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To evaluate objective (saliva cortisol) and subjective (questionnaire) stress levels during the Coronavirus disease (COVID-19) pandemic compared to before the pandemic and their effects on obstetric and neonatal outcomes.This cohort study included 36 women with low-risk, singleton, term deliveries at a tertiary academic center during the COVID-19 pandemic and 49 who delivered before. Physiological stress was evaluated with salivary cortisol measurements, and emotional stress with stress scale questionnaires (0-10) during active and full dilation stages of labor, and 2-min postpartum. Cord blood cortisol and pH were obtained. Delivery mode, complications, and neonatal outcomes were evaluated.Psychological stress was higher for the COVID-19 group compared to controls during full dilation (6.2Women who delivered during COVID-19 pandemic had higher stress levels at full dilation and lower cord cortisol levels, as may be expected after exposure to a chronic stressor.

Background There is little data regarding the optimal approach to advanced epithelial ovarian cancer (EOC) with isolated extra-peritoneal disease in the cardiophrenic lymph nodes. This study assessed whether the prognosis and surgical outcomes are affected by the treatment approach among these patients. Material and methods This retrospective cohort study included patients with advanced EOC, who were treated 2012–2020. Computed tomography scans were reviewed for disease extent and the presence of enlarged supradiaphragmatic nodes (SDLN). Demographic, clinical and oncologic data were recorded. Characteristics and outcomes of patients with and without enlarged SDLN were evaluated, and outcomes of patients with enlarged SDLN who underwent upfront surgery and neoadjuvant chemotherapy were compared. Results Among 71 women, 47 (66%) had enlarged supradiaphragmatic lymph nodes. Groups had similar baseline characteristics. Among 47 women who had enlarged SDLN. There was no significant difference in progression free survival among patients who had upfront cytoreduction compared to those who received neoadjuvant chemotherapy. Only one asymptomatic chest recurrence was observed. Conclusion Patients with enlarged SDLN have comparable outcomes with either upfront surgery or neoadjuvant chemotherapy. Moreover, the frequency of chest recurrences in patients presenting with enlarged SDLN is exceedingly low.

Objective To assess the correlation between maternal mobility after cesarean delivery and postoperative morbidity. Methods A prospective study was conducted in a tertiary hospital among patients after cesarean delivery. The women were recruited after surgery and before ambulation. Each participant received an accelerometer and routine instructions for mobilization. The patients were asked to wear the accelerometer constantly. It was collected at discharge. Electronic files were reviewed and patients' outcomes were analyzed. The Mann-Whitney U test was used to compare groups and a receiver operating characteristic curve was calculated for the threshold of number of steps. Results Data were analyzed for 199 patients, among which 107 (54.4%) deliveries were urgent and 90 (45.6%) were elective. The median number of steps was higher for multiparous women compared to nulliparous women (P = 0.035). Patients who developed complications after discharge walked significantly less during their hospitalization compared to those who did not. There was a trend toward increased risk for in-hospitalization complications among patients who walked less while hospitalized. A threshold of more than 9716 steps per hospitalization was found to be associated with fewer post-discharge complications. Conclusion There is a significant correlation between the extent of ambulation after cesarean delivery and fewer postoperative complications.

Contains fulltext : 241226.pdf (Publisher’s version ) (Closed access) BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.

High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy with a need for better understanding the disease pathogenesis. The biologically active thyroid hormone, T3, is considered a tumor suppressor by promoting cell differentiation and mitochondrial respiration. Tumors evolved a strategy to avoid these anticancer actions by expressing the T3 catabolizing enzyme, Deiodinase type 3 (DIO3). This stimulates cancer proliferation and aerobic glycolysis (Warburg effect). We identified DIO3 expression in HGSOC cell lines, tumor tissues from mice and human patients, fallopian tube (FT) premalignant lesion and secretory cells of normal FT, considered the disease site-of-origin. Stable DIO3 knockdown (DIO3-KD) in HGSOC cells led to increased T3 bioavailability and demonstrated induced apoptosis and attenuated proliferation, migration, colony formation, oncogenic signaling, Warburg effect and tumor growth in mice. Proteomics analysis further indicated alterations in an array of cancer-relevant proteins, the majority of which are involved in tumor suppression and metabolism. Collectively this study establishes the functional role of DIO3 in facilitating tumorigenesis and metabolic reprogramming, and proposes this enzyme as a promising target for inhibition in HGSOC.

This study compares characteristics of advanced stage, high grade serous ovarian cancer, presenting with high or low serum CA125 level. This was a retrospective cohort of 118 patients with high grade serous ovarian, fallopian tube or primary peritoneal cancer, stages IIIC-IV diagnosed from January 1 1997 through January 9 2017. Patient demographics, tumour characteristics, surgical findings, chemotherapy protocols and clinical outcomes were collected. Three groups were evaluated: group A: 21 patients with CA125 serum level ≤152 U/ml, group B: 97 patients with CA125 serum level >152 U/ml, group C: 43 patients from group B with CA125 serum level >500 U/ml and

To describe patterns of physiological and psychological stress during induced labor and their correlation to obstetrical and neonatal outcomes. This prospective, observational study included 167 women, with low-risk, singleton pregnancies, who delivered at term, at a tertiary academic center from 2015 through 2018. Among them, 72 (43%) underwent induction and 95 (57%) had spontaneous labor onset. Physiological stress was evaluated by salivary cortisol measurements and emotional stress by questionnaires (visual analogue stress scale 0–10) during latent phase, active phase and full dilation stages of labor, as well as 2 min and 2 h postpartum. Cord blood cortisol and pH were obtained. Stress patterns were compared between parturients who did or did not undergo induction. Modes of delivery, labor and delivery complications, and early neonatal outcomes were compared. Mothers completed the Hospital Anxiety and Depression Scale. Induced women had lower cortisol concentrations during the latent phase compared to spontaneous onset of labor (p = 0.003), with no differences during active (p = 0.237), full dilation (0.668), 2 min and 2 h after delivery (p = 0.666). Stress scale and Hospital Anxiety and Depression Scale scores were similar between groups. Cord cortisol (p = 0.294), 1-min Apgar score ≤ 7 (p = 0.502) and 5-min Apgar score ≤ 7 (p = 0.37) were similar. All had cord pH > 7. Induction does not increase stress during labor. Moreover, it might have a positive effect on reducing cortisol during the latent phase. These findings might reassure women who are concerned about induction of labor.

Israel’s unique population is comprised of two main ethnic groups—Jews (75%) and Arabs (21%), with differing socioeconomic, cultural, and genetic profiles. This study’s objective was to evaluate disparities in the incidence, presentation, and outcomes of gynecologic cancers among Israeli women of Arab and Jewish ethnicity. Data on the Israeli female population diagnosed with gynecologic cancers during the years 2000–2012 was obtained from the National Cancer Registry and the National Population Registry. Disease incidence rates by ethnic origin were calculated, and the “Segi World standard population” was used for age standardization. Data for Jewish and Arab patients was compared using chi-square test for categorical variables and T test for continuous variables. Survival outcomes were compared using the log-rank test and Cox proportional hazards modeling. Annual ASR (age-standardized rate) for ovarian, cervical, and uterine cancers, are all significantly higher among Israeli women of Jewish ethnicity. Israeli Arab women are diagnosed with cervical cancer at an older age (mean, 60.9 vs 55.9, p < 0.001). Stage distribution for uterine, ovarian, and cervical cancers is similar in both ethnic groups. The age-adjusted hazard ratio for mortality from uterine cancer is significantly lower among Jewish Israeli women compared to Arab Israeli women (HR = 0.67, 95% CI 0.57–0.78, p < 0.0001). During the study period, there was a significant decline in the ASR for ovarian cancer among Jewish Israeli women. The ASR for pre-invasive cervical disease increased significantly in both ethnic groups. Disparities in gynecological cancer rates, presentations, and outcomes are evident between two major ethnic groups in Israel. Lower cancer incidence rates among Israeli Arab women are likely multifactorial. Uterine cancer outcomes between the two ethnic groups need to be further assessed in order to identify opportunities for improved outcomes among Israeli Arab women.

