Adipose tissue-derived FABP4 mediates glucagon-stimulated hepatic glucose production in gestational diabetes.

AIMS: One of the most common complications of pregnancy is gestational diabetes mellitus (GDM), which may result in significant health threats of the mother, fetus and the newborn. Fatty acid-binding protein 4 (FABP4) is an adipokine that regulates glucose homeostasis by promoting glucose production and liver insulin resistance in mouse models. FABP4 levels are increased in GDM and correlates with maternal indices of insulin resistance, with a rapid decline post-partum. We therefore aimed to determine the tissue origin of elevated circulating FABP4 levels in GDM and to assess its potential contribution in promoting glucagon-induced hepatic glucose production. MATERIALS AND METHODS: FABP4 protein and gene expression was determined in biopsies from placenta, subcutaneous (sWAT) and visceral (vWAT) white adipose tissues from GDM and normoglycaemic pregnant women. FABP4 differential contribution in glucagon-stimulated hepatic glucose production was tested in conditioned media before and after its immune clearance. RESULTS: We showed that FABP4 is expressed in placenta, sWAT and vWAT of pregnant women at term, with a significant increase in its secretion from vWAT of women with GDM compared with normoglycaemic pregnant women. Neutralizing FABP4 from both normoglycaemic pregnant women and GDM vWAT secretome, resulted in a decrease in glucagon-stimulated hepatic glucose production. CONCLUSIONS: This study provides new insights into the role of adipose tissue-derived FABP4 in GDM, highlighting this adipokine, as a potential co-activator of glucagon-stimulated hepatic glucose production during pregnancy.

Laparoscopy with or without robotic assistance does not negatively impact long-term oncologic outcomes in patients with uterine serous carcinoma.

OBJECTIVES: We sought to compare outcomes between minimally invasive surgery (MIS) and laparotomy in patients with clinical stage I uterine serous carcinoma (USC). METHODS: Patients who underwent surgery for newly diagnosed USC between 11/1/1993 and 12/31/2017 were retrospectively identified and assigned to either the MIS cohort or the laparotomy cohort. Patients with conversion to laparotomy were analyzed with the MIS cohort. Chi-square and Mann-Whitney tests were used to compare categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival and compared using the log-rank test. RESULTS: In total, 391 patients met inclusion criteria; 242 underwent MIS (35% non-robotic and 65% robotic-assisted laparoscopies) and 149 underwent laparotomy. Age, BMI, stage, and washings status did not differ between cohorts. Patients who underwent MIS were less likely to have lymphovascular space invasion (LVSI; 35.1% vs 48.3%), had fewer nodes removed (median, 9 vs 15), and lower rates of paraaortic nodal dissection (44.6% vs 65.1%). Rates of adjuvant therapy did not differ between cohorts. Median follow-up times were 63.0 months (MIS cohort) vs 71.0 months (laparotomy cohort; P = .04). Five-year PFS rates were 58.7% (MIS) vs 59.8% (laparotomy; P = .1). Five-year OS rates were 65.2% (MIS) compared to 63.5% (laparotomy; P = .2). On multivariable analysis, higher stage, deep myometrial invasion, and positive washings were associated with decreased PFS. Age ≥ 65 years, higher stage, LVSI, and positive washings were associated with shorter OS. CONCLUSIONS: MIS does not compromise outcomes in patients with newly diagnosed USC and should be offered to these patients to minimize surgical morbidity.

Ethnic disparity in cervical cancer stage at diagnosis: A retrospective study in an Israeli referral-center.

OBJECTIVE: To compare stage and survival of cervical cancer between Jewish and Arab women in a tertiary medical center in Israel. METHODS: Retrospective study of consecutive women diagnosed with cervical cancer in a single institution between 2010 and 2021. We compared Jewish and Arab patients using univariate, multivariable, and survival curves analysis. RESULTS: Overall, 207 Jewish women and 45 Arab women were included with a median follow up of 20 months (interquartile range 7-46 months). The groups did not differ in median body mass index, mean age at diagnosis, or menopausal status. Arab women had higher parity. Arab women were at a higher risk to be diagnosed with advanced stage disease (≥2b) (84.4% vs. 57% Arab and Jewish women, respectively, P < 0.001). In a multivariable regression analysis, Arab descent was found to be the only independent factor associated with advanced stage disease (odds ratio 3.95, 95% confidence interval 1.54-10.10). Overall survival and stage-specific survival were not different between the ethnic groups. CONCLUSIONS: Advanced stage at diagnosis was more prevalent in Arab women compared with Jewish women with cervical cancer, whereas stage-specific survival was similar. Further studies addressing possible contributing factors to inequality should be undertaken to find corrective measures.

