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Contains fulltext : 283536.pdf (Publisher’s version ) (Closed access) The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

Objective To compare oncological outcomes in women with lower uterine segment involvement (LUSI) in endometrial carcinoma (EC) stage ≥ II - staged by a minimally invasive surgery (MIS) versus laparotomy. Study design A retrospective multi-center cohort study. Univariate analysis, Kaplan-Meier survival and Cox proportional hazard analysis were performed to compare between women staged by MIS and those staged by laparotomy. Results Over a median follow-up period of 3 years (interquartile range, 1.5–6 years) 212 women were included, 68 (32.1%) were surgically staged by MIS. Stages of disease did not vary between MIS and laparotomy and were 32.1%, 51.9%, and 16.0%, in stages II, III and IV – respectively. Adjuvant radiation and chemotherapy rate did not differ between groups. Overall recurrence rate was comparable (p = 0.084). Locoregional recurrence rate was higher in the MIS group odds ratio 2.17, 95% confidence interval 1.19–4.20). Overall and progression free survival were similar in both groups (log rank test p = 0.08 and p = 0.912 respectively). In Cox regression model adjusting for age, comorbidities, tumor grade, stage and adjuvant therapy, route of surgery (MIS vs. laparotomy) was not associated with overall survival (p = 0.169). Conclusions In women with advanced EC and LUSI, although MIS is associated with locoregional recurrences, survival is comparable to laparotomy.

Objective Gynecologic Sarcomas are rare, aggressive tumors. The aim of this study was to explore the incidence and outcomes of gynecologic sarcomas in a large national data registry and to compare them with reports from other countries. Study Design Records of gynecologic sarcomas diagnosed in Israel (1980–2014) were extracted from the National Cancer Registry and classified according to International Classification of Diseases for Oncology-3 and characterized according to anatomical site, morphology and demographics. Age-standardized incidence rates and 1, 3, 5 and 10-year relative survival rates were calculated for 3 time periods (1980–1994, 1995–2001 and 2005–2014) according to patient age, stage and years of diagnosis. Results During 1980–2014, 1271 new gynecologic sarcomas were diagnosed in Israel, with incidence slightly increasing in 1980–2004, to an age-standardized incidence rate of 13 per million women. The most common histologic diagnosis was leiomyosarcoma (48%) and the most common anatomical site was the uterus (89%). The age-standardized incidence rate for uterine sarcoma is higher in Israel (10.55 per million) than in England (7.4 per million) and Germany (5.8 per million) respectively. The 5-year overall survival was significantly poorer in patients >70-years, as compared to younger patients (p Conclusions Uterine leiomyosarcoma was the most common gynecologic sarcoma found in the Israeli, European and American registries. Older patients and those with leiomyosarcoma have the worst prognoses. Histological and anatomical variations in Israel are comparable with global statistics, but the incidence in Israel seems higher than in Europe.

Objective To evaluate trends in the incidence and survival of gynecologic carcinosarcoma over the last 35 years and to explore ethnic disparities. Study design Using the Israeli National Cancer Registry database, all cases of gynecologic carcinosarcoma were included (1980-2014). Age at diagnosis, patient's ethnicity and anatomical site were extracted. Age-standardized incidence rates (ASRs) were calculated for 3 time periods (1980-1994, 1995-2004 and 2005-2014). Relative survival was calculated using the Pohar-Perme method. Results Overall, 935 cases of gynecologic carcinosarcomas were diagnosed during 1980-2014. The most common gynecologic anatomical site was the uterus (83.4%). Most cases (66%) were diagnosed at ages 60-80, with median age of 69 years. There was a steady increase in ASRs from 5.6 to 8.2 per million women. Throughout 1980-1994 and 2005-2014, ASRs were significantly higher in the Jewish compared to the Arab population (5.8 vs. 3.1, p = 0.02 and 8.5 vs. 5.2, p = 0.002, respectively). Relative survival rates increased throughout the study period. No significant differences were noted in relative survival between the Jewish and Arab populations (p = 0.18). Conclusion The incidence of gynecologic carcinosarcoma increased significantly from 1980 through 2014. Nevertheless, survival rates increased during this time, with no difference in survival between the Jewish and Arab populations.

ObjectiveEndometrial cancer prognosis is related to stage, histology, myometrial invasion, and lymphovascular space invasion. Several studies have examined the association between pretreatment thrombocytosis and patient outcomes with contrasting results regarding prognosis. Our aim was to evaluate the association of pretreatment platelet count with outcomes in endometrial cancer patients.MethodsThis is an Israeli Gynecologic Oncology Group multicenter retrospective cohort study of consecutive patients with endometrial cancer, who underwent surgery between January 2002 and December 2014. Patients were grouped as low risk (endometrioid G1-G2 and villoglandular) and high risk (endometrioid G3, uterine serous papillary carcinoma, clear cell carcinoma, and carcinosarcoma). Those with stage I disease were compared with stages II–IV. Disease stages were reviewed and updated to reflect International Federation of Gynecology and Obstetrics (FIGO) 2009 staging. All patients underwent pelvic washings for cytology and total abdominal or laparoscopic hysterectomy with bilateral salpingo-oophorectomy. Pelvic lymph node assessment was performed in patients with tumors of moderate–high risk histology or deep myometrial invasion. Para-aortic sampling was performed at the surgeon’s discretion. Patients were categorized by pretreatment platelet count into two groups: ≤400×109/L and >400×109/L (defined as thrombocytosis). Clinical and pathological features were compared using Student t-test, χ2 or Fisher’s exact test. Survival measures were plotted with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards model was used for multivariable comparison of associations.ResultsOf the 1482 patients included, most had stage I disease (961; 74.8%) and most had endometrioid histology (927; 64.1%). A total of 1392 patients (94%) had pretreatment platelet counts ≤400×109/L and 90 (6%) had pretreatment thrombocytosis. Patients with thrombocytosis had a significantly higher rate of high-grade malignancy, advanced stage, lymphovascular space invasion, low uterine segment involvement, and lymph node metastases. They also had shorter 5 year disease-free survival (65% vs 80%, p=0.003), disease-specific survival (63% vs 83%, pConclusionsPretreatment thrombocytosis is an independent prognostic factor for decreased disease-specific survival and overall survival among patients with endometrial cancer, and can serve as a predictor of poor outcome.