Pregnancy-associated breast cancer (PABC) is usually diagnosed at an advanced stage in comparison to non-pregnant women. The placenta secretes hormones and cytokines, which affect breast cancer progression. Previously, we demonstrated that human placental secretome facilitates the survival and migration of ERα+ breast cancer cells (BCCL), but pregnant women have a relatively high frequency of ERα-negative tumors. In the current study, we analyzed the effect of placental secretome on ERα-negative BCCL.BCCL [MCF-7(estrogen/progesterone receptor positive (ERα+/PR+), ERα reduced MCF-7 (siRNA, MCF-7 ERα-), HS-578 and BT-549 cells (both ER-/PR-)] were exposed to supernatants (collected from first trimester human placental explants and from control BCCL) or to E2 + P4 (estrogen + progesterone) in placental supernatant concentrations and then tested for cell proliferation (number, cell cycle, PCNA), cell-death, cell migration, STAT3 pathway activation and functionality.Silencing ERα in the MCF-7 cells negated the placental supernatant and E2 + P4 enhancement of cell migration ( 130%, p 0.05), number ( 120%) and survival (~ 130%). However, it had no such effect on MCF-7-ER- migration, which was still elevated in the presence of placental secretome. ER-/PR- BCCL were unaffected by the hormones, but placental secretome significantly elevated their migration (115%), number (140-170%), STAT3 phosphorylation (~ 180%) and BT-549 STAT3 level. These effects were negated by the STAT3 inhibitor.Placental supernatant facilitates BCCL malignant characteristics by activating ERα in estrogen responsive cells and STAT3 in ERα- BCCL. This indicates a possible mechanism that may underlie PABC's advanced state and suggests STAT3 pathway as a therapeutic target for PABC.

ObjectiveHigh grade and non-endometrioid endometrial cancers carry a poor prognosis, and the lack of randomized prospective data has led to a wide range of practice regarding adjuvant therapy. The objective of this study was to evaluate the outcomes of different treatment strategies in patients with high-risk, early-stage endometrial cancer.MethodsPatients with high-grade endometrioid, serous endometrial cancer and carcinosarcoma diagnosed between 2000 and 2012 were identified from databases in three gynecologic oncology divisions, in Toronto and in Israel. Adjuvant treatment practices differed across the centers, creating a heterogeneous cohort. A comparison of stage I patients stratified by adjuvant treatment was undertaken. Log-rank tests and Cox proportional hazards models were employed to compare recurrence and survival across treatment groups.Results490patients with high risk endometrial cancer were identified, among them 213 patients with stage I disease. Israeli patients received more chemotherapy (41% vs 10% in stage I disease; PConclusionsIn this retrospective analysis, neither adjuvant radiation nor chemotherapy were associated with improved outcome in stage I, high risk endometrial cancer.

To assess oncologic outcomes in endometrial cancer patients with low-volume metastasis (LVM) in the sentinel lymph nodes (SLNs).Patients with endometrial cancer and SLN-LVM (≤2 mm) from December 3, 2009, to December 31, 2018, were retrospectively identified from 22 centers worldwide. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV, adnexal involvement, or unknown adjuvant therapy (ATx) were excluded.Of 247 patients included, 132 had isolated tumor cell (ITC) and 115 had micrometastasis (MM). Overall 4-year recurrence-free survival (RFS) was 77.6% (95% CI, 70.2%-85.9%); median follow-up for patients without recurrence was 29.6 (interquartile range, 19.2-41.5) months. At multivariate analysis, Non-endometrioid (NE) (HR, 5.00; 95% CI, 2.50-9.99; P .001), lymphovascular space invasion (LVSI) (HR, 3.26; 95% CI, 1.45-7.31; P = .004), and uterine serosal invasion (USI) (HR, 3.70; 95% CI, 1.44-9.54; P = .007) were independent predictors of recurrence. Among 47 endometrioid ITC patients without ATx, 4-year RFS was 82.6% (95% CI, 70.1%-97.2). Considering 18 ITC patients with endometrioid grade 1 disease, without LVSI, USI, or ATx, only 1 had recurrence (median follow-up, 24.8 months).In patients with SLN-LVM, NE, LVSI, and USI were independent risk factors for recurrence. Patients with any risk factor had poor prognosis, even when receiving ATx. Patients with ITC and grade 1 endometrioid disease (no LVSI/USI) had favorable prognosis, even without ATx. Further analysis (with more patients and longer follow-up) is needed to assess whether ATx can be withheld in this low-risk subgroup.

Objective Among patients with endometrial cancer, longer wait times to surgery were associated with decreased survival. Although endometrial cancer survival rate is high, about 45% of patients receive adjuvant therapy. The aim of this study was to examine whether a longer interval from diagnosis to surgery is associated with increased need for adjuvant treatment among patients with low-risk endometrial cancer. Methods A retrospective cohort study of endometrioid endometrial cancer patients treated with surgery between the years 1999 and 2013 was conducted. Patients with pre-operative histology of hyperplasia, grade 1/2 cancers were included. Patients with stage IV disease were excluded. Demographic, clinicopathologic and surgical parameters were collected and correlation with wait time was evaluated. The risk for adjuvant therapy was in two-week intervals from biopsy to hysterectomy. Results 468 patients were included in the final cohort. 84.3% had stage I disease and 43.8% patients received adjuvant treatment. Mean time from diagnosis to surgery was 63.88 days (SD 10.3, 31–94). The risk for adjuvant therapy was not increased at any of the time intervals that were examined. Conclusion In low risk endometrial cancer, longer time interval between diagnosis and surgery did not increase the need for adjuvant therapy.

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.

Objectives The aim of the study was to describe the experience of one institution in management and outcome of tubo-ovarian abscess (TOA) in pre- and postmenopausal women and to reassess the optimal approach for TOA in postmenopausal women. Methods A retrospective cohort study included women diagnosed with TOA between 2003 and 2017 in a tertiary referral center. TOA was diagnosed by sonography or computerized tomography and at least one of the following criteria: temperature more than 38°C, leukocytosis more than 15,000 mm, or surgically proven disease. Women were followed up for a mean of 7.6 years (range 6 mo to 14 y). The rates of conservative management and pelvic malignancy were evaluated. Results The study cohort included 144 (69.23%) women who met the inclusion criteria, of which 105 (72.92%) were premenopausal and 39 (27.08%) were postmenopausal. Univariate analysis found no differences in risk factors and disease characteristics between the two groups. Among the study sample, 22 (56.4%) postmenopausal women and 48 (45.7%) premenopausal women were treated surgically (P = 0.5). None of the premenopausal women and 1 (2.6%) postmenopausal woman were diagnosed with pelvic malignancy. Conclusion In postmenopausal women with TOA, the prevalence of concurrent pelvic malignancy was 2.6%, which is higher than in the general population, but lower than that reported in the literature; 44% were conservatively managed without any apparent cases of misdiagnoses of cancer.

