 expression might affect the efficacy of primary endocrine treatment of breast cancer. Methods GPER-1 expression was determined in tissue samples from patients with early breast cancer by means of immunohistochemistry and a GPER-1 score of >= 3 was considered to be positive. In a total of 165 patients, the response to a primary therapy with tamoxifen (TAM) or aromatase inhibitors (AI) was assessed by ultrasound imaging for up to 6 months. The primary endpoint of this study was the response to treatment evaluated by RECIST 1.1 criteria. Results GPER-1 expression was observed in 127 (77.0%) out of 165 cases. Based on GPER-1 expression and the type of endocrine treatment, the patients were divided into 4 groups: GPER-1 negative/TAM (12.1%), GPER-1 negative/AI (10.9%), GPER-1 positive/TAM (44.8%), and GPER-1 positive/AI (32.1%). The groups were well balanced regarding different clinical and pathological factors. After 4 and 6 months of treatment, a high level of stable disease or progressive disease was observed in the GPER-1 positive/TAM group only (p < 0.0001), whereas in the other three groups of patients, the most common objective response was classified as partial response. We observed a continuous reduction of mean tumor size in patients treated with aromatase inhibitors irrespective of the GPER-1 status and in GPER-1 negative patients treated with TAM. In contrast, in GPER-1 positive patients treated with TAM, a reduction of mean tumor size was observed only in the first 2 months after beginning of treatment. Four and six months after start of treatment, no reduction, but even a slight increase of tumor size was observed in this patients group. Conclusions GPER-1 expression is significantly associated with a reduced effect of primary treatment with tamoxifen in breast cancer patients

Management of elderly women with cervical cancer

Background Elderly women with cervical cancer receive less therapy in comparison with their younger counterparts. The exact reason(s) for this treatment strategy remains unclear. Patients and methods We performed a multicenter, retrospective registry-based study of 1559 patients with cervical cancer. The primary outcome was the reason for not performing the indicated treatment. Results Median follow-up was 67.8 months. A total of 956 women were eligible for analysis: 693 (64.2%) were younger than 60 years and 387 (35.8%) were aged 61 years old and older. Elderly women were more likely to have undifferentiated cervical cancer at an advanced stage. For early stage (stage IA1-IIA), tumors patients 61 years old and older were less likely to receive surgery [odds ratio (OR) 0.39; 95% CI 0.20-0.77] and radiochemotherapy (OR 0.37; 95% CI 0.21-0.66) compared with the group of patients aged < 60 years. The rate of lymphadenectomy was similar in both age groups. Patients 61 years old and older with advanced stage (IIB-IV) cervical cancer were also less likely to receive surgery [odds ratio (OR) 0.42; 95% CI 0.27-0.66], lymphadenectomy (OR 0.30; 95% CI 0.12-0.51) and radiochemotherapy (OR 0.31; 95% CI 0.20-0.48) compared with patients aged < 60 years. Notably, the rate of indicated but not performed therapies proportionally increased with an increase in patient age and the most important reason for this phenomenon was the failing of recommendation. Conclusions Elderly women with cervical cancer are undertreated and this is more likely because the therapy was not recommended

Endometrial cancer subtypes are associated with different patterns of recurrence

To evaluate the pattern of endometrial cancer recurrence according to its biological subtype in a large cohort of patients. Patients were stage eligible if they had a description of registry risk of recurrence status and were not primary metastatic. Data were prospectively collected. The primary endpoints were the subtype-dependent pattern and time of recurrence. The median follow-up time was 84 months. The highest 10-year recurrence-free and overall survival were seen in the group of patients at low risk of recurrence, 83.1 and 94.1%, respectively. The 10-year recurrence-free survival for intermediate and high risk group was 65.7 and 56.2%, respectively, whereas the estimated 10-year overall survival for both groups was 84.5 and 79.3%, respectively. Patients at high risk demonstrated the highest levels of disease recurrence in the first 3-4 years after diagnosis and the most common site of metastasis was the lung. In contrast, the rate of recurrence for patients at intermediate and low risk of recurrence in the first 5 years was relatively low but remained continuous up to 10 years of follow-up. Overall, the most common site of relapse was local recurrence. Endometrial cancer subtypes are associated with different times and patterns of recurrence and this should be considered when determining the treatment strategy

Comparison of survival of patients with endometrial cancer undergoing sentinel node biopsy alone or systematic lymphadenectomy

