Araştırma Çıktıları
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Item Sentinel lymph node biopsy in early stage endometrial cancer: a Turkish gynecologic oncology group study (TRSGO-SLN-001)(BMJ PUBLISHING GROUP, 2020-01-01) Taskin, Salih; Altin, Duygu; Vatansever, Dogan; Tokgozoglu, Nedim; Karabuk, Emine; Turan, Hasan; Takmaz, Ozguc; Kahramanoglu, Ilker; Naki, Mehmet Murat; Gungor, Mete; Kose, Faruk; Ortac, Firat; Arvas, Macit; Ayhan, Ali; Taskiran, CagatayObjective The aim of this multicenter study was to evaluate the feasibility of sentinel lymph node (SLN) mapping in clinically uterine confined endometrial cancer. Methods Patients who underwent primary surgery for endometrial cancer with an SLN algorithm were reviewed. Indocyanine green or blue dye was used as a tracer. SLNs and/or suspicious lymph nodes were resected. Side specific lymphadenectomy was performed when mapping was unsuccessful. SLNs were ultrastaged on final pathology. Results 357 eligible patients were analyzed. Median age was 59 years. Median number of resected SLNs was 2 (range 1-12) per patient. Minimal invasive and open surgeries were performed in 264 (73.9\%) and 93 (26.1\%) patients, respectively. Indocyanine green was used in 231 (64.7\%) and blue dye in 126 (35.3\%) patients. The dyes were injected into the cervix in 355 (99.4\%) patients. The overall and bilateral SLN detection rates were 91.9\% and 71.4\%, respectively. The mapping rates using indocyanine green or blue dye were comparable (P=0.526). There were 43 (12\%) patients with lymphatic metastasis. The SLN algorithm was not able to detect 3 of 43 patients who had isolated paraaortic metastasis. After SLN biopsy, complete pelvic lymphadenectomy was performed in 286 (80.1\%) patients. Sensitivity and negative predictive value were both 100\% for the detection of pelvic lymph node metastases. In addition, 117 (32.8\%) patients underwent completion paraaortic lymphadenectomy after SLN biopsy. In these patients, sensitivity for detecting metastases to pelvic and/or paraaortic lymph nodes was 90.3\% with a negative predictive value of 96.6\%. The risk of non-SLN involvement in patients with macrometastatic SLNs, micrometastatic SLNs, and isolated tumor cells in SLNs were 61.2\%, 14.3\% and 0\%, respectively. Conclusions SLN biopsy had good accuracy in detecting lymphatic metastasis. However, one-third of cases with metastatic SLNs also had non-SLN involvement and this risk increased to two-thirds of cases with macrometastatic SLNs. The effect of leaving these nodes in situ on survival should be evaluated in further studies.Item The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells(OXFORD UNIV PRESS, 2015-01-01) Yuksel, Aytac; Bildik, Gamze; Senbabaoglu, Filiz; Akin, Nazli; Arvas, Macit; Unal, Fehmi; Kilic, Yagmur; Karanfil, Isil; Eryilmaz, Baldan; Yilmaz, Pelin; Ozkanbas, Can; Taskiran, Cagatay; Aksoy, Senai; Guzel, Yilmaz; Balaban, Basak; Ince, Umit; Iwase, Akira; Urman, Bulent; Oktem, OzgurSTUDY QUESTION: Do different chemotherapy drugs exert the same magnitude of cytotoxicity on dormant primordial follicles and the growing follicle fraction in the ovary in vivo and on mitotic non-luteinized and non-mitotic luteinized granulosa cells in vitro? SUMMARY ANSWER: Cyclophosphamide (alkylating agent) and cisplatin (alkylating like) impacted both primordial and pre-antral/antral follicles and both mitotic and non-mitotic granulosa cells, whereas the anti-metabolite cancer drug gemcitabine was detrimental only to pre-antral/antral follicles and mitotic non-luteinized granulosa cells. WHAT IS KNOWN ALREADY: It is already known that anti-metabolite cancer drugs are less detrimental to the ovary than alkylating and alkylating like agents, such as cyclophosphamide and cisplatin. This assumption is largely based on the results of clinical reports showing lower rates of amenorrhea in women receiving anti-metabolite agent-based regimens compared with those treated with the protocols containing an alkylating drug or a platinum compound. But a quantitative comparison of gonadotoxicity with a histomorphometric proof of evidence has not been available for many chemotherapy drugs. Therefore, we combined in this study in vivo and in vitro models of human and rat origin that allows a comparative analysis of the impact of different chemotherapy agents on the ovary and granulosa cells using real-time quantitative cell indices, histomorphometry, steroidogenesis assays, and DNA damage and cell death/viability markers. We also aimed to investigate if there is a difference between mitotic and non-mitotic