During placental implantation, cytotrophoblast cells differentiate to extravillous trophoblast (EVT) cells that invade from the placenta into the maternal uterine blood vessels. The heat shock protein-27 (HSP27), the signal transducer and activator of transcription-3 (STAT3) and the eukaryotic translation initiation factor 4E (EIF4E) are involved in regulating EVT cell differentiation/migration. EIF4E and EIF4G compose the translation initiation complex, which is a major control point in protein translation. The molecular chaperone distinctiveness of HSP27 implies that it directly interferes with many target proteins. STAT3, EIF4E, and EIF4G were found to be HSP27 client proteins in tumor cells. We aimed to analyze if HSP27 regulate STAT3 and EIF4G levels in first trimester human placenta. We found that like STAT3, EIF4G is highly expressed in the EVT cells (immunohistochemistry). Silencing HSP27 in HTR-8/SVneo cells (siRNA, EVT cell line) and in placental explants reduced STAT3 level (47 and 33 %, respectively, p

Metastatic ovarian cancer, the most lethal of gynecologic malignancies, is typically managed by debulking surgery, followed by chemotherapy. However, despite significant efforts, survival rate remains low. We have previously demonstrated, in mouse models, a specific systemic homing of labeled fibroblasts to solid ovarian tumors. Here, we demonstrate the feasibility of utilizing this specific homing of genetically modified fibroblasts for detection and targeted therapy of orthotopic metastatic ovarian carcinoma model in immune-deficient mice. Using an in vivo metastatic mouse model for ovarian cancer, we demonstrated that fibroblasts expressing fluorescent reporters injected intra-peritoneally, were specifically recruited to peritoneal tumor nodules (resulting in 93-100% co-localization). We further used fibroblasts over expressing the soluble receptor variant of VEGFR1 (s-Flt1). Mice bearing tumors were injected weekly with either control or s-Flt1 expressing fibroblasts. Injection of s-Flt1 expressing fibroblasts resulted in a significant reduction in the ascites volume, reduced vascularization of adherent metastases, and improved overall survival. Using fluorescently labeled fibroblasts for tumor detection with readily available intra-operative fluorescence imaging tools may be useful for tumor staging and directing biopsies or surgical efforts during exploratory or debulking surgery. Fibroblasts may serve as a beacon pointing to the otherwise invisible metastases in the peritoneal cavity of ovarian cancer patients. Utilizing the recruited fibroblasts also for targeted delivery of anti angiogenic or antitumor molecules may aid in controlling tumor progression. Thus, these results suggest a novel approach for targeting ovarian tumor metastases for both tumor detection and therapy.

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.

The extracellular matrix (ECM) affects cancer cell characteristics. Inability of normal epithelial cells to attach to the ECM induces apoptosis (anoikis). Cancer cells are often anoikis resistant, a prerequisite for their metastatic spread. Previously we demonstrated that the placenta manipulates its surrounding ECM in a way that prevents breast cancer cells (BCCL) attachment and induces their motility and aggregation. This fits with the fact that although breast cancer during pregnancy is often advanced, metastasis to the placenta is rarely observed. Placental intervillous space provides suitable conditions for cancer cell arrival. Yet, the outcome of the short communication between the placental ECM to the BCCL and its effect on BCCL malignant potential are unknown, and are the focus of our study. In the current study we analyzed the effect of placental ECM on BCCL survival pathways and drug resistance. Microarray analysis suggested activation of the NF-κB and stress response pathways. Indeed, the placenta-conditioned ECM induced autophagy in ERα + BCCL, inactivated the NF-κB inhibitor (IκB) and increased integrin α5 in the BCCL. The autophagy mediated MCF-7 and T47D migration and the placental ECM-BCCL interactions reduced the BCCL sensitivity to Taxol. We also demonstrated by using siRNA that integrin α5 was responsible for the MCF-7 autophagy and suggest this molecule as a suitable target for therapy.

Background Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib. Methods This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0–1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2:1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (6–12 months vs ≥12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01874353, and is ongoing and no longer recruiting patients. Findings Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19·1 months [95% CI 16·3–25·7]) than with placebo (5·5 months [5·2–5·8]; hazard ratio [HR] 0·30 [95% CI 0·22–0·41], p

Aim: Carboplatin-induced immediate hypersensitivity reactions are relatively common among patients with gynecological malignancies. Once this occurs, the patient might be at risk for future carboplatin-induced reactions. This study evaluated the efficacy of allergic consultation, carboplatin skin testing and desensitization as a single intervention strategy in this population. Methods: Patients with a well-documented immediate reaction to carboplatin were offered allergy consultation, carboplatin skin testing and a desensitization plan in a single visit between scheduled chemotherapy sessions. Results: Fifty-five patients with an immediate reaction were evaluated. After allergist assessment, 44 (89%) of 49 patients skin tested had a positive result. A total of 207 carboplatin desensitization cycles were administered to 49 women. Among them, 10 patients had a mild immediate hypersensitivity reaction during desensitization. Five patients subsequently tolerated carboplatin administered in the prolonged desensitization protocol. Conclusions: In the data presented, we propose a strategy that is both cost effective and very convenient for the patient. The diagnostic procedure, including allergist consultation and skin test, can be completed in less than 2 h. In most cases where carboplatin is indispensable, desensitization can be administered without overnight hospitalization.

Postpartum readmission after initial hospitalization for delivery can be diminished if better understood. The aim of this study was to determine the risk factors and indications for maternal re-hospitalization after delivery, in order to identify preventable factors. This was a case control study based on retrospective cohort of patients who delivered at our institution. The patients that were readmitted within 2 weeks of their delivery were included in the study group while the control group was conducted from patients who delivered at the same time but were not re-hospitalized and included twice the number of patients. Demographic characteristics as well as pregnancy, labour and postpartum courses were compared between the two groups. A total of 227 women were re-hospitalized within 14 days after initial discharge. The control group consisted of 450 women. The demographic characteristics were similar among the two groups, so were the rates of obesity, gestational weight gain and smoking. The major indication for readmission was postpartum infections, most of which were not related to immediate postpartum febrile morbidity. Emergency cesarean section was found to be an independent risk factor for readmission. The rate of patients with high-risk pregnancies and complicated deliveries is higher among postpartum maternal readmissions. These data might suggest more cautious postpartum care for those patients.