Background Recently, sentinel lymph node mapping was introduced in the surgical staging of endometrial cancer as alternative to systematic lymphadenectomy. However, the survival impact of sentinel node mapping is not well characterized yet. Methods We performed retrospective study of 104 patients with endometrial cancer treated with sentinel lymph node alone (n = 52) or with pelvic and para-aortic lymphadenectomy (n = 52). For sentinel node mapping, indocyanine green was used. The outcome measure was disease-free survival. Results Median follow-up was 42 months. Fifty-two patients staged by sentinel lymph node mapping were matched in 1:1 ratio with 52 patients staged by lymphadenectomy using patient age, histological type, tumor stage, tumor grade and lymph and vascular space invasion as matching criteria. The median number of removed lymph node was 3 (range 1-6) and 36 (13-63) in the sentinel and lymphadenectomy group, respectively. The rate of lymph node metastases was not significantly higher in the sentinel group (19.2%) in comparison with the lymphadenectomy group (14.3%). The overall detection rate of sentinel lymph nodes was 100% with a bilateral mapping of 98.1%. Most of the 152 lymph nodes identified and removed were localized in upper paracervical pathway (n = 143, 94.1%). During the follow-up period, overall 21 (20.2%) events were observed, 8 (15.4%) in the sentinel group and 13 (25.0%) in the lymphadenectomy group. The estimated disease-free survival was 84.6% and 75.0% for patients in the sentinel and lymphadenectomy groups, respectively. The survival curves demonstrated similar disease-free survival in two groups (p = 0.774). Conclusion Sentinel lymph node mapping did not compromise the outcome of patients with endometrial cancer

Vaginal brachytherapy for endometrial cancer

There is limited information about survival effect of vaginal brachytherapy (VBT) and its comparison to external beam pelvic radiotherapy (EBRT) and no radiotherapy (no-RT) of endometrial cancer patients. We performed a multicenter retrospective registry study of 1550 patients with endometrial cancer treated by no-RT (n = 702), VBT (n = 430) and EBRT +/- VBT (n = 418). The outcome measure was overall survival. RT did not improve the overall survival of patients with a low risk of recurrence. In univariate analysis, the survival effect of VBT was significant in patients with intermediate and high risk of recurrence (HR 0.42, CI 0.29-0.60, p < 0.0001). EBRT +/- VBT demonstrated no survival effect in these groups. Multivariate analysis showed that VBT (HR 0.50, CI 0.36-0.71) significantly reduced the mortality risk in patients with an intermediate and high risk compared with no-RT after adjustment for age, tumor grading, tumor stage, lymphadenectomy, adjuvant therapy and comorbidities. Matching for age, histological type, tumor stage, tumor grade, and performance status between patients treated with no-RT and VBT was performed. The matching analysis again demonstrated the favorable survival effect of VBT compared to no-RT on overall survival with an absolute risk reduction of 17.7%. Notably, in a further 106 matched pairs, EBRT +/- VBT did not demonstrate any survival effect over VBT among patients at intermediate and high risk of recurrence. VBT should be performed in patients at intermediate and high risk of recurrence of endometrial cancer, after operative determination of lymph node status

G protein-coupled estrogen receptor 1 (GPER-1) and agonist G-1 inhibit growth of ovarian cancer cells by activation of anti-tumoral transcriptome responses: impact of GPER-1 mRNA on survival

Purpose The present study intended to further elucidate the role of G protein-coupled estrogen receptor 1 (GPER-1) in ovarian cancer by comparing the effects of a GPER-1 knockdown and treatment with its agonist G-1 on cell growth, apoptosis, and the transcriptome of two ovarian cancer cell lines. Furthermore, the role of GPER-1 in ovarian cancer survival was examined. Methods GPER-1 expression in OVCAR-3 and OAW-42 ovarian cancer cells was knocked down by RNAi. The effects on cell growth were measured by means of the fluorimetric cell titer blue assay and on the transcriptome by Affymetrix GeneChip analysis. The effect of GPER-1 on patient's survival was examined using open source mRNA and clinical data of 1657 ovarian cancer patients. Results GPER-1 knockdown resulted in a significant growth stimulation of both cell lines, whereas treatment with agonist G-1 decreased growth of both cell lines in a dose-dependent manner. Transcriptome analyses revealed a set of 18 genes being conversely regulated after GPER-1 knockdown and G-1 treatment. Generally, treatment with G-1 led to a transcriptome response associated with growth inhibition. In contrast, knockdown of GPER-1 exerted opposite effects, stimulating pathways activating mitosis, but inhibiting pathways associated with apoptosis or interferon signaling. Further analyses using open-access mRNA and clinical data by bioinformatical online tools revealed a longer OS (HR = 0.86,p = 0.057) and PFS (HR = 0.81,p = 0.0035) of ovarian cancer patients with high GPER-1 mRNA expression. Conclusions The results of this study clearly support the hypothesis that GPER-1 acts as a tumor suppressor in ovarian cancer