Cervical HPV Infections, Sexually Transmitted Bacterial Pathogens and Cytology Findings-A Molecular Epidemiology Study.

Prevalent cervical HPV infection and high-risk HPV persistence consequences have been extensively investigated in the literature; nevertheless, any causative interrelations of other sexually transmitted bacterial infections (STIs) with cervical HPV infection have not yet been fully elucidated. This study aimed to investigate the possible association of STIs with cervical cytology aberrations and HPV genotyping results in a representative sample of predominantly young Greek women. Liquid-based cytology and molecular detection for bacterial STIs and HPV as well as extended HPV genotyping were simultaneously assessed in cervical samples from 2256 individuals visiting several urban outpatient Gynecology Departments for well-woman visits or cervical screening throughout a 20-month period. All specimens were centrally processed with validated molecular assays. The mean age of the studied women was 37.0 ± 11.7 years; 722 women (33.30%) tested positive for STI (mean age 34.23 ± 10.87 years). A higher mean age (38.34 ± 11.83 years (p < 0.05)) was associated with negative STI testing. Chlamydia trachomatis was detected in 59 individuals (8.2%), Mycoplasma hominis in 156 (21.6%), Mycoplasma genitalium in 14 (1.9%), and Ureaplasma spp. in 555 (76.9%); infections with two bacterial pathogens were identified in 73 samples (10.1%). Cervical HPV was detected in 357 out of 1385 samples with a valid HPV typing result (25.8%). The mean age of HPV-positive women was 32.0 ± 8.4 years; individuals testing HPV-negative were slightly older (N = 1028): 34.4 ± 9.2 (p < 0.05). Among the 1371 individuals with valid results both for bacterial STIs and cervical HPV detection, women with an HPV-positive sample were more likely to harbor an STI (OR: 2.69, 95% CI 2.10-3.46, p < 0.05). Interestingly, bacterial STI positivity illustrated significant heterogeneity between NILM and LSIL cases, with 28.88% of NILM and 46.33% of LSIL cases harboring an STI, respectively (p < 0.05). In brief, in a population with a high prevalence for STIs, especially Ureaplasma spp., an association was documented between bacterial pathogen detection and cervical HPV infection, as well as abnormal cytology; these findings merit further investigation.

Comprehensive Analysis of DNA Methyltransferases Expression in Primary and Relapsed Ovarian Carcinoma.

BACKGROUND: Despite recent advances in epithelial ovarian carcinoma (EOC) treatment, its recurrence and mortality rates have not improved significantly. DNA hypermethylation has generally been associated with an ominous prognosis and chemotherapy resistance, but the role of DNA methyltransferases (DNMTs) in EOC remains to be investigated. METHODS: In the current study, we systematically retrieved gene expression data from patients with EOC and studied the immunohistochemical expression of DNMTs in 108 primary and 26 relapsed tumors. RESULTS: Our results showed that the DNMT1, DNMT3A, DNMT3B and DNMT3L RNA levels were higher and the DNMT2 level was lower in tumors compared to non-neoplastic tissue, and DNMT3A and DNMT2 expression decreased from Stage-II to Stage-IV carcinomas. The proteomic data also suggested that the DNMT1 and DNMT3A levels were increased in the tumors. Similarly, the DNMT1, DNMT3A and DNMT3L protein levels were overexpressed and DNMT2 expression was reduced in high-grade carcinomas compared to non-neoplastic tissue and low-grade tumors. Moreover, DNMT1 and DNMT3L were increased in relapsed tumors compared to their primaries. The DNMT3A, DNMT1 and DNMT3B mRNA levels were correlated with overall survival. CONCLUSIONS: Our study demonstrates that DNMT1 and DNMT3L are upregulated in primary high-grade EOC and further increase in relapses, whereas DNMT3A is upregulated only in the earlier stages of cancer progression. DNMT2 downregulation highlights the presumed tumor-suppressor activity of this gene in ovarian carcinoma.

The ErbB Signaling Network and Its Potential Role in Endometrial Cancer.