Background Labor is considered a stressful event, yet no study has described the course of stress measured by cortisol during labor and postpartum. Objective The objective of the study was to describe the patterns of physiological and psychological stress during labor as measured by salivary cortisol concentrations and stress questionnaires and their correlation to obstetric and neonatal outcomes. Study Design This prospective, observational study included 167 women with low-risk, singleton, term deliveries at a tertiary academic center. Physiological stress was evaluated by salivary cortisol measurements and emotional stress by questionnaire (stress scale ranging from 0 to 10) during the latent phase, active phase, and full dilation stages of labor as well as 2 minutes, 2 hours, and 24 hours after delivery. Cord blood cortisol and pH were also obtained. Modes of delivery, complications during labor and delivery, and early neonatal outcomes were evaluated. Results Salivary cortisol concentrations increased gradually from latent phase to active phase. The maximum increase was observed within 2 minutes of the delivery (from an average of 1.06 μg/dL to 1.67 μg/dL; 57% increase). Within 2 hours after delivery, cortisol decreased and reached a nongravid concentration after 24 hours (0.16 μg/dL). Cortisol concentrations during labor and up to 2 hours postpartum were above the average concentration of nongravid women (0.5 μg/dL). Women with epidural anesthesia had lower cortisol concentrations at complete dilation (P = .026) and 2 hours postpartum (P = .016) compared with women without epidural. Psychological stress peaked during latent and full dilation phases (mean 4.56 and 4.29, respectively). Maximum decrease from 4.29 to 2.04 (52%) occurred immediately postpartum. Cord cortisol was higher among women delivered by vacuum extraction compared with spontaneous vaginal delivery (17 ± 2 vs 11 ± 3.8, P = .03). Conclusion This study reveals the course of cortisol concentrations during labor for low-risk pregnancies, with maximum increase immediately postpartum. Subjective stress levels decreased over the course of labor. Salivary cortisol portrays stress during labor and may be used as a reference to evaluate complicated pregnancies and to evaluate the role of cortisol during these deliveries.

Background Postcoital bleeding (PCB) is a common gynecological symptom that may cause concern among both patients and physicians. Current literature is inconclusive regarding management recommendations. Objective To identify risk-factors for dysplasia/cancer among patients presenting post-coital bleeding (PCB). Methods Using large health maintenance organization (HMO) database, all women reporting PCB in 2012–2015 were identified. PCB patient records in a single colposcopy center were reviewed. Age, marital status, ethnicity, gravidity, parity, BMI, smoking, PAP smear result (within 1 year of PCB presentation), colposcopy and biopsy results were recorded. Cases were matched by age and socio-economic enumeration area to controls accessing primary care clinics for routine care. Results Yearly incidence of PCB ranged from 400 to 900 per 100,000 women; highest among patients aged 26–30 years. Among the sample of 411 PCB cases with colposcopy, 201 (48.9%) had directed biopsy. Biopsy results included 68 cervicitis (33.8%), 61 koilocytosis/CIN 1/condyloma (30.3%), 44 normal tissue (21.9%), 25 cervical polyp (12.4%), 2 CIN 2/3 (1%) and 1 carcinoma (0.5%). Positive predictive value for koilocytosis/CIN 1 or higher pathology was 15.6% (64/411) and 0.7% for CIN 2 or higher grade pathology (3/411). In conditional logistic regression, multiparty was a protective factor: OR 0.39 (95% CI 0.22–0.88, P = 0.02), while pathological PAP smear was a related risk-factor: OR 3.3 (95% CI 1.31–8.35, P = 0.01). When compared to controls, PCB patients were significantly (P = 0.04) more likely to present CIN 1 or higher grade pathology (OR 1.82, 95% CI 1.02–3.33). Conclusions Study results indicate that PCB may require colposcopy, especially for nulliparous women with an abnormal PAP smear.

Objective To explore the pattern of chemotherapy (beyond the second-line) used to treat patients with recurrent epithelial ovarian cancer (including primary peritoneal carcinoma). Study design This retrospective study included 156 patients with recurrent epithelial ovarian cancer and primary peritoneal carcinoma who were treated in the Gynecologic Oncologic Department at Meir Medical Center between November 1995 and December 2003. Clinical characteristics and data regarding the surgery, chemotherapy, and response to treatment were abstracted from the patients’ medical records to determine patient response to advanced lines of chemotherapy for recurrent epithelial ovarian cancer. Results Of the 156 patients, 63 (40%) were treated beyond second-line chemotherapy. Clinical response to third-line chemotherapy was 11.9% (6.8% had complete clinical response and 5.1% partial clinical response) and 3.4% had stable disease. A total of 17% did not show immediate progression, with a median progression free-interval of 1.5 months. A drastic decline in clinical response rates was shown beyond third-line chemotherapy. Any response to treatment in more advanced lines was consistently under 5%. Conclusion These results imply that advanced lines of chemotherapy are associated with low response rates, although a small percentage of patients showed some clinical response or remained with stable disease at the end of treatment. Along with patient preferences, the advantages and disadvantages of continued therapy should be considered, for the side effects of each treatment cannot be overlooked.

Two topotecan treatment schedules in patients with recurrent epithelial ovarian cancer were evaluated. Protocol A (21 days) was 1.5 mg/m(2)/day topotecan on days 1 through 5 of a 21-day cycle; Protocol B (weekly) 4 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Efficacy was determined by clinical exam, CT scan, and CA125 levels. Forty-three patients on Protocol A and 21 on Protocol B were evaluated. As second-line treatment, Protocol A response was 9/20 (45%). Response to Protocol B was 4/17 (23.5%; NS). As third line or more, the response on Protocols A and B together was only 3/27 (11%). High-grade haematological toxicity was reported in 12/43 (27.9%) on Protocol A and 1/21 (4.8%) on Protocol B (p = 0.04). There was no difference in progression-free-intervals between schedules in second-line treatment. The weekly protocol had lower severe haematological toxicity. Clinical response in third line or more was very low.

Objective To compare approval rates of late termination of pregnancy (LTOP) requests before and after a policy change in Israel in late 2007. Methods In a retrospective study, LTOP requests and board decisions from 2002–2007 (group 1) were compared with those from 2007–2012 (group 2) at 3 university-affiliated medical centers in Israel. Reasons for application, approval, or rejection were compared between the groups. Results There were 552 applications for LTOP. The overall approval rate for LTOP and the specific approval rate per medical indication did not differ significantly between the groups. The rate of requests due to confirmed genetic anomalies decreased from 18.4% in group 1 to 11.3% in group 2 (P = 0.03). Compared with group 1, the rate of rejection for intrauterine infection increased from 8.3% to 26.3% (P = 0.2), and that for pregnancy complications decreased from 62.5% to 35.0% (P = 0.2) in group 2 but these differences were not statistically significant. Requests due to structural anomalies were declined because they were considered to be minor cardiac, renal, cerebral, or skeletal anomalies. Conclusion The more stringent 2007 criteria for approving requests for LTOP did not affect the rate of rejection of requests due to structural anomalies between the 2 time periods.

background: Pregnant women with breast cancer present with a more advanced disease compared with non-pregnant women. Nevertheless, breast cancer metastasis to the placenta is rare. Trophoblast/tumor implantations share the same biochemical mediators, while only the first is stringently controlled. We hypothesized that the same mechanisms that affect/restrain placental implantation may inhibit metastatic growth in the placenta. We aimed to analyze the effects of human placenta on breast cancer cells. methods: First trimester human placental explants were co-cultured with MCF-7/T47D-eGFP tagged cells. Following culture, placenta/ cancer cells/both were fixed, paraffin embedded and sliced for immunohistochemical analysis or sorted by their eGFP expression for future analysis. The tested parameters were: proliferation (immunohistochemistry)/cell cycle (FACS), apoptosis (immunohistochemistry/FACS), cell count/adhesion/distribution around the placenta (cell sorter, visual observation and counting), matrix metalloproteinase activity (zymogram) and estrogen receptor (ER) expression (western blotting, immunohistochemistry). results: Reduced breast cancer cell numbers (45%� , 48%� for MCF-7/T47D, respectively, P , 0.05) were observed near the placenta. The placenta elevated MCF-7 sub-G1 phase and modestly elevated apoptosis (3 –17%� for T47D/MCF-7, respectively, P , 0.05). Our findings demonstrate breast cancer cell migration from the placenta as: (i) T47D/MCF-7 cells changed their morphology to that of motile cells; (ii) elevated MMPs activity was found in the co-culture; (iii) placental soluble factors detached breast cancer cells; and (4) the placenta reduced MCF-7/T47D cells’ ER expression (a characteristic of motile cells). conclusions: MCF-7/T47D cells are eliminated from the placental surroundings. Analyzing the causes of these phenomena may suggest biological pathways for this event and raise new therapeutic targets.