granulosa cells in terms of their sensitivity to the cytotoxic actions of chemotherapy drugs with different mechanisms of action. This issue has not been addressed previously. STUDY DESIGN, SIZE, DURATION: This translational research study involved in vivo analyses of ovaries in rats and in vitro analyses of granulosa cells of human and rat origin. PARTICIPANTS/MATERIALS, SETTING, METHODS: For the in vivo assays, 54 4- to 6-week old Sprague-Dawley young female rats were randomly allocated into four groups of 13 to receive a single IP injection of: saline (control), gemcitabine (200 mg/kg), cisplatin (50 mg/kg) or cyclophosphamide (200 mg/kg). The animals were euthanized 72 h later. Follicle counts and serum AMH levels were compared between the groups. In vitro cytotoxicity studies were performed using mitotic non-luteinized rat (SIGC) and human (COV434, HGrC1) granulosa cells, and non-mitotic luteinized human (HLGC) granulosa cells. The cells were plated at a density of 5000 cells/well using DMEM-F12 culture media supplemented with 10\% FBS. Chemotherapy agents were used at their therapeutic blood concentrations. The growth of mitotic granulosa cells was monitored real-time using xCelligence system. Live/dead cell and apoptosis assays were also carried out using intravital Yo-Pro-1 staining and cleaved caspase-3 expression, respectively. Estradiol (E2), progesterone (P) and anti-Mullerian hormone (AMH) levels were assayed with ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: Cyclophosphamide and cisplatin caused massive atresia of both primordials and growing follicles in the rat ovary whereas gemcitabine impacted pre-antral/antral follicles only. Cyclophosphamide and cisplatin induced apoptosis of both mitotic non-luteinized and non-mitotic luteinized granulosa cells in vitro. By contrast, cytotoxicity of gemcitabine was confined to mitotic non-luteinized granulosa cells. LIMITATIONS, REASONS FOR CAUTION: This study tested only three chemotherapeutic agents. The experimental methodology described here could be applied to other drugs for detailed analysis of their ovarian cytotoxicity. WIDER IMPLICATIONS OF THE FINDINGS: These findings indicate that in vivo and in vitro cytotoxic actions of chemotherapy drugs on the ovarian follicles and granulosa cells vary depending upon the their mechanism of action and the nature of the granulosa cells.Item The mammalian target of rapamycin protein expression in human granulosa cell tumors(GALENOS YAYINCILIK, 2019-01-01) Guralp, Onur; Bese, Tugan; Bildik, Gamze; Demikiran, Fuat; Ince, Umit; Malik, Eduard; Arvas, Macit; Oktem, OzgurObjective: To investigate the role of mammalian target of rapamycin (mTOR) in human granulosa cell ovarian tumors and the therapeutic effect of rapamycin in COV434 mitotic granulosa cell lines. Material and Methods: A retrospective evaluation of the medical records and pathologic sections of patients with granulosa cell ovarian carcinoma was performed. mTOR and p-mTOR expression was immunohistochemically investigated. A COV434 cell culture were treated with 0.5, 1, 2, and 5 mu M rapamycin. Real-time growth curve analysis via xCELLigence system and apoptotic cell analysis via YO-PROT-1 Iodide were performed to assess the therapeutic effect of rapamycin on cancer cells. Results: A total of twenty patients were evaluated. mTOR staining was detected in 18 (90\%) patients. Mild, moderate, intense, and very intense staining was observed in three (15\%), eight (40\%), six (30\%), and one (5\%) sample, respectively. The mean mTOR staining ratio was 59 +/- 41\%. P-mTOR staining was observed in two ( 10\%) patients. One (5\%) patient had 5\% staining, and one (5\%) patient had 100\% staining for p-mTOR. Both of the latter patients had very intense staining. Rapamycin caused a dose-dependent growth arrest and induced apoptosis in COV434 mitotic granulosa cells. The real-time growth curves of the cells treated with these drugs were distinguished by a marked reduced slope after exposure for several hours, indicating a rapid onset of apoptosis. Live/dead cell analysis with YO-PRO-1 staining showed that rapamycin induced apoptosis in 24\% of the cells when used at 1 mu M concentration, whereas the rate increased to 61\% and 72\% when the cells were treated with 2 mu M and 5 mu M rapamycin, respectively. Conclusion: mTOR expression is observed in various degrees in 90\%, and p-mTOR expression is observed in only 10\% of patients with granulosa cell ovarian carcinoma. Rapamycin caused a dose-dependent growth arrest and apoptosis in COV434 mitotic granulosa cells.