Background The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. Methods The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. Results The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3–11.3), 5.4 (4.8–5.8) and 2.9 (2.8–4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1–22.4) and 8.3 (7.1–10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). Conclusions This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.

Objective To compare outcomes of symptomatic and asymptomatic women with endometrial cancer and a preoperative diagnosis of an endometrial polyp. Design An Israel Gynecologic Oncology Group multi-center retrospective cohort study. Methods Of 635 patients with endometrial cancer and a preoperative diagnosis of an endometrial polyp who underwent surgery between 2002 and 2014 in one of 11 centers in Israel were divided into two groups according to the presence of bleeding symptoms. Outcome measures included recurrence-free survival, disease-specific survival and overall survival. Survival data were plotted according to the method of Kaplan and Meier and compared using the log-rank test. Results There were 513 symptomatic and 122 asymptomatic women with endometrial cancer and a preoperative diagnosis of an endometrial polyp. The median follow-up was 52 months (range 12-120 months). There were no differences between patients who experienced bleeding and those who did not in 5-year recurrence-free survival (85.2 % vs. 85.7 %; p=0.83, respectively), disease-specific survival (88.2 % vs. 89.2 %; p=0.71, respectively), or overall survival (80.2% vs. 78.4 %; p=0.97, respectively). Conclusion The diagnosis of endometrial cancer in patients with asymptomatic endometrial polyps is not associated with improved outcomes as compared with patients with bleeding. In the absence of factors indicating a high risk of endometrial cancer, clinical and sonographic follow-up is the advised management strategy for these patients.

INTRODUCTION Advanced age is considered an adverse factor in endometrial cancers but may be a surrogate for other conditions that impact outcomes. The study objective was to assess the association of age with endometrial cancer features, treatment and prognosis. MATERIAL AND METHODS In this multicenter cohort study, consecutive women with endometrial cancer treated at 10 Israeli institutions between 2000 and 2014 were accrued in an assimilated database. Postmenopausal women were stratified into age groups with a cut-off of 80. Clinical, pathological and treatment data were compared using t test or Mann-Whitney test for continuous variables, and Chi-square Test or Fisher's Exact test for categorical variables. Main outcome measures included disease recurrence and disease-specific and overall survival; these were plotted using the Kaplan-Meier method and compared using the log-rank test. The association between age and recurrence and survival, adjusted for other clinical and pathological factors, was assessed using multivariable Cox regression modeling. RESULTS A total of 1764 postmenopausal women with endometrial cancer were identified. Adverse pathological features were more prevalent in older women, including high-risk histologies (35% vs 27%, P = .025), deep myoinvasion (44% vs 29%, P = .001) and lymphovascular involvement (22% vs 15%, P = .024). Surgical staging was performed less frequently among older women (33% vs 56%; P

Objectives Primary, to explore correlation between the extent of pelvic lymphadenectomy in the surgical staging of endometrial cancer and the number of nodes with metastasis. Secondary, evaluate survival measures in relation to the number of excised nodes. Methods A retrospective multi-center study of prospectively collected information of 2014 women with endometrial cancer, 1032 of whom underwent lymph node staging. Spearman's rank correlation was used to assess the correlation between the number of pelvic nodes excised and the number of metastatic nodes. Women's data were dichotomized by the median number of excised pelvic nodes. Kaplan-Meier and log rank tests were used to examine the effect of the number of pelvic nodes excised on survival. Results There was no significant correlation between the number of pelvic nodes harvested and the number of metastatic lymph nodes (r = 0.301; p = 0.28). The median number of excised pelvic nodes was 9 (range 1–77). There was no difference between women with up to 9 and women with more than 9 lymph nodes excised in the 5-year recurrence-free survival (82.4% vs. 83.9%; p = 0.90), disease-specific survival (83.6% vs. 86.7%; p = 0.37), or overall survival (75.8% vs. 82.8%; p = 0.11). Conclusions The extent of pelvic lymphadenectomy in the surgical staging of endometrial cancer is not associated with a higher yield of metastatic nodes or with longer survival. Current focus should be on sentinel node procedures that offer women the benefit of accurate staging without the complications associated with extensive lymphadenectomy.

Endometrial cancer is the most common gynecologic malignancy in developed countries. The overall risk of recurrence is associated with traditional risk factors.Machine learning was used to predict recurrence among women who were diagnosed and treated for endometrial cancer between 2002 and 2012 at elven university-affiliated centers. The median follow-up time was 5 years. The following data were retrieved from the medical records and fed into the algorithm: age, chronic metabolic diseases, family and personal cancer history, hormone replacement therapy use, endometrial thickness, uterine polyp presence, complete blood count results, albumin, Ca-125 level, surgical staging, histology, depth of myometrial invasion, LVSI, grade, pelvic washing cytology, and adjuvant treatment. We used XGBoost algorithm, which fits the training data using decision trees, and can also rate the factors according to their influence on the prediction.1935 women were identified of whom 325 had recurrent disease. On the randomly picked samples, the specificity was 55% and the sensitivity was 98%. Our model showed an operating characteristic curve with AUC of 0.84.A machine learning algorithm presented promising ability to predict recurrence of endometrial cancer. The algorithm provides an opportunity to identify at-risk patients who may benefit from adjuvant therapy, tighter surveillance, and early intervention.