Proteomic signature for detection of high-grade ovarian cancer in germline BRCA mutation carriers.

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

Sentinel lymph node mapping in endometrial cancer: A comparison of main national and international guidelines.

OBJECTIVES: To compare national and international guidelines regarding sentinel lymph node (SLN) mapping in endometrial cancer. METHODS: A descriptive comparative study of the National Comprehensive Cancer Network (NCCN), the Society of Gynecologic Oncology (SGO), the European Society of Gynecological Oncology (ESGO), the British Gynecological Cancer Society (BGCS), and the Japan Society of Gynecologic Oncology (JSGO) guidelines. RESULTS: There is a broad consensus that SLN mapping is an appropriate alternative to pelvic lymphadenectomy for uterine-confined endometrioid endometrial cancer (five of five guidelines). It is broadly accepted that a full lymphadenectomy should be performed in case of failed SLN mapping (four of five guidelines), and that mapping with the fluorescent dye indocyanine green is superior to other methods (four of five guidelines). It is agreed that the cervix is the preferable site for dye injection (four of five guidelines), and pathology ultrastaging is advocated by most guidelines (three of five guidelines). Regarding high-risk patients (i.e., high-grade histology and non-endometroid carcinomas), some guidelines accept (three of five), but others currently do not advocate (one of five guidelines), SLN mapping as a sole method for lymph node evaluation. There is no consensus regarding para-aortic lymph node evaluation in pelvic SLN-positive patients. CONCLUSION: Guidelines for SLN mapping are comparable with regards to surgical technique, ultrastaging, and management in case of failed mapping. Nevertheless, some variations exist regarding the management of high-grade histology and positive pelvic lymph nodes.

Ovarian cancer risk management in BRCA-mutation carriers: A comparison of six international and national guidelines.

OBJECTIVE: Germline mutations in the BRCA gene account for most hereditary ovarian and breast cancer. Management of healthy carriers aims to prevent and allow early detection of breast and ovarian cancer. This study compares six different hereditary ovarian cancer management guidelines, highlighting areas of controversy between different societies. We aim to compare international and national guidelines regarding BRCA carriers' management. STUDY DESIGN: A comparative study. We retrieved, reviewed, and compared the most recent guidelines of BRCA mutation carriers from the specializing societies NCCN (National Comprehensive National network) and ESMO (European society of medical oncology), and national societies of the United States (American College of Obstetricians and Gynecologists), England (the Royal College of Obstetricians and Gynecologists), Canada (the Society of Obstetricians and Gynaecologists of Canada) and Spain (Sociedad Española de Oncología Médica). RESULTS: There is a broad consensus regarding the limited role of screening for early ovarian cancer detection (4 out of 6) (4/6) and regarding the recommendation for implementation of Risk-reducing salpingo-oophorectomy (RRSO) (6/6), some variations exist for age at RRSO. It is widely accepted that risk reducing salpingectomy should be performed only as part of research (5/6), and that the addition of risk-reducing hysterectomy should be individualized (3/6). Not all guidelines address fertility issues, and controversy exists regarding hormone replacement therapy (HRT) recommendations in unaffected young BRCA-mutation carriers following RRSO. CONCLUSION: BRCA carrier's management guidelines consist of well-agreed topics such as the ineffective screening for early detection of ovarian cancer and the recommendation of RRSO. HRT remains controversial. Conforming unified recommendations is needed for providing evidence-based recommendations.

The MEMORY Study: MulticentEr study of Minimally invasive surgery versus Open Radical hYsterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy. METHODS: This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used. RESULTS: We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5). CONCLUSION: This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.

Radical Hysterectomy for Cervical Cancer: the Right Surgical Approach.

OPINION STATEMENT: Radical hysterectomy with pelvic lymph node assessment is the standard initial therapy for early-stage cervical cancer. Radical hysterectomy via laparotomy (an "open" approach) was first described more than 100 years ago and has been the standard for decades. Minimally invasive surgery (MIS) has been increasingly adopted by many surgeons due to its reported perioperative benefits. MIS was deemed safe for radical hysterectomy for many years based on multiple retrospective publications. Recently, the Laparoscopic Approach to Cervical Cancer (LACC) trial reported that patients randomized to MIS had inferior oncologic outcomes. The results of the LACC trial and subsequent retrospective studies led multiple professional societies to state that open radical hysterectomy should remain the gold standard surgical approach. We acknowledge that the open approach for radical hysterectomy is an appropriate option for all cervical cancer patients eligible for surgical treatment. However, considering the limitations of the LACC trial and the available data from other retrospective studies, we feel the MIS approach should not be simply abandoned. There may still be a role for MIS in cervical cancer surgery for properly and carefully selected cases and with detailed counseling; surgeons should analyze their own outcomes closely in order to perform such counseling. Modification of surgical technique and maintaining proper oncologic surgical principles are key for MIS to remain a viable option. Tumor manipulation and contamination should be avoided. Transcervical uterine manipulators should not be used. Cervical and tumor containment prior to colpotomy, as is performed during an open approach, is required. This will all require validation in future trials. We await the results of ongoing randomized trials to further inform us. A one-size-fits-all approach may be short-sighted; we may need to decide treatment strategy based on the notion of the right surgical approach for the right patient by the right surgeon.

