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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.

Objective BRCA mutations are the most frequent mutations causing homologous recombination defects in epithelial ovarian cancers (EOC). Germline mutation carriers are heterozygous for the mutation and harbor one defective allele in all cells. This has been hypothesized to cause increased susceptibility to DNA damage in healthy cells as well as neoplastic ones. Our objective was to assess chemotherapy-associated toxicities in patients with epithelial ovarian cancer with and without a germline BRCA mutation. Mateials and Methods A retrospective cohort study of patients with EOC receiving first-line platinum-based chemotherapy at a single center between 2006 and 2016. Indices of chemotoxicity, including blood counts, transfusion requirements, granulocyte colony-stimulating factor (gCSF) prescriptions, episodes of febrile neutropenia, and treatment delays were compared for BRCA mutation carriers and noncarriers. Results A total of 90 women met the inclusion criteria, including 31 BRCA mutation carriers (34%) and 59 noncarriers (66%). Mean hemoglobin, neutrophil count, and platelet counts during treatment were comparable for the two patient groups. There was a trend toward a higher frequency of hematological events in BRCA mutation carriers (neutropenia Conclusion BRCA mutation carriers and noncarriers receiving first-line platinum-based chemotherapy for EOC have similar hematologic toxicity profiles. Clinicians treating these patients can be reassured that chemotherapy dosing or schedule do not require adjustment in patients carrying BRCA mutations. Implications for Practice Patients with ovarian cancer carrying BRCA mutations are more likely to have serous tumors and present with higher CA125 levels. Germline BRCA mutation status is not associated with increased frequency of adverse hematologic events among patients with ovarian cancer being treated with first-line platinum-based chemotherapy. Germline BRCA mutations are also not associated with more treatment delays or a lower number of courses completed in this patient population. These findings should reassure practitioners engaged in care for patients with ovarian cancer that BRCA mutation status most likely will not affect chemotherapy dosing or schedule.

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.

Nuclear translocation of transmembrane proteins was reported in high-grade serous ovarian cancer (HGSOC), a highly aggressive gynecological malignancy. Although the membrane receptor αvβ3 integrin is amply expressed in HGSOC and involved in disease progression, its nuclear localization was never demonstrated. Nuclear αvβ3 was explored in HGSOC cells (OVCAR3, KURAMOCHI, and JHOS4), nuclear localization signal (NLS) modified β3 OVCAR3, Chinese hamster ovaries (CHO-K1) and human embryonic kidney (HEK293) before/after transfections with β3/β1 integrins. We used the ImageStream technology, Western blots (WB), co immunoprecipitations (Co-IP), confocal immunofluorescence (IF) microscopy, flow cytometry for cell counts and cell cycle, wound healing assays and proteomics analyses. Fresh/archived tumor tissues were collected from nine HGSOC patients and normal ovarian and fallopian tube (FT) tissues from eight nononcological patients and assessed for nuclear αvβ3 by WB, confocal IF microscopy and immunohistochemistry (IHC). We identified nuclear αvβ3 in HGSOC cells and tissues, but not in normal ovaries and FTs. The nuclear integrin was Tyr 759 phosphorylated and functionally active. Nuclear αvβ3 enriched OVCAR3 cells demonstrated induced proliferation and oncogenic signaling, intact colony formation ability and inhibited migration. Proteomics analyses revealed a network of nuclear αvβ3-bound proteins, many of which with key cancer-relevant activities. Identification of atypical nuclear localization of the αvβ3 integrin in HGSOC challenges the prevalent conception that the setting in which this receptor exerts its pleiotropic actions is exclusively at the cell membrane. This discovery proposes αvβ3 moonlighting functions and may improve our understanding of the molecular basis of ovarian cancer pathogenesis.

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.