Objective To compare survival measures of women with early-stage endometrial cancer who underwent either hysteroscopy or a non-hysteroscopic procedure as a diagnostic procedure. Study design An Israel Gynecologic Oncology Group multicenter study of 1324 patients with stage I endometrial cancer who underwent surgery between 2002 and 2014. Patients were divided into two groups: hysteroscopy and non-hysteroscopy (curettage or office endometrial biopsy). Clinical, pathological, and survival measures were compared between the groups. Results There were 355 patients in the hysteroscopy group and 969 patients in the non-hysteroscopy group. The median follow-up was 52 months (range 12–120 months). There were no differences between the groups in the 5-year recurrence-free survival (90.2% vs. 88.2%; p = 0.53), disease-specific survival (93.4% vs. 91.7%; p = 0.5), and overall survival (86.2% vs. 80.6%; p = 0.22). Conclusion Our findings affirm that hysteroscopy does not compromise the survival of patients with early-stage endometrial cancer.

Objective To assess whether statin use by endometrial cancer patients was associated with a survival advantage. Methods A retrospective chart review study, by the Israeli Gynecologic Oncology Group, of consecutive endometrial cancer patients who underwent surgery in one of 11 medical centers between 2002 and 2014. Clinical and pathological reports, and measures of survival were compared between statin users and nonusers. Kaplan-Meier and Cox proportional hazard models were used to assess the effect of using statins on survival measures. Results Over a mean follow-up period of 6.2 years (range, 1-12 years) for 2017 endometrial cancer patients with complete data, 663 (32.8%) used statins prior to diagnosis and 1354 (67.1%) did not. No statistically significant differences between the groups were observed for most demographic and clinical characteristics. There was no difference between statin users and nonusers in 5-year recurrence-free survival (82% vs 83%; P=0.508), disease-specific survival (86% vs 84%; P=0.549), or overall survival (77% vs 75%; P=0.901). Conclusions In this large cohort of patients with endometrial cancer, no significant associations were found between use of statins and endometrial cancer survival.

Objective To report the efficacy of combined systemic and local methotrexate treatment for cesarean scar pregnancy and review data from selected, similar case series. Study design A retrospective case series of 12 patients with cesarean scar pregnancy treated in a university hospital between 2014 and 2018. The intervention was combined treatment of systemic and local methotrexate. Results Twelve patients were treated with combined systemic and local methotrexate. Clinical characteristics, clinical course and treatment efficacy were evaluated. Mean gestational age at diagnosis was 7.5 weeks (range 5.9–9.1). βhCG levels at diagnosis ranged from 1581 to 345,427 U/L with a mean of 77,795 U/L. All 12 patients were successfully treated without surgical intervention and with no significant side-effects. Mean hospitalization duration was 9 days (5.8–12.6) and mean time to normalization of βhCG levels was 98 days (63–132). Conclusions Treatment of cesarean scar pregnancy with a combination of systemic and local methotrexate was effective and safe. Although the treatment course tends to be longer than with other modalities, this protocol offers excellent success rates, with fertility preservation and few complications.

Women with cervical cancer who undergo radical hysterectomy are often treated postoperatively with chemoradiation. Patient selection that minimizes adjuvant treatment is valuable. We compared two methods for predicting postoperative adjuvant treatment of women with tumor size ≥2 cm and4 cm.This multicenter retrospective study included 272 women with tumor size ≥2 cm and4 cm. A receiver operating characteristic curve (ROC) analysis was used to determine the optimal tumor cutoff size to predict adjuvant treatment. A second analysis compared the rate of adjuvant treatment between women with and without lymph vascular space involvement (LVSI).According to the ROC, the optimal cutoff value of tumor size for predicting adjuvant treatment was 2.95 cm (sensitivity 0.70, specificity 0.67). Tumors were ≥3.0 cm in 166 (61.0%) women. The rate of adjuvant treatment was higher in women with larger tumor diameter (73.8% vs. 47.9%, p 0.0001). Of the 241 women with a LVSI record, LVSI was present in 81 (34%) women. Among women with LVSI, rates were higher of positive lymph nodes (41.0% vs 14.5%, p 0.0001) and postoperative adjuvant treatment (83.3% vs. 53.7%, p 0.001). Among women with tumor size ≥3.0 cm and LVSI, the rate of adjuvant treatment was 90.0%. In the multivariate analysis, both tumor size ≥3.0 cm and the presence of LVSI were independently associated with adjuvant treatment (OR 3.9, 95% CI 2.1-7.1; p 0.0001 and OR 4.9, 95% CI 2.4-10.0; p 0.0001, respectively).In women with cervical cancer who underwent radical hysterectomy, tumors ≥3 cm were associated with a70% rate of adjuvant treatment, and LVSI was associated with a80% rate. These data should be weighed in multidisciplinary consultation with radiation oncologists when deciding treatment strategy.

To compare the rates of post-operative radiotherapy between two methods of lymph nodes assessment during surgical staging for endometrial cancer (EC).We conducted a comparative study of all consecutive women with endometrial cancer who underwent sentinel lymph node detection and biopsy using blue dye and isotope scan (SLNB) at Kaplan Medical Center and patients from the IGOG database, who underwent staging lymphadenectomy (PLND). The primary outcome was the rate of adjuvant and therapeutic radiation. The secondary outcome was a comparison of disease-free survival (DFS) and overall survival (OS).There were 138 patients in the SLNB group and 1022 women in the PLND group. The detection rate of SLN was 74% for unilateral detection and 54% for bilateral detection. In the PLND group 57% were high risk patients vs. 47% in SLNB group (p = 0.03). 43% of high-risk patients in the PLND group received adjuvant or therapeutic pelvic radiation vs. 28% of high-risk women in the SLNB arm (p = 0.017). No statistically significant difference in recurrence rates nor in death rates had been observed in the high-risk group patients. The 5-years survival in the high-risk PLND group was 80% and the recurrence rate was 19% vs. 75% 5-year survival and 14% recurrence in high-risk SLNB cohort, log-rank p = 0.82 for survival and long-rank p = 0.25 for recurrence.Endometrial cancer patients undergoing lymph node assessment by sentinel lymph node biopsy, receive less pelvic radiotherapy.