Comparative analysis of ultrasound and MRI in the diagnosis of placenta accreta spectrum.

OBJECTIVES: Placenta accreta spectrum constitutes one of the most complicated challenges in modern obstetrics. Given the conflicting data regarding the added value of MRI in the diagnosis of invasive placentation, we aim to assess individual and combined ability of multiple sonographic and MRI signs to diagnose placenta accreta spectrum in suspected cases. METHODS: We assessed 28 cases of suspected placenta accreta spectrum in the third trimester. All cases underwent ultrasound assessment as well as MRI scan. Diagnosis was confirmed during surgery. The value of sonographic and MRI signs in the detection of placenta accreta spectrum was assessed. RESULTS: A total of 23 cases were diagnosed with placenta accreta spectrum during cesarean delivery. Overall, ultrasound was found to be more sensitive and specific compared to MRI (sensitivity of 0.96 and specificity of 0.6 in ultrasound vs. sensitivity of 0.83 and specificity of 0.4 in MRI). However, the use of a post-hoc structured model improved MRI performance to a similar level of ultrasound (sensitivity of 0.96 and specificity of 0.6). CONCLUSIONS: Ultrasound is superior to MRI in the detection of placenta accreta spectrum. However, MRI performance can be greatly improved by the use of a structured scoring system.

Minimally invasive surgery versus laparotomy for radical hysterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: To compare oncologic and perioperative outcomes in patients who underwent minimally invasive surgery (MIS) compared to laparotomy for newly diagnosed early-stage cervical carcinoma. METHODS: We retrospectively identified patients who underwent radical hysterectomy for stage IA1 with lymphovascular invasion (LVI), IA2, or IB1 cervical carcinoma at our institution from 1/2007-12/2017. Clinicopathologic characteristics and surgical and oncologic survival outcomes were compared using appropriate statistical testing. Multivariable Cox regression analysis was used to control for potential confounders. RESULTS: We identified 196 evaluable cases-117 MIS (106 robotic [90.6%]) and 79 laparotomy cases. Cohorts had similar age, BMI, substage, histologic subtype, clinical and pathologic tumor size, positive margins, and presence of LVI. The MIS group had more cases with no residual tumor in the hysterectomy (24.8% vs. 10.1%, P = 0.01). The laparotomy group had more cases with positive nodes (29.1% vs. 17.1%, P = 0.046) and more patients who received adjuvant therapy (53.2% vs. 33.3%, P = 0.006). Median follow-up was ~4 years. Five-year disease-free survival (DFS) rates were 87.0% in the MIS group and 86.6% in the laparotomy group (P = 0.92); 5-year disease-specific survival (DSS) rates were 96.5% and 93.9%, respectively (P = 0.93); and 5-year overall survival (OS) rates were 96.5% and 87.4%, respectively (P = 0.15). MIS was not associated with DFS, DSS, or OS on multivariable regression analysis. The rate of postoperative complications was significantly lower in the MIS cohort (11.1% vs. 20.3%; P = 0.04). CONCLUSIONS: MIS radical hysterectomy for cervical carcinoma did not confer worse oncologic outcomes in our single-center and concurrent series of patients with early-stage cervical carcinoma.

Microvesicle Proteomic Profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection.

High-grade ovarian cancer (HGOC) is the leading cause of mortality from gynecological malignancies, because of diagnosis at a metastatic stage. Current screening options fail to improve mortality because of the absence of early-stage-specific biomarkers. We postulated that a liquid biopsy, such as utero-tubal lavage (UtL), may identify localized lesions better than systemic approaches of serum/plasma analysis. Further, while mutation-based assays are challenged by the rarity of tumor DNA within nonmutated DNA, analyzing the proteomic profile, is expected to enable earlier detection, as it reveals perturbations in both the tumor as well as in its microenvironment. To attain deep proteomic coverage and overcome the high dynamic range of this body fluid, we applied our method for microvesicle proteomics to the UtL samples. Liquid biopsies from HGOC patients (n = 49) and controls (n = 127) were divided into a discovery and validation sets. Data-dependent analysis of the samples on the Q-Exactive mass spectrometer provided depth of 8578 UtL proteins in total, and on average ∼3000 proteins per sample. We used support vector machine algorithms for sample classification, and crossed three feature-selection algorithms, to construct and validate a 9-protein classifier with 70% sensitivity and 76.2% specificity. The signature correctly identified all Stage I lesions. These results demonstrate the potential power of microvesicle-based proteomic biomarkers for early cancer diagnosis.

