Uterine sparing management in patients with endometrial cancer: a narrative literature review.

Endometrial cancer is the most common malignancy of the female genital tract. Approximately 25% of cases occur in premenopausal women, and up to 5% of cases occur in women who are younger than 40 years old. The survival rate in these cases is 99%; therefore, uterine-sparing management could be considered under strict criteria selection and the strong desire of the woman to preserve uterus and fertility. Diagnosis should be performed after a hysteroscopic biopsy instead of dilatation and curettage. The highest remission rate was achieved after combining a hysteroscopic resection with hormonal therapy compared to single hormonal treatment. The most common regiments are the following progestins: megestrol acetate (MA) and medroxyprogesterone acetate (MPA) taken orally with a daily dosage of 160 mg-320 mg for MA and 250 mg-600 mg for MP. Evaluations at three and six months could be performed by office endometrial biopsy and/or hysteroscopic directed biopsy especially in the presence of levonorgestrel intrauterine system, and in cases of remission, either a pregnancy attempt or maintenance therapy should be considered. After childbearing, hysterectomy with bilateral salpingo-oophorectomy is recommended, whereas ovarian preservation could be considered depending on the patient's age and whether they fulfil the strict criteria selection.

Increased Fibroblast Growth Factor 21 (FGF21) Concentration in Early Second Trimester Amniotic Fluid and Its Association with Fetal Growth.

Altered fetal growth, either reduced or exacerbated, is associated with adverse perinatal outcomes. The underlying pathogenetic mechanisms of altered growth remain unclear. Fibroblast growth factor 21 (FGF21) and insulin are both considered to be major regulators of tissue growth and metabolism. The aim of our study was to investigate the association of second trimester amniotic fluid FGF21 and insulin concentrations with fetal growth. The amniotic fluid concentrations of FGF21 and insulin were determined in 80 cases of different fetal growth patterns (SGA-small for gestational age, LGA-large for gestational age, and AGA-appropriate for gestational age fetuses). Both peptides were found to be increased in cases of abnormal fetal growth, reduced growth velocity (SGA), or macrosomia (LGA). Specifically, FGF21 was significantly increased, as higher FGF21 levels were observed in the amniotic fluid of SGA and LGA fetuses compared with AGA fetuses (p < 0.05). Furthermore, the more severe the fetal smallness, the higher the FGF21 levels (p < 0.05). Similarly, higher insulin levels were noted in the amniotic fluid of SGA and LGA fetuses compared with those in AGA fetuses, though this was not statistically significant (p > 0.05). Again, the more severe the reduced fetal growth, the higher the insulin levels.

Effects of Hormone Therapy and Flavonoids Capable on Reversal of Menopausal Immune Senescence.

Menopause, probably the most important natural change in a woman's life and a major component of female senescence, is characterized, inter alia, by cessation of ovarian estrogen and progesterone production, resulting in a gradual deterioration of the female immune system. Hormone replacement therapy (HRT) is used in postmenopausal women to relieve some of the peri- and postmenopausal symptoms, while there is also evidence that the therapy may additionally partially reverse menopausal immune senescence. Flavonoids, and especially isoflavones, are widely used for the treatment of menopausal symptoms, although it is not at present clear whether they can reverse or alleviate other menopausal changes. HRT reverses the menopausal CD4/CD8 ratio and also limits the general peri- and postmenopausal inflammatory state. Moreover, the increased levels of interleukins (IL)-1ß, IL-6, and IL-8, as well as of tumor necrosis factor-α (TNF-α) are decreased after the initiation of HRT. However, some reports show no effect of HRT on IL-4, IL-10, and IL-12. It is thus evident that the molecular pathways connecting HRT and female immune senescence need to be clarified. Interestingly, recent studies have suggested that the anti-inflammatory properties of isoflavones possibly interact with inflammatory cytokines when applied in menopause treatments, thereby potentially reversing immune senescence. This narrative review presents the latest data on the effect of menopausal therapies, including administration of flavonoid-rich products, on age-associated immune senescence reversal with the aim of revealing possible directions for future research and treatment development.

A Systematic Review of Bisphenol A from Dietary and Non-Dietary Sources during Pregnancy and Its Possible Connection with Fetal Growth Restriction: Investigating Its Potential Effects and the Window of Fetal Vulnerability.

Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical (EDC), is increasingly hypothesized to be a factor contributing to changes in fetal growth velocity. BPA exposure may be environmental, occupational, and/or dietary, with canned foods and plastic bottles contributing significantly. Our systematic review aims to evaluate the current literature and to investigate the role of BPA in abnormal fetal growth patterns. A search was conducted in the PubMed and Cochrane databases. A total of 25 articles met the eligibility criteria and were included in this systematic review. Eleven of them failed to show a clear relationship between BPA and abnormal fetal growth. The majority of the remaining studies (9/14) found an inverse association of BPA with indicators of fetal growth, whereas three studies suggested increased fetal growth, and two studies produced contradictory findings. Of note, both of the studies that collected a sample (amniotic fluid) directly reflecting BPA concentration in the fetus during the first half of pregnancy revealed an inverse association with birth weight. In conclusion, there is mounting evidence that combined exposure to BPA from dietary and non-dietary sources during pregnancy may contribute to abnormal fetal growth; a tendency towards fetal growth restriction was shown, especially when exposure occurs during the first half.

Partial deletion of chromosome 6p causing developmental delay and mild dysmorphisms in a child: molecular and developmental investigation and literature search.

BACKGROUND: The interstitial 6p22.3 deletions concern rare chromosomal events affecting numerous aspects of both physical and mental development. The syndrome is characterized by partial deletion of chromosome 6, which may arise in a number of ways. CASE PRESENTATION: We report a 2.8-year old boy presenting with developmental delay and mild dysmorphisms. High-resolution oligonucleotide microarray analysis revealed with high precision a 2.5 Mb interstitial 6p deletion in the 6p22.3 region which encompasses 13 genes. CONCLUSIONS: Identification and in-depth analysis of cases presenting with mild features of the syndrome will sharpen our understanding of the genetic spectrum of the 6p22.3 deletion.

Perinatal Inflammation: Could Partial Blocking of Cell Adhesion Molecule Function Be a Solution?

In spite of the great advances made in recent years in prenatal and perinatal medicine, inflammation can still frequently result in injury to vital organs and often constitutes a major cause of morbidity. It is today well established that in neonates-though vulnerability to infection among neonates is triggered by functional impairments in leukocyte adhesion-the decreased expression of cell adhesion molecules also decreases the inflammatory response. It is also clear that the cell adhesion molecules, namely, the integrins, selectins, and the immunoglobulin (Ig) gene super family, all play a crucial role in the inflammatory cascade. Thus, by consolidating our knowledge concerning the actions of these vital cell adhesion molecules during the prenatal period as well as regarding the genetic deficiencies of these molecules, notably leukocyte adhesion deficiency (LAD) I, II, and III, which can provoke severe clinical symptoms throughout the first year of life, it is anticipated that intervention involving blocking the function of cell adhesion molecules in neonatal leukocytes has the potential to constitute an effective therapeutic approach for inflammation. A promising perspective is the potential use of antibody therapy in preterm and term infants with perinatal inflammation and infection focusing on cases in which LAD is involved, while a further important scientific advance related to this issue could be the combination of small peptides aimed at the inhibition of cellular adhesion.

Laparoscopic nerve-sparing radical hysterectomy without uterine manipulator for cervical cancer stage IB: description of the technique, our experience and results after the era of LACC trial.

PURPOSE: The aim of this study is to evaluate surgical data and oncological outcome of laparoscopic nerve-sparing radical hysterectomy without uterine manipulator for cervical cancer stage IB, over the last 8 years. METHODS: This retrospective study includes 32 patients with cervical cancer Figo stage (2009) IB who underwent laparoscopic nerve-sparing radical hysterectomy without using any kind of uterine manipulator. Patients were eligible if they had squamous cell carcinoma, adenocarcinoma, or adeno-squamous carcinoma, and no para-aortic lymph node involvement by imaging or after frozen section. The median value and range were assessed for operative outcomes and relapse rate and disease-free survival rate were evaluated using the Kaplan-Meier method. RESULTS: In the study, 32 patients were included and among them 27 women were stage IB1 (18 cases with tumor size 2-4 cm) and 5 women stage IB2 (Figo stage 2009). The median age of patients was 50.5 years (range 31-68) and median body mass index (B.M.I) was 25.3 kg/m2 (range 19-33.5 kg/m2). The average operating time was 228 min (range 147-310 min) and median hospital stay was 2.7 days (range 2-7 days). Approximate blood loss was 188 ml (range 120-300 ml). After a median follow-up of 37 months, we had 2 recurrences out of 32 cases and no death. Especially for patients with Figo stage (2009) IB1, the recurrence rate was 3.7% (1/27). The 3-year PFS was 93.7% and the number at risk 23 (71.8%) and especially for the IB1 stage (2009) women, the 3-year PFS was 96.1% and the number at risk 21 (77.7%). The 3-year OS was 100% with no. at risk 71.8%. CONCLUSIONS: Laparoscopic nerve-sparing radical hysterectomy without uterine manipulator is feasible and safe surgical procedure for cervical cancer with acceptable surgical and oncological outcomes in the hands of well-trained and experienced laparoscopic surgeons. Our retrospective study reveals better oncological outcome compared to other studies on the minimally invasive approach, where uterine manipulator was routinely used and no vaginal sealing of the tumor was made.

