Are Systemic Voriconazole and Caspofungin Ototoxic? An Experimental Study with Rats

Emine Aydın,Filiz Aydoğan,,Eren Taştan,,Ayşe İriz,Gökhan Karaca,İlknur Haberal Can 대한이비인후과학회 2012 Clinical and Experimental Otorhinolaryngology Vol.5 No.3

Objectives. To determine whether systemic administration of voriconazole and caspofungin causes ototoxicity. Methods. This study was conducted on 32 healthy male Wistar albino rats. The baseline auditory brainstem response (ABR)thresholds of all animals were obtained under general anesthesia. Then, the rats were randomly divided into 4 groups (groups I-IV), each group consisting of 8 rats. Rats in group I were injected intraperitoneally with voriconazole 10 mg/kg/day for 7 days, and the rats in the group II were injected intraperitoneally with caspofungin 5 mg/kg/day for 7 days. Group III received 120 mg/kg/day gentamicin for 7 days. Group IV received saline for 7 days. The animals were then observed for 7 days, and on 14th day of the trial, posttreatment ABRs of both ears were recorded. Results. We did not find any significant differences between pretreatment and posttreatment median ABR thresholds in the voriconazole, caspofungin, or saline groups. In the gentamicin group, there was a statistically significant difference between pretreatment and posttreatment ABR thresholds. Conclusion. Caspofungin and voriconazole did not change ABR thresholds in speech frequencies after a 7-day-period of their administration. We believe that further animal studies must be performed after administration of these agents for a longer time period, and these findings must be consolidated with histopathological investigations. Objectives. To determine whether systemic administration of voriconazole and caspofungin causes ototoxicity. Methods. This study was conducted on 32 healthy male Wistar albino rats. The baseline auditory brainstem response (ABR)thresholds of all animals were obtained under general anesthesia. Then, the rats were randomly divided into 4 groups (groups I-IV), each group consisting of 8 rats. Rats in group I were injected intraperitoneally with voriconazole 10 mg/kg/day for 7 days, and the rats in the group II were injected intraperitoneally with caspofungin 5 mg/kg/day for 7 days. Group III received 120 mg/kg/day gentamicin for 7 days. Group IV received saline for 7 days. The animals were then observed for 7 days, and on 14th day of the trial, posttreatment ABRs of both ears were recorded. Results. We did not find any significant differences between pretreatment and posttreatment median ABR thresholds in the voriconazole, caspofungin, or saline groups. In the gentamicin group, there was a statistically significant difference between pretreatment and posttreatment ABR thresholds. Conclusion. Caspofungin and voriconazole did not change ABR thresholds in speech frequencies after a 7-day-period of their administration. We believe that further animal studies must be performed after administration of these agents for a longer time period, and these findings must be consolidated with histopathological investigations.

Prognostic impact of p16 and p53 gene expressions in stage 1a epithelial ovarian cancer

( Emre Gunakan ),( Yusuf Aytac Tohma ),( Latife Atasoy Karakaş ),( Huseyin Akıllı ),( Asuman Nihan Haberal ),( Ali Ayhan ) 대한산부인과학회 2020 Obstetrics & Gynecology Science Vol.63 No.4

Objective Epithelial ovarian cancer (EOC) is rarely detected at stage 1a. Most of the patients have a good prognosis and there are limited factors that affect their survival. In the present study, we evaluated the p16 and p53 gene expressions of stage 1a EOC patients. Prognostic effects of these gene expressions, as well as those of other factors on short term survival were analyzed. Methods Our study included 29 patients. The specimens of the ovary with cancer were stained for p16 and p53. Gene expressions and other prognostic factors were evaluated. Results The median age of the patients was 51 years (27-84). The mean numbers of dissected pelvic and paraaortic lymph nodes were 27 and 12, respectively. The mean follow-up time was 33.7±18.9 months. During this period, recurrence occurred in two patients. One of the patients had grade 2 mucinous carcinoma and died of the disease at month 12 after the recurrence occurred at month 7. The second patient had clear cell carcinoma and recurrence occurred at month 34. p16 and p53 gene expressions or other factors were not associated with overall survival (OS) or diseasefree survival in the short term. The lower p16 positivity rate in the non-clear cell group was found to be statistically significant (P=0.003). Both p53 and p16 positivity rates were higher in the high-grade carcinoma. Conclusion The levels of none of the common prognostic factors, including those of p16 and p53 gene expression, were associated with the progression-free survival or OS of stage 1a in the short term. Appropriate surgical staging and non-omission of subclinical metastases seem to be of central importance.