Gynecologic Sarcomas are rare, aggressive tumors. The aim of this study was to explore the incidence and outcomes of gynecologic sarcomas in a large national data registry and to compare them with reports from other countries.Records of gynecologic sarcomas diagnosed in Israel (1980-2014) were extracted from the National Cancer Registry and classified according to International Classification of Diseases for Oncology-3 and characterized according to anatomical site, morphology and demographics. Age-standardized incidence rates and 1, 3, 5 and 10-year relative survival rates were calculated for 3 time periods (1980-1994, 1995-2001 and 2005-2014) according to patient age, stage and years of diagnosis.During 1980-2014, 1271 new gynecologic sarcomas were diagnosed in Israel, with incidence slightly increasing in 1980-2004, to an age-standardized incidence rate of 13 per million women. The most common histologic diagnosis was leiomyosarcoma (48%) and the most common anatomical site was the uterus (89%). The age-standardized incidence rate for uterine sarcoma is higher in Israel (10.55 per million) than in England (7.4 per million) and Germany (5.8 per million) respectively. The 5-year overall survival was significantly poorer in patients70-years, as compared to younger patients (p0.001) and in those with leiomyosarcoma compared to endometrial stromal sarcoma (p0.001). The survival rate of patients with leiomyosarcoma in Israel are comparable to survival rates reported by other studies, although substantially lower regarding endometrial stromal sarcoma.Uterine leiomyosarcoma was the most common gynecologic sarcoma found in the Israeli, European and American registries. Older patients and those with leiomyosarcoma have the worst prognoses. Histological and anatomical variations in Israel are comparable with global statistics, but the incidence in Israel seems higher than in Europe.

Objectives We evaluated the incidence of breast cancer and overall survival in a multi-center cohort of ovarian cancer patients carrying BRCA1/2 mutations in order to assess risks and formulate optimal preventive interventions and/or surveillance. Methods Medical records of 502 BRCA1/2 mutation carriers diagnosed with ovarian cancer between 2000 and 2018 at 7 medical centers in Israel and one in New York were retrospectively analyzed for breast cancer diagnosis. Data included demographics, type of BRCA mutations, surveillance methods, timing of breast cancer diagnosis, and family history of cancer. Results The median age at diagnosis of ovarian cancer was 55.8 years (range, 23.9–90.1). A third (31.5%) had a family history of breast cancer and 17.1% of ovarian cancer. Most patients (67.3%) were Ashkenazi Jews, 72.9% were BRCA1 carriers. Breast cancer preceded ovarian cancer in 17.5% and was diagnosed after ovarian cancer in 6.2%; an additional 2.2% had a synchronous presentation. Median time to breast cancer diagnosis after ovarian cancer was 46.0 months (range, 11–168). Of those diagnosed with both breast cancer and ovarian cancer (n = 31), 83.9% and 16.1% harbored BRCA1 and BRCA2 mutations, respectively. No deaths from breast cancer were recorded. Overall survival did not differ statistically between patients with an ovarian cancer diagnosis only and those diagnosed with breast cancer after ovarian cancer. Conclusion The low incidence of breast cancer after ovarian cancer in women carrying BRCA1/2 mutations suggests that routine breast surveillance, rather than risk-reducing surgical interventions, may be sufficient in ovarian cancer survivors.

Study Objective To compare oncological outcomes of women with stage II -IIIc endometrial cancer (EC) who underwent minimally invasive surgery (MIS) versus laparotomy. Design A retrospective cohort study. Setting Academic multi-center. Patients or Participants Consecutive women with EC treated at 11 Israeli institutions between 2002 and 2017 were recorded in an assimilated database with a median follow-up of 52 months (range 12-120 months). Women with stage II -IIIc were stratified into groups by intentional route of surgery; MIS vs. laparotomy. Clinical, pathological and outcome data were compared. Interventions MIS and laparotomy. Measurements and Main Results Three hundred and four women met criteria: 200 underwent laparotomy and 104 MIS. Women in the MIS group were younger, had lower rate of diabetes and lower CA-125 level. Women who underwent laparotomy had higher grade EC and more advanced stage disease; Odds Ratio (OR) and 95% Confidence Interval (CI) 0.34 (0.21-0.56) and 0.56 (0.34-0.92), respectively. Brachytherapy rate was comparable between groups (p=0.715). In a multivariable analysis, including age, comorbidities, disease stage, tumor grade and lymph-vascular space invasion, MIS was not associated with an increased risk for recurrence, progression or decreased overall survival. However, patients operated by MIS had higher risk to recur locally (vaginal cuff or pelvic) (26.9% vs. 16.5%, p=0.032, OR, 1.86, 95% CI 1.05-3.30). MIS was the only independent factor associated with local recurrence, adjusted OR, 2.09, 95% CI 1.12-3.90. Conclusion In women with stage II-IIIc EC, MIS was associated with an increased risk for local recurrence compared to laparotomy.

We aimed to assess the association of pre-operatively evaluated ultrasonographic endometrial thickness with outcomes of patients with endometrial cancer.An Israel Gynecologic Oncology Group multicenter retrospective cohort study of consecutive patients with endometrial cancer who underwent surgery between 2002 and 2014 in one of eleven academic centers. Patients were categorized by endometrial thickness into two groups: ≤20 mm and20 mm. Clinical and pathological features were compared using Student T-test for continuous variables and Chi-square or Fisher's exact test for categorical variables. Survival measures were plotted with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards model was used for multivariable comparison of associations.1113 patients in whom endometrial thickness data was recorded were the subject of this study and included 2 groups: ≤20 mm (n = 930),20 mm (n = 183). The median follow-up was 52 months (range 12-120 months). Patients with endometrial thickness20 mm had significantly lower recurrence-free survival (log rank, p .0001), disease-specific survival (log rank, p = .01), and overall survival (log rank, p .0001). On multivariate Cox proportional hazards analysis, endometrial thickness20 mm remained independently associated with an increased hazard of recurrence and death (HR = 1.77, 95% CI 1.07-2.96, p = .03 for recurrence; and HR = 1.68; 95% CI 1.07-2.65; p = .03 for overall survival).In patients with endometrial cancer, endometrial thickness20 mm as measured preoperatively by ultrasound, is independently associated with decreased recurrence-free and overall survival. This finding suggests that thick endometrium may be considered as one of the risk factors for poor prognosis.