OBJECTIVE: To empower residents-in-training through personal mentorship from a senior physician who dedicates time and guidance to their personal development and provides professional and emotional support. METHODS: A structured model of personal mentoring for residents was designed and implemented in the Department of Obstetrics & Gynecology. The process was assessed by a special-purpose survey constructed and reviewed by established medical mentors. The survey examined residents’ attitudes towards personal aspects associated with their residency. The questionnaires were filled out anonymously before launching and 1 and 3 years after initiating the personal mentoring process. RESULTS: The residents’ reports showed a distinct trend of increased positive attitudes towards the personal mentoring throughout the process. The residents reported on an improvement in the mentors’ availability to address personal aspects within the mentoring relationship (empathy, emotional support in deliberations, career guidance, etc.). The general satisfaction with the residency program improved as well. CONCLUSIONS: Mentoring is a significant element in a comprehensive, multi-dimensional process. Integrating personal mentoring into a residency program, with the focus on interpersonal relational characteristics as empathy, availability, open communication, and guidance, led to improvements in residents’ professional development and skills. They also received optimal support and guidance in their professional careers and personal deliberations.

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.

Objective To assess diagnostic accuracy, related findings, and outcomes of fetuses with clubfoot. Methods Sonographic characteristics, pregnancy work-up, and postnatal outcomes were evaluated in 109 fetuses with clubfoot. Results Among 40 320 prenatal ultrasound anomaly scans, clubfoot was diagnosed in 150 (0.37%). Analysis included 108 pregnancies (72%) with 109 fetuses. Bilateral clubfoot was diagnosed in 51/109 (46.7%) fetuses and unilateral in 58/109 (53.2%). Clubfoot was diagnosed as an isolated anomaly in 76/109 (69.7%) and complex in 33/109 (30.2%). Amniocentesis or chorionic villus sampling in 48/109 (44%) yielded 6 (12.5%) with abnormalities (5.5% of the entire cohort). Diagnosis was confirmed in 65/91 (71.4%) liveborn infants. In singletons, 7/63 (11.1%) cases considered isolated on ultrasound had additional anomalies postpartum and 8/14 (57.1%) complex cases were verified after birth. Sonographic diagnosis of clubfoot was verified postpartum in more singletons than twins (p = 0.05). Bilateral clubfoot was verified postpartum more often than unilateral [29/33 (87.9%) vs. 29/44 (65.9%), respectively; p = 0.03]. Bilateral clubfoot resulted in additional prenatal testing without increased likelihood of finding additional anomalies and was associated with more surgical interventions postnatally. Conclusions Prenatal ultrasound diagnosis of clubfoot is more accurate in singletons with bilateral findings. Bilateral findings do not increase the likelihood of additional anomalies. Karyotyping should be considered even with isolated clubfoot. © 2017 John Wiley & Sons, Ltd.

Introduction/Background Enlarged supradiaphragmatic lymph nodes (ESDLN) in patients with advanced epithelial ovarian cancer (EOC) are associated with poor prognosis. This study assessed whether the prognosis is also affected by the treatment approach and surgical outcomes among these patients. Methodology A retrospective cohort study comparing patients with Stage 3 EOC and ESDLN to those without SDLN, who underwent surgery at a single center from 2006 to 2016. CT scans were retrospectively reviewed by the same radiologist for disease extent and ESDLN. Extent of disease at diagnosis (defined by carcinomatosis score), results of surgery, and progression-free survival (PFS) were recorded. Results Based on imaging, among 71 women who met the inclusion criteria, 47 (66%) had ESDLN and 24 (34%) did not. There was no significant difference between groups in baseline characteristics except for elevated CA125 at diagnosis in the ESDLN group (1,797 U/ml vs. 708 U/ml, p=0.04). There was a trend toward longer PFS in the negative SDLN group (19.6 months vs. 12.6 months, p=0.09). Although not significant, among patients who underwent complete cytoreduction, those without ESDLN had longer PFS compared to patients with ESDLN (21.9 vs. 13.6 months, p=0.29). Similarly, a trend toward better prognosis was observed in the negative SDLN group when comparing treatment modalities (21.5 vs. 15.1 months for primary surgery, and 16.5 vs. 9.7 months after neoadjuvant chemotherapy and interval debulking, p=0.16). Conclusion ESDLN in patients with advanced EOC are associated with poor prognosis. In seems that even when optimal intra-abdominal cytoreduction is achieved, whether at primary surgery or after neoadjuvant chemotherapy, PFS is compromised in patients with ESDLN. Disclosure Nothing to disclose.