The prognostic value of lymph node ratio in stage IIIC cervical cancer patients triaged to primary treatment by radical hysterectomy with systematic pelvic and para-aortic lymphadenectomy

Koray Aslan,Mehmet Mutlu Meydanli,Murat Oz,Yusuf Aytac Tohma,Ali Haberal,Ali Ayhan 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.1

Objective: The aim of this study was to determine the prognostic value of lymph node ratio (LNR) in women with 2018 International Federation of Gynecology and Obstetrics stage IIIC cervical cancer. Methods: In this retrospective dual-institutional study, a total of 185 node-positive cervical cancer patients who had undergone radical hysterectomy with systematic pelvic and para-aortic lymphadenectomy were included. All of the patients received adjuvant chemoradiation after surgery. LNR was defined as the ratio of positive lymph nodes (LNs) to the total number of LNs removed. The patients were categorized into 2 groups according to LNR; LNR <0.05 and LNR ≥0.05. The prognostic value of LNR was evaluated with univariate log-rank tests and multivariate Cox regression models. Results: A total of 138 patients (74.6%) had stage IIIC1 disease and 47 (25.4%) patients had stage IIIC2 disease. With a median follow-up period of 45.5 months (range 3–135 months), the 5-year disease-free survival (DFS) rate was 62.5% whereas the 5-year overall survival (OS) rate was 70.4% for the entire study population. The 5-year DFS rates for LNR <0.05 and LNR ≥0.05 were 78.2%, and 48.4%, respectively (p<0.001). Additionally, the 5-year OS rates for LNR <0.05 and LNR ≥0.05 were 80.6%, and 61.2%, respectively (p=0.007). On multivariate analysis, LNR ≥0.05 was associated with a worse DFS (hazard ratio [HR]=2.12; 95% confidence interval [CI]=1.15–3.90; p=0.015) and OS (HR=1.95; 95% CI=1.01–3.77; p=0.046) in women with stage IIIC cervical cancer. Conclusions: LNR ≥0.05 seems to be an independent prognostic factor for decreased DFS and OS in stage IIIC cervical carcinoma.

Risk for Malignant and Borderline Ovarian Neoplasms Following Basic Preoperative Evaluation by Ultrasonography, Ca125 Level and Age

Karadag, Burak,Kocak, M.,Kayikcioglu, F.,Ercan, F.,Dilbaz, B.,Kose, M.F.,Haberal, A. Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.19

Objective: To verify the basic preoperative evaluation in the discrimination between benign and malignant adnexal masses in our clinical practice. Materials and Methods: Data were collected on the records of 636 women with adnexal masses who had undergone surgery either by open or endoscopic approaches. Those with obvious signs of malignancy, any history of cancer, emergency surgeries without basic evaluation were excluded. The preoperative features by age, ultrasound and serum Ca125 level were compared with final histopathological diagnosis at the four departments of the institution. These are the general gynecology (Group 1: exploratory laparotomy), the gynecologic endoscopy (Group 2: laparoscopy and adnexectomy), the gynecological oncology (Group 3: staging laparotomy) and the gynecologic endocrinology and infertility (Group 4: laparoscopy and cystectomy). Results: There were simple and complex cyst rates of 22.3% and 77.2%, respectively. There were 86.3% benign, 4.1% (n:20) borderline ovarian tumor (BOT) and 6.4% (n:48) malignant lesions. There were 3 BOT and 9 ovarian cancers in Group 1 and one BOT and two ovarian cancer in the Group 2. During the surgery, 15 BOT (75%) and 37 ovarian cancer (77%) were detected in the Group 3, only one BOT was encountered in the Group 4. The risk of rate of unsuspected borderline or focally invasive ovarian cancer significantly increased by age, size, complex morphology and Ca125 (95% CI, OR=2.72, OR=6.60, OR=6.66 and OR=4.69, respectively). Conclusions: Basic preoperative evaluation by comprehensive ultrasound imaging combined with age and Ca125 level has proved highly accurate for prediction of unexpected malignancies. Neither novel markers nor new imaging techniques provide better information that allow clinicians to assess the feasibility of the planned surgery; consequently, the risk of inadvertent cyst rupture during laparoscopy may be significantly decreased in selected cases.