Endometrial cancer (EC) is the second most common malignancy of the female reproductive system worldwide. The updated EC classification emphasizes the significant role of various signaling pathways such as PIK3CA-PIK3R1-PTEN and RTK/RAS/ß-catenin in EC pathogenesis. Some of these pathways are part of the EGF system signaling network, which becomes hyperactivated by various mechanisms and participates in cancer pathogenesis. In EC, the expression of ErbB receptors is significantly different, compared with the premenopausal and postmenopausal endometrium, mainly because of the increased transcriptional activity of ErbB encoding genes in EC cells. Moreover, there are some differences in ErbB-2 receptor profile among EC subgroups that could be explained by the alterations in pathophysiology and clinical behavior of various EC histologic subtypes. The fact that ErbB-2 receptor expression is more common in aggressive EC histologic subtypes (papillary serous and clear cell) could indicate a future role of ErbB-targeted therapies in well-defined EC subgroups with overexpression of ErbB receptors.

Effect of Condom Use after CIN Treatment on Cervical HPV Biomarkers Positivity: Prolonged Follow Up Study.

Background: Several factors contribute in the cervical healing process following local surgical treatment; in a previous work our group has documented a beneficial mid-term role of regular condom use immediately postoperatively in terms of CIN relapse prevention and expression of active viral biomarkers. Materials and Methods: Aiming to investigate whether the favorable contribution of consistent condom use could be extrapolated in the longer term, we conducted a prospective single center observational study including women scheduled to undergo conservative excisional treatment for CIN (LLETZ procedure). In all women a strong recommendation for consistent use for the first 6 months was given. For 204 women who underwent the procedure and completed successfully the two-year follow up a complete dataset of HPV biomarkers' results obtained six months and two years postoperatively was available. Patients were asked to complete a questionnaire to assess condom use compliance. A 90% compliance rate represented the threshold for consistent use. An LBC sample was obtained and tested for HPV genotyping, E6 & E7 mRNA by NASBA technique as well as flow cytometry, and p16 at 0 (pre-treatment), 6 and 24 months. HPV DNA and other related biomarkers status at 6 and 24 months, treatment failures at 24 months and condom use compliance rates represented study outcomes. Results: Six months post-operatively we documented a reduction in the rates of HPV DNA positivity, which was detected in only 23.2% of compliant condom users in comparison to 61.9% in the non-compliant group (p < 0.001, OR: 0.19, 95%CI: 0.1−0.36). For the HPV mRNA test, either assessed with the NASBA method or with flow cytometry, reduced positivity percentages were observed in the compliant group, in particular 1.6% vs. 8% for NASBA and 7.1% vs. 16.4% using flow cytometry, although these differences were not statistically significant (p = 0.1039 and 0.0791, respectively). Finally, reduced p16 positivity rates were documented in the compliant group. At the two year follow up, a more pronounced difference in HPV DNA positivity rates was observed, specifically only 13% positivity among the compliant women compared with 71% of the non-compliant (p < 0.0001); this illustrates a further decreasing trend compared with the 6th month in the compliant group as opposed to an increasing tendency in the non-compliant group, respectively (difference: 9.0%, 95% CI: 0% to 20.6%, p = 0.1523). At that time, 80% of the failed treatments were HPV mRNA positive compared to 10% positivity for the cases treated successfully (OR: 34, 95%CI: 6.8−173, p < 0.0001), a finding indicative that HPV mRNA E6 & E7 positivity accurately predicts treatment failure; p16 positivity was also observed at higher rates in cases with treatment failure. Conclusions: Consistent condom use following conservative excisional CIN treatment appears to significantly reduce rates of CIN recurrence and biomarkers of HPV expression. Additional HPV vaccination at the time of treatment could further enhance the positive effect of consistent condom use.

Teenage pregnancies in Western Greece: experience from a university hospital setting.