Laparoscopic emergency cervicoisthmic cerclage in second trimester of pregnancy: A case series report.

PURPOSE: The aim of this study was to evaluate the feasibility and safety of Laparoscopic emergency cervicoisthmic cerclage in second trimester of pregnancy. METHODS: Between November 2015 and March 2019 5 patients underwent Laparoscopic emergency cervicoisthmic cerclage. All women had showed cervical insufficiency with dilation in the second trimester due to extensive conisation (3 patients) or re-conisation (2 patients) and failed transvaginal cerclage (5 patients) due to a short vaginal cervix. Patients' characteristics were obtained from hospital's medical record and we evaluated surgical data, intra, postoperative complications, and perinatal outcome. All operations were performed by the same surgeon. RESULTS: The average operation time was 88 min (ranging from 80 to 95 minutes), the average estimated blood loss during the procedure was less than 100 mL and there were no perioperative or postoperative complications. The mean gestational age at surgery was 14.4 (ranging from 14.2 to 16) weeks. All women underwent an elective CS after 38 weeks of gestation. The overall pregnancy survival rate was 100 %, the mean gestational age at delivery was 38.1 weeks (ranging from 38.0 to 38.5 weeks) and the mean birth weight was 3190 g (g) (ranging from 2980 g to 3350 g). CONCLUSION: Laparoscopic cervicoisthmic cerclage might be an alternative approach even in the early second trimester of pregnancy. Our study's success rates compare favourably to the laparotomy approach and the laparoscopic cervicoisthmic cerclage showed a relatively high success rate in women who are at risk of poor obstetric outcomes. Of course, the surgeon's experience and competence plays a key role and this approach should only be attempted in well-organized units.

Total laparoscopic hysterectomy without uterine manipulator. A retrospective study of 1023 cases.

OBJECTIVE: The aim of this study was to evaluate the feasibility and safety of a total laparoscopic hysterectomy (TLH) without the use of a uterine manipulator in women with benign indications for hysterectomy. STUDY DESIGN: Between January 2011 and January 2020, 1023 patients underwent a TLH without the use of any type of uterine manipulator. The indications for hysterectomy were all benign conditions. The patients' details were obtained from the hospital medical records and the indications for hysterectomy, the surgical data and the intra and postoperative complications were evaluated. All operations were performed by the same surgical team. RESULTS: The median age was 48.2 years, while the BMI ranged from between 26.2 kg/m2 and 47.8 kg/m2. A small percentage of the women were menopausal (278, 27 %) and, following a detailed consultation with 563 (55 %) of the patients, we performed a TLH with adnexectomy. The mean operative time was 78 min (43-168 min), while the estimated blood loss was 59 mL (20-260 ml) and the mean uterine weight was 255 g (40-1510 g). There was no case of conversion to laparotomy. A blood transfusion was required for 14 patients (1.4 %), while there was one case of ureteral injury and three cases where the bladder was opened and fixed laparoscopically. The average hospital stay was 1.1 days, with only 38 patients staying for two or more days. In the long term, we had five cases (0.5 %) of vaginal vault dehiscence and one case of vaginal vault hematoma. CONCLUSION: A TLH without the use of a uterine manipulator is a feasible and safe procedure. While it is perhaps a more demanding procedure for young doctors, when performed by well-trained and experienced laparoscopic surgeons, the procedure entails a short operative time and a low complications rate. As such, it should be the first step in the training of young doctors for performing laparoscopic radical hysterectomies.

Laparoscopic sacrocolpopexy comparing polypropylene mesh with polyvinylidene fluoride mesh for pelvic organ prolapse: Technique description and long term outcomes.