Impact of lymph node ratio on survival in stage III ovarian high-grade serous cancer: a Turkish Gynecologic Oncology Group study

Ali Ayhan,Nazlı Topfedaisi Ozkan,Mustafa Erkan Sarı,Husnu Celik,Murat Dede,Özgür Akbayır,Kemal Güngördük,Hanifi Şahin,Ali Haberal,Tayfun Güngör,Macit Arvas,Mehmet Mutlu Meydanlı 대한부인종양학회 2018 Journal of Gynecologic Oncology Vol.29 No.1

Objective: The purpose of this study was to investigate the prognostic value of lymph node ratio (LNR) in patients with stage III ovarian high-grade serous carcinoma (HGSC). Methods: A multicenter, retrospective department database review was performed to identify patients with ovarian HGSC at 6 gynecologic oncology centers in Turkey. A total of 229 node-positive women with stage III ovarian HGSC who had undergone maximal or optimal cytoreductive surgery plus systematic lymphadenectomy followed by paclitaxel plus carboplatin combination chemotherapy were included. LNR, defined as the percentage of positive lymph nodes (LNs) to total nodes recovered, was stratified into 3 groups: LNR1 (<10%), LNR2 (10%≤LNR<50%), and LNR3 (≥50%). Kaplan-Meier method was used to generate survival data. Factors predictive of outcome were analyzed using Cox proportional hazards models. Results: Thirty-one women (13.6%) were classified as stage IIIA1, 15 (6.6%) as stage IIIB, and 183 (79.9%) as stage IIIC. The median age at diagnosis was 56 (range, 18–87), and the median duration of follow-up was 36 months (range, 1–120 months). For the entire cohort, the 5-year overall survival (OS) was 52.8%. An increased LNR was associated with a decrease in 5-year OS from 65.1% for LNR1, 42.5% for LNR2, and 25.6% for LNR3, respectively (p<0.001). In multivariate analysis, women with LNR≥0.50 were 2.7 times more likely to die of their tumors (hazard ratio [HR]=2.7; 95% confidence interval [CI]=1.42–5.18; p<0.001). Conclusion: LNR seems to be an independent prognostic factor for decreased OS in stage III ovarian HGSC patients.

Impact of Treatment Strategies on Local Control and Survival in Uterine Carcinosarcomas in Turkey

Kucukoztas, Nadire,Dizdar, Omer,Rahatli, Samed,Dursun, Polat,Yalcin, Selim,Altundag, Ozden,Ozen, Ozlem,Reyhan, Nihan Haberal,Tarhan, Cagla,Yildiz, Ferah,Ayhan, Ali Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.5

Background: The purpose of this study was to determine the clinical characteristics, patterns of recurrence and survival outcomes in patients with uterine carcinosarcomas treated in our institution. Materials and Methods: Records of 26 patients diagnosed between 2007 and 2011 with uterine carcinosarcoma were retrospectively evaluated for demographic features, tumor characteristics, treatment regimens and patient outcomes in terms of DFS and OS Results: Median age was 61 (range 43-78). 10 patients (38%) had stage I disease at diagnosis, 3 (12%) had stage II, 4 (15%) had stage III and 9 (35%) had stage IV. Sixteen patients (62%) received chemotherapy with paclitaxel and carboplatin for 6 cycles. One patient underwent radiotherapy. Median follow up was 17 months. Sixteen patients relapsed and 13 died during follow up. Considering recurrence, 5 out of 16 patients had lung metastases, one had brain metastases and 9 had only intraabdominal recurrence. The 3 year DFS was 37% and the 3 year OS was 30%. Conclusions: Our data show that uterine carcinosarcomas tend to be at advanced stage at diagnosis and despite the use of chemotherapy, overall prognosis is poor. Surgery remains the mainstay of treatment. More effective adjuvant strategies are needed to reduce relapse and death rates.