PURPOSE: Teenage pregnancies have consistently been associated with preterm labor in a wide range of studies. Evidence regarding the incidence and potential complications of teenage pregnancies in Greece is at present scarce. The aim of this study was to evaluate the perinatal outcomes as well as the risk of perinatal and obstetric complications of teenage pregnancies. METHODS: This retrospective study was conducted at the Department of Obstetrics and Gynecology of the University Hospital of Patras, Greece, and all data recorded concerned the year 2019 (January-December). We retrospectively reviewed 643 cases of singleton pregnancies divided into two groups, as follows: Group A included women of average maternal age (AMA) (20-34 years old), and Group B included teenagers, defined as women less than 20 years old. Data regarding demographic and pregnancy characteristics as well as obstetric and neonatal complications were collected. RESULTS: Teenage pregnancies accounted for 6.7% of all deliveries. We detected significantly higher rates of preterm births (p = 0.025), primiparity (p < 0.001), and negative marital status (p < 0.001) in teenage mothers compared to pregnant women of AMA. There were no significant differences concerning other factors between the two groups. CONCLUSIONS: The findings of the present study raise concern regarding the perinatal, obstetric, and social consequences of teenage pregnancies in Greece. Extended studies that will include further information on antenatal care and detailed socioeconomic factors (i.e., level of education, income, and ethnicity) are required to formulate reliable conclusions concerning teenage pregnancies and their effect on maternal and neonatal health.

DNA Methylation in Epithelial Ovarian Cancer: Current Data and Future Perspectives.

Ovarian cancer is an aggressive disease, and only a few cases are diagnosed at early stages due to the absence of symptoms. Τhe majority of malignant ovarian tumors (>90%) are of epithelial origin and are subdivided into five histological sub types according to different molecular pathogenesis and clinical behavior. High-grade serous ovarian cancer is the most common subtype (70%). However, the different histotypes of ovarian cancer should be viewed as separate diseases both clinically and in biomarker studies. At present, surgical debulking and platinum/taxane - based chemotherapy is the standard of care for epithelial ovarian cancer. Most patients show an initial response to this therapeutic approach, but the majority of them experience disease recurrence at which point cure is no longer possible, due to acquired resistance in those chemotherapeutic regimens. Nevertheless, the current treatment model is still a "one-sizefits- all" approach. Epigenetic modifications represent heritable modifications in gene expression without alteration of the DNA sequence. DNA methylation is the best-studied epigenetic mechanism, and in epithelial ovarian cancer, the methylenome is widely altered. In addition, patterns of DNA methylation may represent potential diagnostic and prognostic markers as well as markers predictive of chemoresistance and potential therapeutic targets. This article systematically reviews the complex area of DNA methylation in ovarian carcinoma and summarizes the current implications and future perspectives of its use as a screening, diagnostic, prognostic and predictive tool as well as in personalized cancer therapy.

Vaginal primary malignant melanoma: a rare and aggressive tumor.

Vaginal primary malignant melanoma is a rare and very aggressive tumor. It most commonly occurs in postmenopausal women, with a mean age of 57 years. Our patient is an 80-year-old, postmenopausal Greek woman presented with a complaint of abnormal vaginal bleeding. On gynecologic examination there was a pigmented, raised, ulcerated, and irregular lesion 5 × 4.5 cm in the upper third of anterior vaginal wall. She underwent a wide local excision of the lesion. The histopathology revealed vaginal primary malignant melanoma with ulceration and no clear surgical margins. She denied any additional surgical interventions and underwent to postoperative adjuvant radiotherapy. Follow up 5 months after initial diagnosis revealed no evidence of local recurrence or distant metastasis. The prognosis of vaginal primary malignant melanoma is very poor despite treatment modality, because most of the cases are diagnosed at advanced stage. Particularly patients with no clear surgical margins and tumor size >3 cm needed postoperative adjuvant radiotherapy.

Mid-trimester maternal serum HCG and alpha fetal protein levels: clinical significance and prediction of adverse pregnancy outcome.