Differential diagnosis of a uterine mass is complex and usually includes leiomyoma and sarcoma. We report a rare case of uterine Ewing sarcoma with its unique sonographic characteristics in a 37-year-old woman. Usually, the diagnosis of uterine Ewing sarcoma is made at an advanced stage. Overall, the mortality and relapse rates for Ewing sarcoma are high. In this case, the diagnosis was made at an early stage. The woman was treated surgically followed by chemotherapy Afterward, the woman was well and was followed in the oncologic gynecology unit.

Purpose: To evaluate different ovarian volume cut-off values to distinguish between normal ovaries, benign lesions, and malignant lesions in menopausal women. Methods: Transvaginal sonographic ovarian volume measurements were performed in 362 menopausal patients prior to gynecologic surgery. Based on the histopathologic results, a total of 466 ovaries were divided into 3 groups: normal ovary, benign lesion, and malignant tumor. Different ovarian volume cut-off values were analyzed via receiver operating characteristic curves to determine the optimal cut-off value. Results: The mean ovarian volumes in the normal ovary, benign lesion, and malignant tumor groups were 3.4 ± 2.2 cm3 (range, 0.6–9.6 cm3), 102 ± 308 cm3 (range, 0.3–3543 cm3), and 368 ± 1176 cm3 (range, 8.1–9908) cm3, respectively. Cut-off values of 8 cm3 and 10 cm3 to distinguish between malignant and nonmalignant lesions had a sensitivity of 100% and 97% and a specificity of 39% and 45%, respectively. Conclusion: In menopausal patients, any ovary with a volume >8 cm3 can potentially harbor a cancer. © 2007 Wiley Periodicals, Inc. J Clin Ultrasound, 2008

Cytotoxic treatment can cause early loss of ovarian function associated with loss of fertility in younger women. To investigate if co-treatment with a combination of gonadotropin-releasing hormone (GnRH) agonist and GnRH antagonist may be useful in preserving ovarian function and fertility in younger women during chemotherapy, we prospectively observed nine young patients receiving different chemotherapies for various malignant diseases and other severe medical conditions who also received simultaneous GnRH agonist and GnRH antagonist. Mean age of the patients was 26.56 +/- 8.78 years, all were < or =35 years old. Eight (88.9%) patients regained normal basal hormonal profile within 3 - 6 months after the completion of chemotherapy. Median level of follicle-stimulating hormone, luteinizing hormone and estradiol was 6.3 +/- 8.8 U/l, 8.2 +/- 25.4 U/l and 118.0 +/- 130.8 pg/ml, respectively. Eight (88.9%) patients resumed spontaneous menses within 3 - 11 months following discontinuation of chemotherapy. Two (22.2%) patients conceived: one spontaneously, and the second following induction of ovulation by injection of gonadotropins. It seems that combined usage of GnRH agonist and GnRH antagonist during chemotherapy may be useful in preserving ovarian function and fertility in a group of young females receiving chemotherapy treatment.

The extracellular matrix (ECM) affects cancer cell characteristics. Its detachment from the ECM induces cell apoptosis, termed anoikis. Cancer cells can develop anoikis resistance, a necessary step for metastasis, by switching integrins, over-expressing growth factor receptors, and inducing epithelial mesenchymal transition (EMT). The placenta is a non-supportive microenvironment for cancer cells. We showed that breast cancer cells (BCCL) were eliminated from placental implantation sites. During implantation, the placenta manipulates its surrounding matrix, which may induce BCCL elimination. Here, we explored the effect of placenta-induced ECM manipulations on BCCL. During experiments, BCCL (MCF-7/T47D) were cultured on placenta/BCCL-conditioned ECM (Matrigel used for first trimester placenta/BCCL culture and cleared by NH

Motor vehicle accidents (MVAs) are a major incidental cause of pregnancy-associated maternal deaths in the US. The goal of this research was to evaluate the incidence, risks, and fetal and maternal outcomes of pregnant women involved in MVAs. In addition, we examined the relationship between the injury severity score (ISS) and car seat location in pregnant and non-pregnant women.: This involved a retrospective cohort study of female patients who were involved in MVAs and hospitalized between the years 2006 and 2013. Data were collected from the Israeli National Trauma Registry. Severity and outcomes of pregnant and non-pregnant women with blunt trauma were compared.: In this study, 3794 pregnant and 3441 non-pregnant patients aged 18–40 years were analyzed. The majority of pregnant patients were drivers (n=2515, 67%) as opposed to passengers (n=1279, 33%). Pregnant patients had lower ISS than non-pregnant patients (PThe severity of injury and the mortality rate of pregnant patients involved in MVAs are significantly lower compared with non-pregnant patients. Pregnant drivers had a significantly lower severity of trauma compared with pregnant passengers.

BACKGROUND: Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme-A reductase, the rate-limiting enzyme of the mevalonate pathway, and are used successfully in the treatment of hypercholesterolaemia. Statins are contraindicated during pregnancy. Lately, we have shown that simvastatin has adverse affects on human first trimester placental explants’ proliferation and migration. The objective of the present study was to investigate the molecules involved in mediating simvastatin’s effect on trophoblast cell migration. We hypothesized that simvastatin attenuates insuline-like growth factor-I (IGF-I) receptor expression (involved in trophoblast motility), matrix metalloproteinase (MMP) activities, and heat shock protein 27 (HSP27) levels (whose mRNA is actively transcribed during trophoblast differentiation) in trophoblast cells thus consequently effecting their migration. METHODS: Human placental explants were cultured above a matrigel with/without simvastatin (10 mM) for 5 days. In this model, trophoblast migrates from the villi into the matrigel. Western-blot and immunohistochemistry served for analysing HSP27 expression. Immunohistochemistry was used for assessing IGF-I receptor localization. MMPs activity was assayed by gel zymography. RESULTS: Simvastatin reduced IGF-I receptor membranal expression, MMP2 activity and HSP27 expression in trophoblast cells ( P< 0.05). CONCLUSIONS: The inhibitory effect of simvastatin on trophoblast cell migration is associated with a significant decrease in the tested molecules, which probably contributes to the impaired migration.