AIM: Our aim was to evaluate the feasibility and safety of laparoscopic sacrocolpopexy (LSCP) and compare the long-term outcomes and complication rates of polypropelene (PP) and polyvinylidene fluoride (PVDF), following up within a minimum of 12 months. METHODS: This was a retrospective cohort study using patients who underwent LSCP for POP involving either PP or PVDF mesh between January 2011 and January 2018. RESULTS: Our study focused on 172 women who underwent LSCP with mesh between January 2011 and January 2018. All procedures were successfully completed laparoscopically, and patients' baseline characteristics were not statistically different in the two groups. Between January 2011 and December 2014, we performed 82 cases of LSC, mainly using PP mesh. Over the last 5 years, since January 2015, we have used PVDF mesh for POP. CONCLUSIONS: LSCP using PVDF mesh was found to provide excellent anatomical and functional outcomes after a median follow-up duration of 41 months, compared with the PP group, which had a median follow-up duration of 54 months. Mesh infection and erosion rates in the PP group were significantly higher than those in the PVDF group. Additionally, rates of vaginal pain and discomfort were significantly lower in the PVDF group when compared with the PP group.

Altered Resistin Concentrations in Mid-trimester Amniotic Fluid of Fetuses With Trisomies 18 and 13: A Window onto the Pathophysiology of Trisomies 18 and 13.

BACKGROUND/AIM: The study aimed to examine whether resistin is present in second trimester amniotic fluid from pregnancies with trisomy 18 and 13 and evaluate its concentration in comparison with euploid pregnancies. PATIENTS AND METHODS: The study included 37 women who underwent amniocentesis. Eleven fetuses had trisomy 18, 3 had trisomy 13, while 23 had a normal karyotype. RESULTS: Resistin was detected in all cases. The mean level of resistin in trisomy 18 was statistically significantly lower compared to euploid controls. Resistin levels in all abnormal cases were below its median concentration in euploid controls. ROC analysis showed very good prognostic value for both trisomies. CONCLUSION: Resistin is a constituent of mid-trimester amniotic fluid of pregnancies with trisomies 13 and 18, exhibiting lower levels than those in euploid fetuses. The reduced levels of resistin in amniotic fluid may be associated with early changes in metabolic pathways and immunoinflammatory responses.

Classification of endometrial lesions by nuclear morphometry features extracted from liquid-based cytology samples: a system based on logistic regression model.

OBJECTIVE: To investigate the potential of a computerized system for the discrimination of benign from malignant endometrial nuclei and lesions. STUDY DESIGN: A total of 228 histologically confirmed liquid-based cytological smears were collected: 117 within normal limits cases, 66 malignant cases, 37 hyperplasias without atypia, and 8 cases of hyperplasia with atypia. From each case we extracted nuclear morphometric features from about 100 nuclei using a custom image analysis system. Initially we performed feature selection, and subsequently we applied a logistic regression model that classified each nucleus as benign or malignant. Based on the results of the nucleus classification process, we constructed an algorithm to discriminate endometrium cases as benign or malignant. RESULTS: The proposed system had an overall accuracy for the classification of endometrial nuclei equal to 83.02%, specificity of 85.09%, and sensitivity of 77.01%. For the case classification the overall accuracy was 92.98%, specificity was 92.86%, and sensitivity was 93.24%. CONCLUSION: The proposed computerized system can be applied for the classification of endometrial nuclei and lesions as it outperformed the standard cytological diagnosis. This study highlights interesting diagnostic features of endometrial nuclear morphology, and the proposed method can be a useful tool in the everyday practice of the cytological laboratory.

The diagnostic accuracy of E6 & 7 mRNA detection as a primary screening test for the detection of severe cervical lesions.

PURPOSE: This prospective accuracy study aimed to assess the diagnostic accuracy of nucleic acid sequence amplification (NASBA) and flow cytometry for E6/7 human papillomavirus (HPV) mRNA detection as a primary screening test compared to cytology in the triage of severe cervical intraepithelial neoplasia (CIN) lesions. METHODS: 1083 women referred to our outpatient gynecology clinics for a routine Pap test were recruited. Residual material of the Pap smears was tested by NASBA and by flow cytometry for E6/7 mRNA expression. Biopsy results were used as reference standards. The accuracy indices of both techniques and of NASBA type-16 HPV were assessed for the detection of CIN2+ lesions and were compared to cytology. RESULTS: An increased lesion severity was associated with increased positivity rates of both NASBA and flow cytometry tests (x(2), p<0.001). A positive correlation between NASBA and flow cytometry was identified when these methods were examined with the Phi coefficient (value 0.369, 95% confidence interval [95%CI] : 0.307-0.426). Furthermore, NASBA (89.7 vs 57.7%, p<0.0005) and flow cytometry (77.3 vs 57.7%, p<0.0005) exhibited higher specificity rates than cytology. However, their sensitivity rates did not exceed those of cytology (NASBA:69.8 vs 84.6%, p=0.051; flow cytometry: 69.12 vs 84.6%, p=0.043). CONCLUSIONS: Both NASBA and flow cytometry exhibited increased specificity for the triage of CIN2+ lesions. However, their relatively lower sensitivity and higher positivity rates when compared to cytology do not make them ideal for a primary screening test. Hence, the role of mRNA detection in the screening for severe cervical lesions remains to be clarified.

