Accumulating epidemiological evidence shows that obesity is associated with an increased risk of several types of adult cancers, including endometrial cancer. Chronic hyperinsulinemia, a typical ...hallmark of diabetes, is one of the leading factors responsible for the obesity-cancer connection. Numerous cellular and circulating factors are involved in the biochemical chain of events leading from hyperinsulinemia and insulin resistance to increased cancer risk and, eventually, tumor development. Metformin is an oral anti-diabetic drug of the biguanide family used for treatment of type 2 diabetes. Recently, metformin was shown to exhibit anti-proliferative effects in ovarian and Type I endometrial cancer, although the mechanisms responsible for this non-classical metformin action remain unclear. The insulin-like growth factors (IGFs) play a prominent role in cancer biology and their mechanisms of action are tightly interconnected with the insulin signaling pathways. Given the cross-talk between the insulin and IGF signaling pathways, the aim of this study was to examine the hypothesis that the anti-proliferative actions of metformin in uterine serous carcinoma (USC) are potentially mediated via suppression of the IGF-I receptor (IGF-IR) pathway. Our results show that metformin interacts with the IGF pathway, and induces apoptosis and inhibition of proliferation and migration of USC cell lines with both wild type and mutant p53. Taken together, our results suggest that metformin therapy could be a novel and attractive therapeutic approach for human USC, a highly aggressive variant of endometrial cancer.
Postcoital bleeding (PCB) is a common gynecological symptom that may cause concern among both patients and physicians. Current literature is inconclusive regarding management recommendations.
To ...identify risk-factors for dysplasia/cancer among patients presenting post-coital bleeding (PCB).
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.
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).
Study results indicate that PCB may require colposcopy, especially for nulliparous women with an abnormal PAP smear.
A correlation between components of the insulin-like growth factor (IGF) system and endometrial cancer risk has been shown in recent studies. The antitumor action of vorinostat, a histone deacetylase ...inhibitor, involves changes in the expression of specific genes via acetylation of histones and transcription factors. The aim of this study was to establish whether vorinostat can modify the expression of specific genes related to the IGF-I receptor (IGF-IR) signaling pathway and revert the transformed phenotype. Human endometrioid (Type I, Ishikawa) and uterine serous papillary (Type II, USPC-2) endometrial cancer cell lines were treated with vorinostat in the presence or absence of IGF-I. Vorinostat increased IGF-IR phosphorylation, produced acetylation of histone H3, up-regulated pTEN and p21 expression, and reduced p53 and cyclin D1 levels in Ishikawa cells. Vorinostat up-regulated IGF-IR and p21 expression, produced acetylation of histone H3, and down-regulated the expression of total AKT, pTEN and cyclin D1 in USPC-2 cells. Of interest, IGF-IR activation was associated with a major elevation in IGF-IR promoter activity. In addition, vorinostat treatment induced apoptosis in both cell lines and abolished the anti-apoptotic activity of IGF-I both in the absence or presence of a humanized monoclonal IGF-IR antibody, MK-0646. Finally, vorinostat treatment led to a significant decrease in proliferation and colony forming capability in both cell lines. In summary, our studies demonstrate that vorinostat exhibits a potent apoptotic and anti-proliferative effect in both Type I and II endometrial cancer cells, thus suggesting that endometrial cancer may be therapeutically targeted by vorinostat.
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 (6.2 ± 3.4 vs. 4.2 ± 3, p = .009). The COVID-19 group had significantly lower cord cortisol levels (7.3
vs. 13.6 mcg/dl, p
= .001). No differences were found regarding salivary cortisol level assessments at active, full dilation and 2-min post-delivery (p
= .584, p
= .254, p
= .829, respectively). No differences were found regarding pH < 7.1 (p
= .487), 1- and 5-min Apgar scores < 7 (p
= .179) and neonatal weight (p
= .958).
Women 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.
•Detection of uncommon sentinel lymph nodes (SLN) was related to lower BMI and the use of Tc99&blue dye or ICG.•Detection of SLN in the para-aortic, parametrium and pre-sacral regions was related to ...recent surgical year.•Detection of SLN in the para-aortic, parametrium and pre-sacral regions was also related to the presence of positive nodes.•It seems that surgical parameters as opposed to tumor characteristics are the main predictors for uncommon SLN.
Sentinel node mapping is widely used in the treatment of gynecologic cancers. The current study aimed to identify predictors of uncommon sentinel lymph node (SLN) locations.
The current study included women who were operated for endometrial or cervical cancer with attempted sentinel lymph node mapping during surgical staging. Data were collected from electronic charts. The pelvis and the external ilia and obturator basins were common node locations. Para-aortic, pre-sacral, common iliac, internal iliac, and parametrial nodes were considered uncommon locations. We conducted analyses stratified according to common, uncommon, and very uncommon (para-aortic, pre-sacral, parametrial) node location sites.
A total of 304 women were enrolled in the current study; 15.8% had SLN in uncommon locations and 4.3% had very uncommon node locations. Body mass index (BMI) was a negative predictor for uncommon SLN locations (OR 0.88, p = 0.03). The use of either indocyanine green (ICG) or Tc99 & blue dye was an independent predictor for uncommon SLN locations (OR 8.24, p = 0.006). More recent surgeries and the presence of positive nodes were independent predictors for very uncommon node locations (OR 2.13, p = 0.011, and OR 9.3, p = 0.002, respectively).
BMI, tracer type, surgical year, and positive nodes were independent predictors for uncommon SLN locations. These findings suggest that surgical effort, technique and experience may result in better identification of uncommon SLN locations.
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.
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.
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.
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.
Purpose
To describe patterns of physiological and psychological stress during induced labor and their correlation to obstetrical and neonatal outcomes.
Methods
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.
Results
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.
Conclusions
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.
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.
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.
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.
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.
•76% of patients having surgery for stage IIA1 cervical cancer receive adjuvant treatment.•Rates of close and involved surgical margins are high in stage IIA1 cervical cancer.•Tumor stage, depth of invasion, LVSI and lymph node spread are independent predictors of radiation.
Abstract The role of the insulin-like growth factors (IGF) in endometrial cancer has been well established. The IGF-I receptor (IGF-IR), which mediates the biological actions of IGF-I, is usually ...overexpressed in endometrial tumours. Uterine serous carcinoma (USC) constitutes a defined histological category among endometrial cancers. Mutation of the p53 gene appears early in the course of the disease and is considered a key event in the initiation of USC. The aim of the present study was to evaluate the potential interactions between p53 and the IGF-IR in USC. In addition, we investigated the role of p53 as a biomarker in IGF-IR targeted therapies. Immunohistochemical analysis in a collection of 35 USC specimens revealed that IGF-IR is highly expressed in primary and metastatic USC. Likewise, p53 was expressed in 85.7% of primary tumours and 100% of metastases. A significant negative correlation between p53 expression and survival was noticed. In addition, using USC-derived cell lines we provide evidence that p53 regulates IGF-IR gene expression via a mechanism that involves repression of the IGF-IR promoter. We show that the mechanism of action of p53 involves interaction with zinc finger protein Sp1, a potent transactivator of the IGF-IR gene. Finally, we demonstrate that USC tumours overexpressing p53 are more likely to benefit from anti-IGF-IR therapies. In summary, we provide evidence that p53 regulates IGF-IR gene expression in USC cells via a mechanism that involves repression of the IGF-IR promoter. The interplay between the p53 and IGF-I signalling pathways is of major basic and translational relevance.
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.
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