Objective. To assess the frequency of uterine involvement in primary peritoneal carcinoma (PPC) and to describe selected clinical characteristics in patients with and without hysterectomy. Methods. All incident cases of histologically confirmed cancer of the ovary or peritoneum, diagnosed in Israeli Jewish women between March 1 1994 and June 30, 1999, were identified within the framework of a nationwide epidemiological study of these neoplasms. The study population was accrued through an active search of all newly diagnosed patients in all the departments of gynecology in Israel. The data of 81 PPC patients included in the present study were abstracted from medical records. Results. Hysterectomy was performed in 48 patients. These patients had a lower mean age (62.4 ± 9.4 vs. 66.9 ± 10.4; P = 0.05) at diagnosis and a higher rate of ≤2 cm residual disease (54.2% vs.24.2%; P = 0.02). Of those with hysterectomy, microscopic involvement was verified in all those with macroscopic involvement. Overall microscopic involvement was present in 28 (58.3%) of the patients who underwent hysterectomy. In the majority of them, only the serosa was involved. Macroscopic uterine involvement was present in 27 (33.3%) patients but in only 12% it was >2cm. The median survival in patients with hysterectomy was 36 months and in those without hysterectomy 29 months, this difference was statistically not significant ( P = 0.2). Conclusions. Our study indicates that in an unselected group of PPC patients 33% have any macroscopic uterine involvement. The therapeutic value of routine hysterectomy at the initial operation for PPC should be further investigated.

Objective. Uterine carcinosarcomas are highly aggressive neoplasms with no established effective adjuvant therapy. The aim of the present study was to compare between the outcome in three medical institutions in each of which a different postoperative treatment modality was preferred, namely, chemotherapy in one, whole pelvic irradiation (WPI) in another, and sequential treatment (i.e., chemotherapy followed by WPI) in the third. Methods. The hospital records of all 49 uterine carcinosarcoma patients diagnosed and operated from 1995 to 2003 in the three institutions were reviewed. Non-parametric test was used to compare the median age between the treatment groups. Survival was calculated using the Kaplan–Meier method and compared by the log-rank test. Cox proportional hazard regression model was used to assess the effect of treatment type on survival after adjustment for stage. Results. Only about half of the patients (51%) had stage I at diagnosis and the majority of the patients (83.7%) had postoperative adjuvant treatment. The overall 5-year survival of the 41 patients that had postoperative treatment was 49.6%. The highest median survival and 5-year survival rate was observed in the sequential treatment group. Controlling for stage, this treatment modality was associated with a significant decrease in mortality of about 80% when compared to postoperative chemotherapy alone, and a non-significant decrease in mortality of about 50% when compared to WPI alone (HR = 0.20; 95% CI 0.04–0.99, P = 0.049 and HR=0.50; 95% CI 0.1–2.32, P = 0.4, respectively). Conclusions. The improved outcome in patients who received postoperative sequential treatment seems to indicate that further exploration of this treatment modality is justified.

Our preceding studies have already demonstrated the advantage of intracytoplasmic morphologically selected sperm injection (IMSI) over the conventional IVF-ICSI procedure in terms of pregnancy rate. This study was undertaken to determine whether the increased pregnancy outcome was attributable to the preferred nuclear morphology of the selected spermatozoa, and not to the special sperm preparation technique modified by IMSI.Comparison between two matched IMSI groups, i.e. negative comprising 38 cycles, where no spermatozoa with intact nuclei were available for microinjection; and positive, involving ovum microinjection by spermatozoa with strictly defined morphologically normal nuclei.Implantation and pregnancy rates were significantly higher, and abortion rates significantly lower, in the positive group compared with the negative group (25.0+/-25.9 versus 5.9+/-12.9%, F=15.8, Por =0.01; 52.6 versus 18.4%, chi2=9.7, Por =0.01; and 10.0 versus 57.1%, chi2=7.1, Por =0.02, respectively).Implantation and pregnancy by ICSI is associated with morphological nuclear normalcy of sperm. Sperm with a morphologically abnormal nucleus usually have low fertility potential, but some with certain nuclear abnormalities may still be able to produce pregnancy following ICSI.

Our objective was to compare the genetic abnormalities in the primary tumors of epithelial ovarian cancer and their associated secondary peritoneal implants using comparative genomic hybridization (CGH). CGH was performed on seven apparent stage III ovarian serous cancer cases. Dissected tissue samples from the primary tumor and from the metastatic peritoneal implant were obtained at initial surgical staging and analyzed in each case. We used CGH as this technique allows the entire genome of the tumor to be examined simultaneously for chromosomal imbalances without the need for tissue culture or targeting of specific loci. The chromosomal abnormalities detected in the distinct sites were then reviewed and compared. CGH studies were successful in all 14 samples from the seven patients. The analysis revealed chromosomal aberrations in six patients with certain repeated changes as amplification of 1q, 2p, 2q, 3q, 6q, 8q, and 12p and underrepresentation of 18q and X chromosomes. Comparing the genomes of the primary tumors with the metastatic samples showed four cases with a balanced metastatic CGH profile while the primary site was aberrant. Greater chromosomal complexity associated with the primary site was detected in two other patients. In one case, both primary and secondary sites had no detectable chromosomal imbalances. The cytogenetic patterns in six of the seven primary tumors showed complex karyotypic changes, unlike the inconsistent findings that were associated with the secondary sites. The chromosomes of the secondary sites expressed either normal genomes or fewer genetic aberrations. Such genomic heterogeneity between the primary and secondary sites may indicate that the secondary peritoneal implants are de novo carcinogenesis occurrences. The results may support the concept that at least part of advanced ovarian cancer is a multicentric disease in the early stages. Further genetic studies are needed to reassess this assumption.

Purpose The aim of the study was to evaluate the contribution of gray-scale sonography and Doppler flow studies in differentiating between uterine sarcomas of different histologic types and leiomyomas. Patients and Methods The study included 111 patients, divided retrospectively into 2 groups: 98 patients with leiomyomas and 13 with postoperative diagnosis of uterine sarcoma. This latter group was further divided into a group of 6 patients with uterine leiomyosarcoma and 7 with malignant mixed mesodermal tumor. The gray-scale sonograms and Doppler parameters in the 3 groups were compared. Results The patients with leiomyomas were younger than those with sarcomas (52 years ± 11 versus 65 years ± 15, p < 0.05). No differences were noted between the 3 groups regarding gravidity, parity, symptoms upon admission, or findings during physical examination. The sonographic appearances of the leiomyomas were similar to those of the leiomyosarcomas, but in 6/7 cases, they were different from those of the malignant mixed mesodermal tumors. There was a significant difference between the mean resistance index in arterioles of the leiomyomas (0.59 ± 0.01) and that of the malignant mixed mesodermal tumors (0.41 ± 0.06) (P < 0.001) but not between those of the leiomyomas and the leiomyosarcomas (0.49 ± 0.18). Conclusions Doppler flow studies may assist in differentiating between leiomyomas and malignant mixed mesodermal tumors but not between leiomyomas and leiomyosarcomas. © 2004 Wiley Periodicals, Inc. J Clin Ultrasound 33:10–13, 2005

Objective . To evaluate the diagnostic accuracy of integrated positron emission tomography/computerized tomography (PET/CT) in patients with gynecological cancer. Methods . Fifty-three consecutive patients with gynecologic malignancies were included. The patients were referred to our tertiary center to undergo a PET/CT scan. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT were compared with the conventional imaging assessments [CT, magnetic resonance imaging (MRI) and ultrasonography (US)]. Results . All tested values were higher for PET/CT than those for the conventional modalities: sensitivity 0.97 vs. 0.40, specificity 0.94 vs. 0.65, PPV 0.97 vs. 0.70, and NPV 0.94 vs. 0.34, respectively. Conclusion . PET/CT is a reliable modality for assessing the extent of disease in patients with gynecologic malignancy.