A rapid and reliable intraoperative diagnostic technique to support clinical decisions was developed using Fourier-transform infrared (FTIR) spectroscopy. Twenty-six fresh tissue samples were collected intraoperatively from patients undergoing gynecological surgeries. Frozen section (FS) histopathology aimed to discriminate between malignant and benign tumors was performed, and attenuated total reflection (ATR) FTIR spectra were collected from these samples. Digital dehydration and principal component analysis and linear discriminant analysis (PCA-LDA) models were developed to classify samples into malignant and benign groups. Two validation schemes were employed: k-fold and "leave one out." FTIR absorption spectrum of a fresh tissue sample was obtained in less than 5 minutes. The fingerprint spectral region of malignant tumors was consistently different from that of benign tumors. The PCA-LDA discrimination model correctly classified the samples into malignant and benign groups with accuracies of 96% and 93% for the k-fold and "leave one out" validation schemes, respectively. We showed that a simple tissue preparation followed by ATR-FTIR spectroscopy provides accurate means for very rapid tumor classification into malignant and benign gynecological tumors. With further development, the proposed method has high potential to be used as an adjunct to the intraoperative FS histopathology technique.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. The insulin-like growth factor (IGF) system plays a key role in regulating growth and invasiveness in several malignancies, including ovarian cancer. IGF1R targeting showed antiproliferative activity of EOC cells. However, clinical studies failed to show significant benefit. EOC cells suppress antitumor immune responses by inducing dendritic cell (DC) dysfunction. The IGF1 axis can regulate DC maturation. The current study evaluated involvement of the IGF1 axis in DC differentiation in EOC. Studies were conducted on EOC and on a human monocyte cell line. Tissue microarray analysis (TMA) was performed on 36 paraffin blocks from EOC patients. Expression of IGF1R, p53, Ki67, BRCA1, and DC markers was evaluated using immunohistochemistry. Co-culture of EOC cells with DC pretreated with IGF1R inhibitor blocked cancer cell migration. TMA demonstrated higher rate of IGF1R protein expression in patients with advanced (76.9%) as compared to early (40%) EOC. A negative correlation between IGF1R protein expression and the CD1c marker was found. These findings provide evidence that IGF1R axis inhibition could be a therapeutic strategy for ovarian cancer by restoring DC-mediated antitumor immunity.

Objectives Data on the outcome of stage IIA1 cervical cancer is limited, as these tumors comprise a small percentage of early tumors. NCCN guidelines suggest consideration of surgical management for small tumors with vaginal involvement. Our objective was to evaluate the risk of adjuvant radiotherapy in stage IIA1 cervical cancer and its associated features, in order to improve selection of patients for surgical management. Methods A retrospective cohort study comparing surgically treated cervical cancer patients with stage IB1 and stage IIA1 disease. Women treated between 2000 and 2015 in ten Israeli medical centers were included. Patient and disease features were compared between stages. The relative risk (Fisher's exact test) of receiving post-operative radiation was calculated and compared for each risk factor. A general linear model (GLM) was used for multivariable analysis. Results 199 patients were included, of whom 21 had stage IIA1 disease. Most features were comparable for stage IB1 and stage IIA1 disease, although patients with vaginal involvement were more likely to have close surgical margins (23.8% vs 8.5%, p = 0.03). Patients with stage IIA1 disease were more likely to receive radiation after surgery (76% vs. 46%, RR = 1.65 (1.24–2.2), p = 0.011). Vaginal involvement as well as depth of stromal invasion, LVSI and lymph node metastases were independent predictors of radiation on multivariable general linear modeling. Conclusions Cervical cancer patients with vaginal involvement are highly more likely to require postoperative radiation. We recommend careful evaluation of these patients before surgical management is offered.

OBJECTIVE To compare the outcome of patients with uterine papillary serous cancer (UPSC) carrying a BRCA mutation with that of patients with UPSC who are BRCA wild-type. METHODS The present retrospective, multicenter cohort study included women with UPSC who were diagnosed between January 1, 1993, and December 31, 2014, and were tested for the BRCA mutation at three Israeli medical centers. Data were collected from the medical records, and patient and tumor characteristics and disease outcomes were compared between BRCA mutation carriers and noncarriers. The primary outcome was overall survival. RESULTS In total, 14 BRCA mutation carriers and 50 noncarriers were included. Both groups had similar treatment modalities (P=0.530). A non-significant trend toward BRCA mutation carriers being diagnosed more frequently at an advanced stage compared with noncarriers was observed (P=0.090). Median overall survival (25 vs 37 months; P=0.442), progression-free survival (37 vs 29 months; P=0.536), and disease-specific survival (60 vs 39 months; P=0.316) were similar between the carrier and noncarrier groups. CONCLUSIONS Although not significant, BRCA mutation carriers tended to have more advanced disease at diagnosis. However, the survival was similar irrespective of the BRCA status in this small group. Further research is needed to confirm these findings in a larger cohort.