Comparison of three different risk-stratification models for predicting lymph node involvement in endometrioid endometrial cancer clinically confined to the uterus

Vakkas Korkmaz,Mehmet Mutlu Meydanli,Ibrahim Yalçın,Mustafa Erkan Sarı,Hanifi Sahin,Eda Kocaman,Ali Haberal,Polat Dursun,Tayfun Güngör,Ali Ayhan 대한부인종양학회 2017 Journal of Gynecologic Oncology Vol.28 No.6

Objective: To compare the clinical validity of the Gynecologic Oncology Group-99 (GOG-99), the Mayo-modified and the European Society for Medical Oncology (ESMO)-modified criteria for predicting lymph node (LN) involvement in women with endometrioid endometrial cancer (EC) clinically confined to the uterus. Methods: A total of 625 consecutive women who underwent comprehensive surgical staging for endometrioid EC clinically confined to the uterus were divided into low- and high-risk groups according to the GOG-99, the Mayo-modified, and the ESMO-modified criteria. Lymphovascular space invasion is the cornerstone of risk stratification according to the ESMO-modified criteria. These 3 risk stratification models were compared in terms of predicting LN positivity. Results: Systematic LN dissection was achieved in all patients included in the study. LN involvement was detected in 70 (11.2%) patients. LN involvement was correctly estimated in 51 of 70 LN-positive patients according to the GOG-99 criteria (positive likelihood ratio [LR+], 3.3; negative likelihood ratio [LR−], 0.4), 64 of 70 LN-positive patients according to the ESMO-modified criteria (LR+, 2.5; LR−, 0.13) and 69 of the 70 LN-positive patients according to the Mayo-modified criteria (LR+, 2.2; LR−, 0.03). The area under curve of the Mayo-modified, the GOG-99 and the ESMO-modified criteria was 0.763, 0.753, and 0.780, respectively. Conclusion: The ESMO-modified classification seems to be the risk-stratification model that most accurately predicts LN involvement in endometrioid EC clinically confined to the uterus. However, the Mayo-modified classification may be an alternative model to achieve a precise balance between the desire to prevent over-treatment and the ability to diagnose LN involvement.

Good Outcomes of Patients with Stage IB Endometrial Cancer with Surgery Alone

Rahatli, Samed,Dizdar, Omer,Kucukoztas, Nadire,Oguz, Arzu,Yalcin, Selim,Ozen, Ozlem,Reyhan, Nihan Haberal,Tarhan, Cagla,Yildiz, Ferah,Dursun, Polat,Altundag, Ozden,Ayhan, Ali Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.9

Background: Most patients with endometrial cancer have stage I disease. Adjuvant therapy in stage IB (formerly IC) endometrial cancer is controversial, treatment options including observation or brachytherapy/radiotherapy in grade 1-3 patients with or without chemotherapy. The purpose of this study was to assess the outcomes of our patients with stage IB endometrioid endometrial cancer. Materials and Methods: Sixty two patients with stage IB endometrial cancer and endometrioid histology were retrospectively evaluated. All patients were initially treated surgically by the same surgeon with comprehensive staging, i.e. total abdominal hysterectomy, bilateral salphingooopherectomy, bilateral pelvic and paraaortic lymph node dissection and omentectomy. Adjuvant radiotherapy was discussed with patients and utilized by those who accepted. Adjuvant chemotherapy was not given to any of the patients. Results: Median age was 62 (range, 42-95). Ninety percent of the patients had grade 1-2 disease. Thirteen patients (21%) received intra vaginal brachytherapy (IVBT) and one received whole pelvic radiotherapy (WPRT). Median follow-up time was 46 months (range, 9-77 months). Three patients experienced recurrence (4.8%), two of them died on follow-up and one was still alive at last visit. Two patients with recurrence had FIGO grade 2 tumors and one had a grade 3 tumor. Two patients (3.2%) died without evidence of recurrent disease. Relapse free survival at 5 years was 94.4% and overall survival was 93.1%. Conclusions: Patients with stage IB disease in our study demonstrated relatively low recurrence rates although the majority of them received no adjuvant treatment. Surgery alone may be sufficient for most patients with this stage of endometrial cancer.