Probing the impact of sex steroids and menopause-related sex steroid deprivation on modulation of immune senescence.

Immune senescence denotes the general decline in immune system function, characterized by a reduced immune response and an increased inflammatory state. Menopause is a natural change in a women's life, the menopause-related low estrogen levels affecting many body functions, among them the immune system. Numerous human studies with menopausal women and animal models with surgically induced menopause show a clear impact of sex steroids in immune responses. Female superiority in vaccination response and predisposition to infections are eliminated after menopause, while during menopause inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α), Interleukins-1ß, 6, 8 and 13 (IL-1ß, IL-6, IL-8, IL-13) and Monocyte Chemoattractant Protein-1 (MCP-1) are increased, implying a molecular connection of sex steroid loss with immune senescence. Moreover, immune cells modify their number and function after the menopausal transition, this offering another explanation for immune senescence. Until now most of the existing studies have concluded that menopause plays an additional role to aging in immune senescence. While it is clear that we are as yet far from thoroughly understanding the molecular pathways connecting sex steroids and menopause with immune senescence, such knowledge is highly likely to enable future targeted interventions in treatment and prevention of age-related diseases in women.

Using classification and regression trees, liquid-based cytology and nuclear morphometry for the discrimination of endometrial lesions.

'The objective of this study is to investigate the potential of classification and regression trees (CARTs) in discriminating benign from malignant endometrial nuclei and lesions. The study was performed on 222 histologically confirmed liquid based cytological smears, specifically: 117 benign cases, 62 malignant cases and 43 hyperplasias with or without atypia. About 100 nuclei were measured from each case using an image analysis system; in total, we collected 22783 nuclei. The nuclei from 50% of the cases (the training set) were used to construct a CART model that was used for knowledge extraction. The nuclei from the remaining 50% of cases (test set) were used to evaluate the stability and performance of the CART on unknown data. Based on the results of the CART for nuclei classification, we propose two classification methods to discriminate benign from malignant cases. The CART model had an overall accuracy for the classification of endometrial nuclei equal to 85%, specificity 90.68%, and sensitivity 72.05%. Both methods for case classification had similar performance: overall accuracy in the range 94-95%, specificity 95%, and sensitivity 91-94%. The results of the proposed system outperform the standard cytological diagnosis of endometrial lesions. This study highlights interesting diagnostic features of endometrial nuclear morphology and provides a new classification approach for endometrial nuclei and cases. The proposed method can be a useful tool for the everyday practice of the cytological laboratory.

Acute lung injury in preterm fetuses and neonates: mechanisms and molecular pathways.

Acute lung injury (ALI) results in high morbidity and mortality among preterm neonates and efforts have therefore been devoted to both antenatal and postnatal prevention of the disease. ALI is the result of an inflammatory response which is triggered by a variety of different mechanisms. It mostly affects the fetal lung and, in particular, causes damage to the integrity of the lung's alveolar-capillary unit while weakening its cellular linings. Chemotactic activity and inflammatory products, such as proinflammatory cytokines TNF-α, IL-1, IL-6, IL-11, VEGF,TGF-α and TGF-ß, provoke serious damage to the capillary endothelium and the alveolar epithelium, resulting in hyaline membrane formation and leakage of protein-rich edema fluid into the alveoli. Chorioamnionitis plays a major part in triggering fetal lung inflammation, while mechanical ventilation, the application of which is frequently necessary in preterm neonates, also causes ALI by inducing proinflammatory cytokines. Many different ventilation-strategies have been developed in order to reduce potential lung injury. Furthermore, tissue injury may occur as a result of injurious oxygen by-products (Reactive Oxygen Species, ROS), secondary to hyperoxia. Knowledge of the inflammatory pathways that connect intra-amniotic inflammation and ALI can lead to the formulation of novel interventional procedures. Future research should concentrate on the pathophysiology of ALI in preterm neonates and οn possible pharmaceutical interventions targeting prevention and/or resolution of ALI.