Study Objective To compare oncological outcomes of women with high-grade endometrial carcinoma (HGEC) who underwent surgery by minimally invasive surgery (MIS) versus laparotomy. Design A retrospective cohort study. Setting Academic multi-center. Patients or Participants Consecutive women with HGEC cancer treated at 11 Israeli institutions between 2002 and 2017 were accrued in an assimilated database with a median follow-up of 52 months (range 12-120 months). Women with HGEC were stratified into two groups by route of surgery; MIS vs. laparotomy by an intention to treat. Clinical, pathological and outcome data were compared. Interventions MIS and laparotomy. Measurements and Main Results Six hundred and seventy-eight women met the inclusion criteria: 160 underwent MIS and 518 laparotomy. The two groups were comparable in demographic and clinical characteristics. Local recurrence was more common in the MIS group, Odds Ratio (OR) 95% Confidence Interval (CI) 2.80 (1.80-4.36). Disease progression rates were comparable (p=0.537). In a multivariable analysis, including age, comorbidities, disease stage, CA-125 and lymph-vascular space invasion, MIS was not associated with an increased risk for either overall recurrence rate, disease progression, or overall survival. Independent risk factors for local recurrence were diabetes, stage III-IV, LVSI and MIS, adjusted OR 95% CI 3.30 (1.69-6.48). Conclusion In women with HGEC, MIS is associated with higher rates of local recurrence as compared to laparotomy.

Introduction: The insulin-like growth factors (IGFs) are a family of secreted peptide hormones with important roles in different cellular and organism functions. The biological activities of the IG...

Introduction/Background Niraparib is a poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the United States and Europe for maintenance treatment of patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer (ROC) following complete or partial response to platinum-based chemotherapy. Here, we present long-term safety data of niraparib, reporting the incidence of treatment-emergent adverse events (TEAEs) among patients in the ENGOT-OV16/NOVA trial. Methodology ENGOT-OV16/NOVA enrolled 553 patients with ROC who received 2–3 prior lines of platinum-based chemotherapy. Patients were randomised 2:1 to receive niraparib (300 mg once daily) or placebo in independent germline BRCA-mutated (gBRCAmut) or non-gBRCAmut cohorts. We report TEAE incidence monthly for the first 6 months and for months 7–12 combined. After month 12, we report TEAEs to the safety data cutoff of September 2017. Results Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%). In month 5, only 7% of patients required dose reductions. The incidence of any-grade and grade ≥3 haematologic and symptomatic TEAEs decreased each month in the first 6 months and remained low thereafter. Incidence of grade ≥3 thrombocytopenia was highest in month 1 (28%) and decreased to 10% and 5% at months 2 and 3, respectively. Treatment discontinuations due to TEAEs were Conclusion The incidence of haematologic and symptomatic TEAEs decreased quickly over the first 3 months and continued to decrease over the duration of the trial. Dose reductions and grade ≥3 thrombocytopenia events were highest in month 1 and decreased rapidly thereafter. Treatment discontinuations due to TEAEs were Disclosure AD, IMBB, DB-R, JH, EK, JB, PD, IB, SL: Nothing to disclose WG, SH, FdJ: Employee of Tesaro MRM: Consulting for Clovis, AstraZeneca, Tesaro BB: Honoraria from AstraZeneca, Insys, Funding from Tesaro SM: Grant and Personal Fees from Tesaro, AstraZeneca, Medac, MSD, PharmaMar, Roche, Teva. Personal Fees from Clovis, Sensor Kinesis PB: Site payment for clinical trial conduct from Tesaro JL: Ad Boards and PI for trials with AstraZeneca, Clovis, Pfizer. Ad Boards for Roche. Clinical Trials with MSD/Merck. BJR: Consulting with AstraZeneca, Tesaro, Genentech/Roche. Honoraria from Genentech UC: Honoraria and fees for consulting and Ad boards from Roche, AstraZeneca IPV: Travel and Accomodations from PharmaMar, Roche. Expert Testimony for AstraZeneca. Research Funding from Novartis, Tesaro DL: Ad Board for Tesaro, Clovis, AstraZeneca. Research Support from Clovis. Study Conduction support from Tesaro and PharmaMar UAM: Consulting for Merck KGaA, Clovis, Geneos, Eli Lilly, 2x Oncology

Objectives Classification of malignant tissue is performed by histopathology, results of which may be obtained within weeks. Faster histopathology analysis is performed using frozen section (FS) analysis, results of which are available within less than an hour. However, the accuracy of the FS test is lower compared to histopathology. We are proposing a real time method based on IR spectroscopy of liquid biopsy from fresh samples of gynecologic cancer tissues as an alternative to the conventional methods. Methods 27 biopsies (ovarian and uterine, 17 classified as benign and 10 malignant) were extracted from suspected tumor sites during gynecologic surgical procedures and sent for both pathological and FTIR analyses. Tissue samples were lightly pressed against the surface of an ATR crystal, leaving on its’ surface impression smears. Mid-IR absorption spectra were obtained within 15 minutes of excision. Histopathological results of these very same samples were used to develop discriminant models from the absorbance data of the measured smears using machine learning techniques (PCA-LDA and SVM). Results IR absorbance spectra of malignant smears were consistently higher from spectra of benign smears in the 850–1450 cm-1 range and they were consistently lower in the 3200–3600cm-1 range. The PCA-LDA discrimination model correctly classified the samples with a sensitivity and specificity of 100%, and the SVM showed a training accuracy of 100% and a cross validation accuracy of 91.3%. Conclusions These preliminary results suggest that ATR-FTIR spectroscopy of tissue smears may have an important role in the development of next-generation techniques for intra-operative tumor classification.