Prognostic factors and treatment outcomes in surgically­staged non­invasive uterine clear cell carcinoma: a Turkish Gynecologic Oncology Group study

Mustafa Erkan Sarı,Mehmet Mutlu Meydanlı,Osman Türkmen,Günsü Kimyon Cömert,Ahmet Taner Turan,Alper Karalök,Hanifi Şahin,Ali Haberal,Eda Kocaman,Özgür Akbayır,Baki Erdem,Ceyhun Numanoğlu,Kemal Güngördü 대한부인종양학회 2017 Journal of Gynecologic Oncology Vol.28 No.4

Objective: To assess the prognosis of surgically-staged non-invasive uterine clear cell carcinoma (UCCC), and to determine the role of adjuvant therapy. Methods: A multicenter, retrospective department database review was performed to identify patients with UCCC who underwent surgical treatment between 1997 and 2016 at 8 Gynecologic Oncology Centers. Demographic, clinicopathological, and survival data were collected. Results: A total of 232 women with UCCC were identified. Of these, 53 (22.8%) had surgically-staged non-invasive UCCC. Twelve patients (22.6%) were upstaged at surgical assessment, including a 5.6% rate of lymphatic dissemination (3/53). Of those, 1 had stage IIIA, 1 had stage IIIC1, 1 had stage IIIC2, and 9 had stage IVB disease. Of the 9 women with stage IVB disease, 5 had isolated omental involvement indicating omentum as the most common metastatic site. UCCC limited only to the endometrium with no extra-uterine disease was confirmed in 41 women (73.3%) after surgical staging. Of those, 13 women (32%) were observed without adjuvant treatment whereas 28 patients (68%) underwent adjuvant therapy. The 5-year disease-free survival rates for patients with and without adjuvant treatment were 100.0% vs. 74.1%, respectively (p=0.060). Conclusion: Extra-uterine disease may occur in the absence of myometrial invasion (MMI), therefore comprehensive surgical staging including omentectomy should be the standard of care for women with UCCC regardless of the depth of MMI. Larger cohorts are needed in order to clarify the necessity of adjuvant treatment for women with UCCC truly confined to the endometrium.

Factors associated with survival after relapse in patients with low-risk endometrial cancer treated with surgery alone

Nazli Topfedaisi Ozkan,Mehmet Mutlu Meydanlı,Mustafa Erkan Sarı,Fuat Demirkiran,Ilker Kahramanoglu,TUGAN BESE,Macit Arvas,Hanifi Şahin,Ali Haberal,Husnu Celik,Gonca Coban,Tufan Oge,Omer Tarik Yalcin,Ö 대한부인종양학회 2017 Journal of Gynecologic Oncology Vol.28 No.5

Objective: To determine factors influencing overall survival following recurrence (OSFR) inwomen with low-risk endometrial cancer (EC) treated with surgery alone. Methods: A multicenter, retrospective department database review was performed to identifypatients with recurrent “low-risk EC” (patients having less than 50% myometrial invasion[MMI] with grade 1 or 2 endometrioid EC) at 10 gynecologic oncology centers in Turkey. Demographic, clinicopathological, and survival data were collected. Results: We identified 67 patients who developed recurrence of their EC after initially beingdiagnosed and treated for low-risk EC. For the entire study cohort, the median time torecurrence (TTR) was 23 months (95% confidence interval [CI]=11.5–34.5; standard error[SE]=5.8) and the median OSFR was 59 months (95% CI=12.7–105.2; SE=23.5). We observed32 (47.8%) isolated vaginal recurrences, 6 (9%) nodal failures, 19 (28.4%) peritoneal failures, and 10 (14.9%) hematogenous disseminations. Overall, 45 relapses (67.2%) were locoregionalwhereas 22 (32.8%) were extrapelvic. According to the Gynecologic Oncology Group(GOG) Trial-99, 7 (10.4%) out of 67 women with recurrent low-risk EC were qualified as highintermediaterisk (HIR). The 5-year OSFR rate was significantly higher for patients with TTR≥36 months compared to those with TTR <36 months (74.3% compared to 33%, p=0.001). On multivariate analysis for OSFR, TTR <36 months (hazard ratio [HR]=8.46; 95% CI=1.65–43.36; p=0.010) and presence of HIR criteria (HR=4.62; 95% CI=1.69–12.58; p=0.003) weresignificant predictors. Conclusion: Low-risk EC patients recurring earlier than 36 months and those carrying HIRcriteria seem more likely to succumb to their tumors after recurrence.