CONTEXT: Maternal serum human Chorionic Gonadotropin (hCG) and Alpha Fetal Protein (AFP) were originally introduced to detect trisomy 21 and neural tube defects. However, in the absence of aneuploidy or neural tube defects, mid-trimester maternal serum hCG and/or maternal serum AFP associated with adverse pregnancy outcomes. Pregnancies with unexplained mid-trimester elevation in maternal serum hCG and/or maternal serum AFP, are at increased risk for pregnancy complications resulting from placental insufficiency. EVIDENCE ACQUISITION: Mid-trimester maternal serum hCG>2.5 MoM associated with an increased risk for pregnancy complications including: late fetal loss, gestational hypertension, preeclampsia, intrauterine growth restriction (IUGR), preterm delivery and intrauterine fetal death(IUFD). Mid-trimester maternal serum AFP levels >2.5 MoM are thought to reflect a defect in placentation and associated with an increased risk for pregnancy complications including: late fetal loss, gestational hypertension, preeclampsia, IUGR, preterm delivery and IUFD. RESULTS: Combined mid-trimester elevation in maternal serum hCG and AFP levels suggest a more complex type of placental pathology. They have stronger association with pregnancy complications including: late fetal loss, gestational hypertension, preeclampsia, IUGR, preterm delivery and IUFD. CONCLUSIONS: Mid-trimester maternal serum hCG or AFP levels alone cannot detect all pregnant women with increased risk to develop pregnancy complications. Multiparameter testing of placental function in mid-trimester (maternal serum hCG and AFP screening, uterine artery Doppler and placental morphology) may allow us to identify women with increased risk to develop severe placental insufficiency and pregnancy complications. However, future prospective studies are needed to confirm the prognostic significance of multiparameter testing of placental function in mid-trimester.

Expression and potential role of ErbB receptors in type II endometrial cancer.

OBJECTIVE: Endometrial cancer is the most common malignancy of the female genital tract. Based on clinical and pathological features, endometrial cancer is classified into two types. The aim of our study was to describe the expression and the potential clinical role of ErbB receptors in Greek patients with type II endometrial cancer. STUDY DESIGN: Between 1991 and 2008, 10 women with histologically confirmed type II endometrial cancer were referred to the Department of Gynecologic Oncology of the University of Patras Medical School. Tissue specimens from endometrial lesions were immunostained for EGFR, ErbB-2, ErbB-3 and ErbB-4. RESULTS: For EGFR, 5 cases were positive (50%) and 5 cases were negative. For ErbB-2, 9 cases were positive (90%) and 1 case was negative. For ErbB-3, all cases were positive. For ErbB-4, 7 cases were positive (70%) and 3 cases were negative. Also for all ErbB receptors, 5 cases were positive (50%). During follow up, 3 patients died from their disease. All of them had papillary serous endometrial cancer and 2 of them were positive for all ErbB receptors. CONCLUSION: Although our study was based on a small number of cases, it is obvious that we had high expression levels of ErbB receptors in patients with type II endometrial cancer. Also the majority of patients with dismal outcome were positive for all ErbB receptors. This is very important, as ErbB-targeted therapies may be clinically active as adjuvant therapy in well-defined subgroups of type II EC patients with EGFR and ErbB-2 overexpression.

Marcadores séricos como predictores de mala evolución durante el segundo trimestre de embarazo / Mid-trimester maternal serum markers as a predictor of adverse pregnancy outcome

Los niveles maternos de alfa fetoproteína (AFP) y gonadotrofina coriónica humana (hCG) durante el segundo trimestre del embarazo se han asociado con mal pronóstico fetal en ausencia de aneuploidías o defectos del tubo neural. Se presume que la concentración de AFP en el suero materno por encima de 2.5 MoM en el segundo trimestre representa una alteración de la placentación y se asocia con mayor riesgo de complicaciones en la fase final de la gestación (pérdida fetal tardía, hipertensión gestacional, preeclampsia, restricción de crecimiento intrauterino, parto prematuro y sufrimiento fetal). Los niveles maternos de hCG mayores de 2.5 MoM en el segundo trimestre se relacionan con las mismas complicaciones tardías. La elevación combinada de los dos parámetros sugiere una forma más compleja de enfermedad placentaria y se asocian en forma más acentuada con pérdida fetal tardía, hipertensión gestacional, preeclampsia, restricción de crecimiento intrauterino, parto prematuro y sufrimiento fetal. La sola determinación de la AFP, la hCG o ambas no permite detectar a todas las embarazadas con alto riesgo de complicaciones gestacionales. Las pruebas multiparamétricas de la función placentaria en el segundo trimestre (niveles maternos de AFP y hCG, ecografía Doppler de arterias uterinas, morfología placentaria) permite identificar a las mujeres con un incremento del riesgo de insuficiencia placentaria grave y complicaciones del embarazo.