Purpose This study was conducted to assess the combination of endometrial thickness, as measured by transvaginal sonography, and time since menopause, in predicting the presence of endometrial cancer in women with postmenopausal bleeding. Methods The study group consisted of 95 women with postmenopausal bleeding who underwent sonographic measurement of endometrial thickness followed by endometrial biopsy. No patient had ever received hormone replacement therapy. Results The mean endometrial thickness was significantly lower in the absence of endometrial carcinoma (6.9 ± 4.3 mm) than in its presence (13.5 ± 7.7 mm) (p < 0.005). The incidence of endometrial carcinoma increased with increases in endometrial thickness and the number of years since menopause. No patient had carcinoma when the endometrium was less than 5 mm thick, but 18.5% did when the thickness exceeded 9 mm. The incidence of cancer was 2.6% in women who had undergone menopause less than 5 years earlier but was 21.4% in women who had undergone menopause more than 15 years prior. Multiple logistic regression analysis showed that time since menopause and endometrial thickness were statistically significant predictors of endometrial carcinoma. Conclusions Time since menopause and endometrial thickness together define cutoff points for the diagnostic biopsy of tissue samples for endometrial carcinoma; that is, within a particular time interval, samspling should not be performed if the thickness is below a given value. When using cutoff points of 6 mm of endometrial thickness for women experiencing menopause 5–15 years prior and 5 mm in those going through menopause 15 or more years prior, approximately 60% of invasive procedures may be avoided. In addition, models derived by multiple logistic regression can be used to calculate a patient's risk of cancer based on her age and endometrial thickness. © 2004 Wiley Periodicals, Inc. J Clin Ultrasound 32:219–224, 2004; Published online in Wiley InterScience (www.interscience.wiley. com). DOI: 10.1002/jcu.20020

Objectives Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure, with an incidence of up to 10.7% of malignancy. Some women tend to develop recurrent polyps. However, no one has yet described any risk factors for the development of recurrent endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients. Methods We compared various clinical features of 64 postmenopausal breast cancer tamoxifen-treated patients with a primary endometrial polyp (Group I), with those of 27 similar patients with recurrent polyps (Group 2). Results Previous exposure to hormone replacement therapy was significantly more common and duration of tamoxifen treatment, up to the diagnosis of primary endometrial polyp, was significantly shorter in Group II patients (P = 0.0217 and P = 0.0148, respectively). Logistic regression analysis revealed that the combination of shorter tamoxifen exposure before the diagnosis of primary polyp, lower parity, lower menopausal age at the diagnosis of primary polyp, and higher years of tamoxifen treatment was found to increase significantly the risk of developing recurrent endometrial polyps. Any additional year of tamoxifen treatment may increase by fivefold the risk of developing recurrent polyps. There was no significant difference in ultrasonographic endometrial thickness measured before resection of the primary polyps in both groups and before the resection of recurrent polyps in Group II. Conclusions Previous use of HRT, shorter duration of tamoxifen exposure, and additional years of tamoxifen treatment may significantly increase the risk of developing recurrent endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients.

The objective of this study was to document and highlight aspects of ovarian cancer treatment that pertain, especially, to elderly women.Data were collected retrospectively from all epithelial ovarian cancer patients who were diagnosed in the Gynecologic Oncology Unit at Meir Hospital, Kfar-Saba, Israel, from January 1994 to December 1998.The study group comprised 143 patients (70 years n = 97,or =70 years n = 46). Both groups presented with the same distribution of stages. The elderly group had fewer primary debulking surgical interventions (54.3%) than the younger group (84.5%) (P = 0.001)). Age was not a limiting factor in achieving optimal debulking in those patients who did undergo surgery (older 53%, younger 54%). Almost 92% of the younger patients entered a first-line chemotherapy regimen compared to 65.2% of the older patients (P = 0.001). The elderly patients were more likely to receive neoadjuvant chemotherapy (43.3.3% vs 13.4%, P0.01) and hematological toxicity was significantly more common (75% vs 36.3%; P = 0.001), although no significant difference was noted between the groups in Grade 3-4 patients (or =70 years, 62.5% vs70 years, 45.5%; P = 0.2). The elderly patients were more likely to have dose reductions and treatment delays compared to the younger patients (60% vs 22.4%; P0.001, and 46.6% vs 19.1%; P = 0.004, respectively) and they had similar overall response rates (RR) and complete response (80% vs 87.6% and 60% vs 71.9%, respectively).Older women who present with the same distribution of stages as their younger counterparts are likely to be treated more conservatively than younger ovarian cancer patients. In this study, however, when surgery was performed, the optimal tumor debulking rates were similar in each group. Although high morbidity, most often hematological toxicity, occurs in elderly patients following chemotherapy, the overall RR compared favorably with that of younger patients.

Objective. Cytokeratins (CKs) are constituents of the intermediate filaments of epithelial cells which are expressed in various combinations, depending on the epithelial type and the degree of differentiation. Using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique, we recently demonstrated that cytokeratin-20 (CK-20), the most recently discovered cytokeratin, is expressed in endometrial carcinoma tumors, in blood, and in lymph nodes with micrometastases of patients treated for endometrial carcinomas. However, CK-20 expression could not be demonstrated in the endometrium of patients with benign diseases, in peripheral blood, in lymph nodes of healthy subjects, or in normal blood cells. The aim of this study was to examine whether CK-20 expression in blood can be used as a biomarker for the detection of the dissemination of malignant cells in patients treated for granulosa cell tumors (GCTs). Methods. In this study, we used RT-PCR to determine the expression of CK-20 in the following groups: (i) blood of patients ( n = 14) treated for GCTs, (ii) GCT samples ( n = 4); (iii) lymph nodes ( n = 2) of patients treated for GCTs; (iv) blood from subjects with benign sex-cord-stromal tumors ( n = 2); (v) normal ovaries of two menstruating women ( n = 4); (vi) tumor specimens of epithelial ovarian carcinomas (EOCs) ( n = 14); and (vii) blood samples ( n = 18) and lymph nodes ( n = 11) of healthy women. Results. In Group I, CK-20 was positive in the blood in 86% (12/14) of the patients. In Group II, CK-20 was positive in 100% (4/4) of the GCT samples. In Group III, CK-20 was positive in 100% (2/2) of the lymph nodes examined. In Groups IV and V, CK-20 was negative in 100% (2/2) of the blood samples and in the normal ovarian specimens (4/4) that were examined. In Group VI, CK-20 was positive in 14% (2/14) of nonmucinous EOCs. In Group VII, CK-20 was negative in 100% (18/18) of blood and in (11/11) lymph node specimens (specificity 100%). Conclusions. These results indicate that RT-PCR of CK-20, because of its high sensitivity and specificity, is a potential biomarker for detecting metastases in blood and in micrometastases in lymph nodes of patients treated for GCTs.