Objectives Survival reports of gynecologic sarcomas are limited. The aim of this study is to explore the incidence and outcome of gynecologic sarcomas in different time periods in Israel and to compare to other national reports. Methods Records of gynecologic sarcomas diagnosed between 1980–2014 were extracted from the National Israeli Cancer Registry. Sarcomas were characterized with respect to anatomical site, morphology and demographic variables. Age-standardized incidence rates (ASRs) and 1,3,5 and 10 –year relative survival rates were calculated for 3 time periods (1980–1994, 1995–2004 and 2005–2014) according to age, stage and years of diagnosis. Results 1271 new gynecologic sarcomas were diagnosed in Israel during 1980–2014, with incidence slightly increasing between 1980–2004 years up to ASR of 13 per million females. Incidence was highest in women 45–65 years old. The most common histologic diagnosis was leiomyosarcoma (48%) and most common anatomical site was uterus (89%). The ASR for uterine sarcoma is higher in Israel compared to USA, England and Germany, 10.55, 9.2, 7.4, 5.8 per million, respectively. The 5 years’ overall survival is significantly worse in elderly patients (>70yo) compared to younger patients (P Conclusions Israeli statistics is comparable with global statistics regarding histologic and anatomical variations but the incidence in Israel seems higher than in European population.

Objectives To compare survival measures of women with early-stage endometrial cancer who underwent either hysteroscopy or a non-hysteroscopic procedure as a diagnostic procedure. Methods An Israel Gynecologic Oncology Group multicenter study of 1324 patients with stage I endometrial cancer who underwent surgery between 2002 and 2014. Patients were divided into two groups: hysteroscopy and non-hysteroscopy (curettage or office endometrial biopsy). Clinical, pathological, and survival measures were compared between the groups. Results There were 355 patients in the hysteroscopy group and 969 patients in the non-hysteroscopy group. The median follow-up was 52 months (range 12–120 months). There were no differences between the groups in the 5-year recurrence-free survival (90.2% vs. 88.2%; p=0.53), disease-specific survival (93.4% vs. 91.7%; p=0.5), and overall survival (86.2% vs. 80.6%; p=0.22). Conclusions Our findings affirm that hysteroscopy does not compromise the survival of patients with early-stage endometrial cancer.

Objectives Epithelial ovarian cancer (EOC) is the most lethal cancer among gynecological malignancies worldwide. The insulin-like growth factor (IGF) system plays a key role in regulating growth and invasiveness of EOC. IGF1R targeting showed anti-proliferative activity of EOC cells, however, clinical studies failed to show significant benefit. EOC cells suppress anti-tumor immune responses, by inducing Dendritic Cells (DCs) dysfunction. Interestingly, recent studies indicate that the IGF axis can regulate DCs maturation. Our study aims to evaluate the involvement and role of the IGF1 axis in DCs differentiation in EOC. Methods Studies were conducted on EOC and a human monocyte cell lines. IGF1R expression levels were evaluated by Western blots. Differentiated DCs were treated with IGF1R inhibitor and co-cultured with EOC cell lines, thereafter scratch assay was performed. Tissue microarray was implemented on 40 paraffin blocks from EOC patients and expression of IGF1R associated proteins and DCs markers was evaluated by immunohistochemistry. Results DCs differentiation was characterized by reduced in total IGF1R levels (50%) and phosphorylated IGF1R levels (95%). In addition, IGF1R inhibitor treated-DCs decreased EOC cell migration. TMA analysis demonstrated higher rate of strong IGF1R, p53 and PD-1 protein expression in patients with advanced-stage compared to early-stage, 87.5% vs 66.66%, 87.5% vs 75%, 62.5% vs 50%, respectively. Conclusions IGF1R pathway inhibition in differentiated DCs suppressed EOC cell migration. Thus, restoring the anti-tumor immune response by IGF1R targeting may be an effective therapy for EOC. TMA analyses imply a correlation between IGF1R and PD-1 expression and EOC-stage, nonetheless, further evaluation is necessary.

Epithelial ovarian cancer (EOC) is the principal cause of death from gynecologic cancer in developed countries. While surgery and chemotherapy can improve survival, the mortality and morbidity rates remain significantly high. The insulin-like growth factor (IGF) axis has been shown to play an important part in carcinogenesis of several human malignancies. Preclinical studies reported a significant anti-proliferative activity of IGF1 receptor (IGF1R) inhibitors in ovarian malignancies, however, clinical studies have shown variable response rates. Recent data indicate that immunotherapy could hold promise in improving EOC treatment. Dendritic cells (DCs) which are antigen presenting cells evoke a positive immune response. Moreover, a recent study shows that IGF treatment can inhibit DC maturation.To investigate the involvement of IGF1R signaling in DCs and the effect of combined DCs and IGF1R inhibitor treatment on EOC cells growth.HL-60 leukemic cells were differentiated to DCs and ligand induced phosphorylated IGF1R levels were measured by Western blotting. Next, inhibition of IGF1R in DCs was applied and the effect of this inhibition on EOC cell lines ES2 and SKOV3 was examined using the migration assay method.The differentiation of HL-60 into DCs was associated with decreased levels of both IGF1R phosphorylation and total IGF1R protein. In addition, in-vitro growth assays (scratch assay) demonstrated an increased growth of both ES2 and SKOV3 cells into the scratch zone when co-cultured with DCs which were not pre-treated with IGF1R inhibitor as compared to treated DCs.Preliminary data suggest that DC differentiation is associated with IGF1R signaling downregulation. Moreover, inhibition of IGF1R signaling in DCs might decrease EOC growth.