Marcadores séricos como predictores de mala evolución durante el segundo trimestre de embarazo / Mid-trimester maternal serum markers as a predictor of adverse pregnancy outcome

Los niveles maternos de alfa fetoproteína (AFP) y gonadotrofina coriónica humana (hCG) durante el segundo trimestre del embarazo se han asociado con mal pronóstico fetal en ausencia de aneuploidías o defectos del tubo neural. Se presume que la concentración de AFP en el suero materno por encima de 2.5 MoM en el segundo trimestre representa una alteración de la placentación y se asocia con mayor riesgo de complicaciones en la fase final de la gestación (pérdida fetal tardía, hipertensión gestacional, preeclampsia, restricción de crecimiento intrauterino, parto prematuro y sufrimiento fetal). Los niveles maternos de hCG mayores de 2.5 MoM en el segundo trimestre se relacionan con las mismas complicaciones tardías. La elevación combinada de los dos parámetros sugiere una forma más compleja de enfermedad placentaria y se asocian en forma más acentuada con pérdida fetal tardía, hipertensión gestacional, preeclampsia, restricción de crecimiento intrauterino, parto prematuro y sufrimiento fetal. La sola determinación de la AFP, la hCG o ambas no permite detectar a todas las embarazadas con alto riesgo de complicaciones gestacionales. Las pruebas multiparamétricas de la función placentaria en el segundo trimestre (niveles maternos de AFP y hCG, ecografía Doppler de arterias uterinas, morfología placentaria) permite identificar a las mujeres con un incremento del riesgo de insuficiencia placentaria grave y complicaciones del embarazo.(AU)

Systemic Sclerosis and Multiple Cancers of the Female Genital Tract: Prolonged Survival following Current Treatment Strategies.

Background. Systemic sclerosis is a rare, chronic, multisystem, and autoimmune disease. There is an overall increased risk of malignancy in patients with systemic sclerosis. However, multiple cancers of the female genital tract in patients with SSc are a very rare event. Our aim is to present a case of SSc and multiple cancers of the female genital tract, with prolonged survival following current treatment strategies. Case. The patient, a 43-year-old nulliparous premenopausal Greek woman suffering from systemic sclerosis, presented with a history of abdominal pain and abnormal uterine bleeding. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, total omentectomy, appendectomy, and pelvic lymph node dissection. The histopathology revealed synchronous primary cancers of the endometrium and left ovary. The final diagnosis was stage Ib endometrial cancer endometrioid type and stage IIIc ovarian cancer endometrioid type. She underwent postoperative adjuvant chemotherapy and remains well without evidence of disease 89 months after initial surgery. Conclusion. Although our patient was diagnosed at advanced stage disease, prolonged survival may be related with radical surgery and postoperative adjuvant chemotherapy according to current treatment strategies.

Inheritance and perinatal consequences of inherited thrombophilia in Greece.

OBJECTIVE: To investigate the impact of inherited thrombophilic factors on the gestational outcome of unselected pregnant women. METHOD: A total of 392 women with spontaneous pregnancy were investigated for Factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations. Adverse pregnancy outcomes were recorded. RESULTS: Thrombophilic genotypes were significantly higher in women with placental abruption. Heterozygocity for Factor V Leiden increased the risk for placental abruption 9.1 times. The MTHFR T677T genotype increased the risk for placental abruption 4.8 times despite folate supplements, and normal serum folate and B(12) levels. Women with inherited thrombophilia and previous obstetric complications were at significant risk for complications in a subsequent pregnancy (P<0.05). CONCLUSION: Women with placental abruption should be screened for thrombophilic factors and plasma homocysteine should be measured. Subgroups of women with inherited thrombophilia and obstetric complications might benefit from prophylactic anticoagulation in subsequent pregnancies.

Sarcoidosis of the vulva: a case report.

Sarcoidosis of the vulva is a very rare condition. Until now, only four cases have been reported in English literature. The patient, a 48-year-old, gravid 3, para 2 postmenopausal Greek woman presented with a 6 months history of perineal pain. The patient underwent a wide local excision of the painful lesion. The histology revealed sarcoidosis of the vulva. She remains well without evidence of relapse 12 months after operation.