Placental factors, progesterone included, facilitate breast cancer cell line (BCCL) motility and thus may contribute to the advanced breast cancer found during pregnancy. Cancer and placental implantations are similar; the last is accompanied by extravillous trophoblast cell invasion and autophagy which are interlinked. We aimed to analyze the effect of first trimester human placenta on BCCL autophagy. BCCLs (MCF-7/T47D) were cultured with placental explants (60 h) or placental supernatants (24 h). Following cultures, BCCLs were sorted out for RNA/protein extraction. RNA served for microarray/qPCR (BNIP3) and protein for Western blot (HIF1α, LC3BII) analyses. Inhibitors were added to the placenta-MCF-7 coculture or placental supernatants (autophagy inhibitor-3MA, progesterone receptor (PR) inhibitor-RU486, and HIF1α inhibitor-Vitexin) in order to evaluate their effects on BCCL motility and LC3BII/HIF1α expression. LC3BII (an autophagy marker) expression was elevated in BCCLs following placental explant coculture and exposure to placental supernatants. The autophagy inhibitor (3MA) repressed the placenta-induced MCF-7/T47D migration, establishing a connection between BCCL autophagy and migration. Microarray analysis of MCF-7 following placenta-MCF-7 coculture showed that “HIF1α pathway,” a known autophagy facilitator, was significantly manipulated. Indeed, placental factors elevated HIF1α and its target BNIP3 in the BCCLs, verifying array results. Lastly, PR inhibitor reduced HIF1α expression and both PR and HIF1α inhibitors reduced MCF-7 LC3BII expression and motility, suggesting involvement of the PR-HIF1α axis in the autophagy process. Placental factors induced BCCL autophagy that is interlinked to their motility. This suggests that autophagy-related molecules may serve as targets for therapy in pregnancy-associated breast cancer.

Women diagnosed with pregnancy associated breast cancer often have advanced cancer with metastases and reduced expression of ERα compared to non-pregnant women. Nevertheless, metastases to the placenta are uncommon. Previously, we demonstrated that breast cancer cells (MCF-7/T47D) migrated from ex vivo human placental explant implantation sites. We aimed to analyze the effect of factors produced during placental implantation or as a result of the interaction between the implanted placentae to cancer cells on cancer cells migration and aggressiveness. We collected supernatants from implanted placentae and placental-breast cancer cells cocultures and analyzed their effects on cancer cells phenotype and pathways. Supernatants collected from breast cancer cells served as controls. We found that supernatants collected from implanted placentae induced modest cancer cells migration that was not accompanied by epithelial to mesenchymal transition (EMT), supported breast cancer cells survival and elevated MCF-7 cell number. The coculture supernatant induced excessive motility and EMT of the MCF-7 cells. This EMT was mediated by Smad3 and JNK/ERK activation. Both placenta and coculture supernatants reduced ERα expression in the cancer cells. Finally, we showed that MCF-7 cocultured with the human placental explants underwent continuous activation of JNK and Smad3 pathways and the EMT process, which led to their migration away from the placental implantation sites. These findings may explain the reduced ERα and elevated metastases found in breast cancer during pregnancy and highlights pathways involved in it.

AIM: To describe the computed tomography (CT) findings of primary serous papillary carcinoma of the peritoneum. MATERIAL AND METHODS: The clinical data and imaging studies of 36 women aged 37-85 years with primary papillary serous carcinoma of the peritoneum were retrospectively evaluated. Twenty-seven patients presented with general abdominal complaints; all had elevated levels of CA-125. Thirty-two women were post-menopausal, four had had bilateral salpingo-oophorectomy. RESULTS: The most common findings on pre-operative abdominal CT, performed in 30 patients, were a variable amount of ascites (n = 29), omental involvement (n = 28), irregular parietal peritoneum thickening (n = 22) and mural thickening of the sigmoid colon (n = 10). Thoracic findings included enlarged cardiophrenic nodes (n = 15) and pleural effusion (n = 11). Six patients had unilateral or bilateral adnexal masses of soft tissue density, which proved to be surface serous papillary carcinoma. CONCLUSION: Diffuse peritoneal disease on CT in patients with normal-sized ovaries or following bilateral salpingo-oophorectomy, with elevated level of serum CA-125, but without an identifiable primary tumour, should suggest the diagnosis of primary serous papillary carcinoma of the peritoneum. Associated adnexal masses or focal bowel wall thickening may be seen, representing surface involvement by this tumour.

Knowledge of the potential association of parity, breastfeeding, and infertility treatment on breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers is important and should be a crucial part of genetic counseling. The discussion of parity and clinical management of infertility in these women is complex, and patient preferences should be considered. Ideally, these preferences should be informed by accurate information on the risks and benefits of the interventions considered. However, this important subject has been investigated in a relatively small number of studies, thus, the existing data remain somewhat limited, and the estimated risk of cancer in BRCA mutation carriers is imprecise.

To evaluate possible predicting factors for endometrial cancer in postmenopausal breast cancer patients with tamoxifen treatment, we compared various clinical features between 12 postmenopausal breast cancer tamoxifen-treated patients with endometrial cancer and a control group of 261 otherwise similar patients without this endometrial pathology. These comparisons were based on a long-term prospective follow-up. Several clinical factors such as longer duration of breast disease, older patient age, lower frequency of chemotherapy administration, and higher frequency of postmenopausal bleeding were found among the tamoxifen-treated patients with endometrial cancers, and were significantly different when compared to the control group. Only eight (66.7%) had postmenopausal bleeding, and a preoperative diagnosis of endometrial cancer was made in only six (50.0%). When considering postmenopausal bleeding as a marker for endometrial cancer in the study patients, sensitivity was 67% and specificity was 98%.

The aim of this study was to assess the clinical activity and toxicity of liposome-encapsulated doxorubicin citrate (Myocet) in a retrospective multicenter cohort of epithelial ovarian, primary peritoneal, and tubal cancer patients. Records of patients with recurrent epithelial ovarian, primary peritoneal, and tubal cancer treated with liposome-encapsulated doxorubicin citrate (60 mg/m on day 1 of a 21-day cycle) after failure of more than one previous regimen were reviewed. Fifty-three patients were evaluated for efficacy and toxicity. The median age of the patients was 59 (range 39-73). The median follow-up was 6 months (range 1-17). One patient (1.9%) showed a complete response and 13 patients (24.5%) showed a partial response, yielding an overall response rate of 26.4% (14/53 patients). Clinical benefit was achieved in 36 patients (67.9%). The median progression-free survival (PFS) for the entire study population was 4.0 months (range 1.0-14.8). The median PFS for platinum-sensitive and platinum-resistant patients was 4.0 months (ranges 1.0-14.8 and 1.0-9.4, respectively; P=0.652). The median overall survival from the start of liposome-encapsulated doxorubicin citrate was 10.0 months. Multivariate survival analysis showed no association between the liposome-encapsulated doxorubicin citrate line of treatment or platinum sensitivity to PFS in age and BRCA status-adjusted models. Only 11.3% of patients experienced grade 3-4 hematologic toxicities, 80% grade-2 alopecia, and 50% grade-1-2 fatigue. No other grade-4 toxicities, no significant cardiac events, or hand and foot syndromes were reported. Liposome-encapsulated doxorubicin citrate was well tolerated, with a good response and high clinical benefit rate. Further evaluation in a larger prospective cohort is warranted.