ObjectiveMost patients with epithelial ovarian cancer will experience a recurrence; currently, there is no cure. In patients with platinum-sensitive disease (platinum-free interval >6 months), a combination similar to that used as frontline therapy (carboplatin and paclitaxel) is recommended. However, it is associated with a high incidence (20%) of neurotoxicity. This study evaluated the efficacy and toxicity of combination docetaxel/carboplatin therapy in patients with platinum-sensitive recurrent ovarian cancer.MethodsForty patients with recurrent, histologically proven ovarian, fallopian tube, or primary peritoneal cancer were enrolled in this phase 2 trial. The study protocol included combination therapy with docetaxel, 30 mg/m2, on days 1 and 8, and carboplatin, area under the curve 5, on day 1, every 21 days. Twenty received the classical paclitaxel/carboplatin regimen (control group), and another 20 received the modified docetaxel/carboplatin protocol (study group).ResultsMedian follow-up was 78 months for the study group and 62 months for the control group. The study group had a higher overall response rate compared to controls: 80% and 30%, respectively (P = 0.004; relative risk, 9.3; 95% confidence interval, 2.18–39.96). Complete response was achieved in 60% and 25%, respectively (P = 0.054). The study group patients showed a superior 2-year survival rate of 75% compared with the 35% of the controls (P = 0.011; relative risk, 5.57; 95% confidence interval, 1.47–21.56). Hematological and neurological toxicity rates did not differ between the groups (P = 0.451 and P = 0.605, respectively).ConclusionsPatients with recurrent ovarian cancer who received the modified docetaxel/carboplatin regimen had higher overall response and survival rates compared to those who had the paclitaxel/carboplatin regimen, with no difference in toxicity. Future larger studies should focus on strategies to compare this regimen to the current standard, with an emphasis on quality of life.

Objective To assess the rate of postoperative adjuvant treatment in patients who underwent radical hysterectomy for early cervical cancer and to suggest criteria for the triage of patients who have a high probability of multimodality treatment. Methods This was a multicenter retrospective study of 514 patients with FIGO stages IA2-IIA cervical cancer who underwent radical hysterectomy between 1999 and 2010. The patients were divided into 2 groups according to whether or not postoperative radiation was administered. The 2 groups were compared with regard to clinical and histopathologic variables divided into major and minor criteria (intermediate risk factors) based on lymph nodes status, parametrial involvement, tumor size, deep stromal invasion, and lymph-vascular space invasion. Results We identified 294 (57.2%) patients who received adjuvant postoperative radiotherapy (RT) or chemoradiation. Fifty-three percent of these patients who were treated by adjuvant radiation had only intermediate risk factors. Combining the various combinations of 2 out of 3 of the following criteria, we found that 89% of patients with tumors ≥2 cm and lymph-vascular space invasion received RT, 76% of patients with tumors ≥2 cm and depth of invasion >10 mm received RT, and 87% of patients with tumors depth of invasion >10 mm and lymph-vascular space invasion received RT. Conclusions This study suggests that in patients with early cervical cancer, clinicopathologic evaluation of tumor size and lymph-vascular space invasion should be undertaken before performing radical hysterectomy. This approach can serve to tailor treatment, reducing the rate of employing both radical hysterectomy and chemoradiation.

Treatment of patients with gynecologic malignancies diagnosed at advanced stages remains a therapeutic challenge. Survival rates of these patients remain significantly low, despite surgery and chemotherapy. Advances in understanding the role of the immune system in the pathogenesis of cancer have led to the rapid evolution of immunotherapeutic approaches. Immunotherapeutic strategies, including targeting specific immune checkpoints, as well as dendritic cell (DC) immunotherapy are being investigated in several malignancies, including gynecological cancers. Another important approach in cancer therapy is to inhibit molecular pathways that are crucial for tumor growth and maintenance, such as the insulin-like growth factor-1 (IGF1) pathway. The IGF axis has been shown to play a significant role in carcinogenesis of several types of tissue, including ovarian cancer. Preclinical studies reported significant anti-proliferative activity of IGF1 receptor (IGF1R) inhibitors in gynecologic malignancies. However, recent clinical studies have shown variable response rates with advanced solid tumors. This study provides an overview on current immunotherapy strategies and on IGF-targeted therapy for gynecologic malignancies. We focus on the involvement of IGF1R signaling in DCs and present our preliminary results which imply that the IGF axis contributes to an immunosuppressive tumor microenvironment (TME). For the long term, we believe that restoring the TME function by IGF1R targeting in combination with immunotherapy can serve as a new clinical approach for gynecological cancers.

Insulin analogues have been developed to achieve further improvement in the therapy of diabetes. However, modifications introduced into the insulin molecule may enhance their affinity for the insulin-like growth factor-1 receptor (IGF1R). Hyperinsulinemia has been identified as a risk factor for endometrial cancer. We hypothesized that insulin analogues may elicit atypical proliferative and signaling activities in endometrial cancer cells. Our results demonstrate that glargine, but not detemir, stimulated cell proliferation, displayed an anti-apoptotic effect, and had a positive effect on cell cycle progression in endometrial cancer cell lines ECC-1 and USPC-1. In addition, we showed that glargine and detemir induced dual activation of the insulin receptor (INSR) and IGF1R in both cell types. Furthermore, we showed that glargine elicited signaling events that are markedly different from those induced by insulin. In conclusion, our data support the concept that, although insulin analogues were designed to display insulin-like metabolic effects, glargine and, possibly, additional analogues exhibit IGF1-like activities and, accordingly, may function as IGF1 analogues.

The insulin-like growth factor-1 receptor (IGF1R) has been identified as a potent anti-apoptotic, pro-survival tyrosine kinase-containing receptor. Overexpression of the IGF1R gene constitutes a typical feature of most human cancers. Consistent with these biological roles, cells expressing high levels of IGF1R are expected not to die, a quintessential feature of cancer cells. Tumor specific chromosomal translocations that disrupt the architecture of transcription factors are a common theme in carcinogenesis. Increasing evidence gathered over the past fifteen years demonstrate that this type of genomic rearrangements is common not only among pediatric and hematological malignancies, as classically thought, but may also provide a molecular and cytogenetic foundation for an ever-increasing portion of adult epithelial tumors. In this review article we provide evidence that the mechanism of action of oncogenic fusion proteins associated with both pediatric and adult malignancies involves transactivation of the IGF1R gene, with ensuing increases in IGF1R levels and ligand-mediated receptor phosphorylation. Disrupted transcription factors adopt the IGF1R signaling pathway and elicit their oncogenic activities via activation of this critical regulatory network. Combined targeting of oncogenic fusion proteins along with the IGF1R may constitute a promising therapeutic approach.