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. 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 NH4 OH). After culturing the cells, we analyzed cancer cell phenotype (death, count, aggregation, MMP) and signaling (microarray analysis and pathway validation). We found that the BCCL did not attach to previous placental implantation sites and instead, similarly to anoikis-resistant cells, migrated away, displayed increased MMP levels/activity, and formed aggregates in distant areas. T47D were less affected than the MCF-7 cells, since MCF-7 also showed modest increases in cell death, EMT, and increased proliferation. Microarray analysis of the MCF-7 highlighted changes in the integrin, estrogen, EGFR, and TGFβ pathways. Indeed, placental ECM reduced ERα, induced Smad3/JNK phosphorylation and increased integrin-α5 expression (RGD-dependent integrin) in the BCCL. Addition of RGD or TGFβR/JNK inhibitors reversed the phenotypic changes. This study helps explain the absence of metastases to the placenta and why advanced cancer is found in pregnancy, and provides possible therapeutic targets for anoikis-resistant cells. © 2016 Wiley Periodicals, Inc.

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.

Background and Aims: Management of bulky cervical tumours is controversial. We describe the addition of high dose rate brachytherapy with concomitant chemotherapy to an attenuated protocol of radiation followed by simple hysterectomy in the management of bulky cervical tumours. Methods: Between January, 2003 and December, 2006, 23 patients diagnosed with bulky cervical tumours underwent a fixed chemo-radiation protocol followed by simple hysterectomy. Fractionated external beam pelvic radiation (4500 cGy) followed by two high-dose rate applications of brachytherapy (700 cGy – prescription dose to point A) was given with weekly concomitant cisplatin (35 mg/m2). Patients then underwent simple hysterectomy. Clinical information was prospectively collected and patient charts were then further reviewed. Results: Twenty patients had stage IB2 and three bulky IIA. Median tumour size was 5 cm. Sixteen patients (70%) achieved a clinical complete and seven (30%) a clinical partial response. All patients had a total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH BSO). On final pathology, 12 patients (52%) had a pathological complete response, whereas 11 patients (48%) had residual carcinoma in the cervix. Surgical margins were not involved. With a median follow-up time of 20 months (range 10–50 months), four patients (17.4%), all from the pathological partial response group, have suffered a pelvic recurrence, within 6 months from therapy; nineteen patients (82.6%) remain free of disease. Conclusions: This attenuated protocol of chemo-radiation using HDR brachytherapy followed by simple hysterectomy is a viable option in the treatment of bulky cervical carcinomas. The rate of residual cervical disease after chemo-radiation is substantial, but simple hysterectomy achieved negative surgical margins in all cases.

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.

Zetiq has introduced a histochemical stain that claims to tinctorially identify cancer and neoplastic cells. Because of the potential importance of such a capability, we undertook to investigate Zetiq's CellDetect® staining technology as applied to cultured cell lines as well as an initial sample of clinical cases. This goal was pursued by investigating four types of comparisons: 1) cancer cell lines before and after differentiation; 2) cervical squamous-cell carcinoma (SCC) biopsies to non-neoplastic squamous epithelium; 3) SCCs to neoplastic, nonmalignant squamous epithelium; and 4) neo-plastic squamous cells to non-neoplastic squamous cells in cytological preparations. The clinical material was also stained with hematoxylin and eosin (biopsies) or Pap (cytologies) for diagnostic purposes. We found that all CellDetect®-stained cells exhibited one of the two tinctorial outcomes. Cell lines with malignant phenotype uniformly had red/purple cytoplasm, whereas the differentiated phenotype changed th...