Quantitative assessment of physical activity in pregnant women with sonographic short cervix and the risk for preterm delivery: A prospective pilot study.

OBJECTIVE: Bed rest or activity restriction is a common obstetrical practice, despite a paucity of data to support its efficacy. The aim of this study was to determine whether physical activity, as assessed by a smart band activity tracker, is associated with preterm birth in pregnant women at high risk for preterm delivery. METHODS: This was a pilot prospective cohort study including pregnant women at high risk for preterm delivery between 24 and 32 weeks-of-gestation. Physical activity level was assessed by smart band activity. Patients with sonographic short cervical length (≤ 20 mm) were asked to wear the smart band activity tracker continuously for at least one week, including one weekend. Both physicians and patients were blinded to the data stored in the smart band activity tracker. No specific recommendations were given to participants as to the level or intensity of physical activity. The primary outcome was the rate of preterm birth (< 37 weeks-of-gestation). Secondary outcomes included the rate of delivery before 34 weeks of gestation and neonatal outcome. Parametric and nonparametric statistics were used for analysis. RESULTS: Study population included 49 pregnant women: 37 women (75.7%) delivered preterm and 12 (24.5%) delivered at or after 37 weeks-of-gestation. The median steps per day was significantly lower in patients who delivered preterm (3576, IQR: 2478-4775 vs. 4554, IQR: 3632-6337, p = 0.02). Regression analysis revealed that the median number of steps per day was independently inversely associated with preterm birth, after adjustment for maternal age, body mass index, gestational age at recruitment, cervical length, cervical dilatation and plurality. CONCLUSION: This pilot study represents the first quantitative assessment of the association between physical activity and preterm birth. The results of this pilot study do not support the efficacy of decreased physical activity in the prevention of preterm birth in patients with sonographic short cervical length.

Omentin, an adipokine with insulin-sensitizing properties, is negatively associated with insulin resistance in normal gestation.

OBJECTIVE: Omentin, a newly identified adipokine, enhances insulin mediated glucose uptake in human adipocytes, thus, inducing systemic insulin-sensitizing effect. The aims of this study were to determine whether circulating maternal omentin levels are associated with insulin resistance indices and to assess which compartment, maternal, fetal, or placental, is the source of omentin in maternal circulation. METHODS: Fasting serum glucose, insulin, and omentin were determined in 25 healthy pregnant women at the third trimester, before and 3 days after elective cesarean section. Cord blood omentin was measured in the 25 term neonates. Homeostasis model assessment (HOMA) was used to evaluate insulin sensitivity before and after delivery. RESULTS: Antepartum maternal omentin levels were negatively correlated with insulin levels (r=-0.41, P=0.04) and positively correlated with insulin sensitivity (HOMA%S; r=0.4, P=0.04). Postpartum omentin levels were negatively correlated with maternal body mass index (r=-0.44, P=0.02). Median maternal omentin levels was comparable before and after delivery (57.2, inter-quartile range: 38.2-76.2 ng/mL vs. 53.4, 39.8-69.4 ng/mL, respectively, P=0.25) and highly correlated (r=0.83, P<0.001). Antepartum maternal and neonatal omentin levels did not differ significantly (fetal: 62.2, 44.3-74.2 ng/mL, P=0.77) and did not correlate (P=0.6). CONCLUSIONS: Circulating maternal omentin levels are correlated with insulin resistance indices, suggesting that this adipokine may play a role in metabolic adaptations of normal gestation. The strong correlation between anteparum and postpartum maternal omentin levels, as well as the lack of association between maternal and neonatal omentin levels, suggest that placental or fetal compartments are unlikely as the main source of circulating maternal omentin.

The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF).

INTRODUCTION: Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown. METHODS: To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins. RESULTS: The mean±SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1±13.2 vs. 70.7±14.1 respectively, P value<0.05). Based on the concordance in clinical manifestations in MZ and DZ twins, the environmental effect on the phenotype of FMF is estimated as 11.9%±6.6% and the MGs effect as 17.4%±15.5% in average. CONCLUSIONS: In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively.