The LADY study: epidemiological characteristics of prevalent and new genitourinary syndrome of menopause cases in Greece.

OBJECTIVE: The genitourinary syndrome of menopause (GSM) is often underdiagnosed and undertreated despite its significant impact on postmenopausal quality of life. We assessed the prevalence of GSM and associated symptoms in Greek perimenopausal/postmenopausal women attending gynecology clinics. METHODS: Four hundred and fifty women, aged 40-70 years (93.1% postmenopausal), attending three gynecology clinics at university hospitals completed a validated questionnaire and underwent pelvic examination. RESULTS: GSM was diagnosed in 87.6% of the women at the study visit, whereas only 16% of the overall sample had been previously diagnosed with the condition. Vaginal dryness (72.7%), vulvar burning sensation or itching (58.0%) and dyspareunia (52.7%) were the most prevalent symptoms. Pelvic signs consisted of vaginal dryness (89.1%), loss of vaginal rugae (80.6%) and vulvovaginal pallor (86.9%). However, only 31.3% of the participants had discussed genitourinary symptoms with their health-care professionals (HCPs). Regarding management, only 11.1% of women had prior experience with any form of therapy, and currently only 8.7% were receiving treatment. CONCLUSION: GSM is highly prevalent in this Greek perimenopausal/postmenopausal population. Nevertheless, the majority of women remain undiagnosed and untreated. Education for both women and HCPs regarding GSM will lead to improved diagnosis and better management of this syndrome.

ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

Background: The standard surgical treatment of endometrial carcinoma (EC) consisting of total hysterectomy with bilateral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in EC in a multidisciplinary setting. While also addressing work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility sparing treatment. Objectives: To define recommendations for fertility-sparing treatment of patients with endometrial carcinoma. Materials and Methods: ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of EC (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives. Results: The multidisciplinary development group formulated 48 recommendations for fertility-sparing treatment of patients with endometrial carcinoma in four sections: patient selection, tumour clinicopathological characteristics, treatment and special issues. Conclusions: These recommendations provide guidance to professionals caring for women with endometrial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy, conservative surgery, and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario. What is new?: A collaboration was set up between the ESGO, ESHRE and ESGE, aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

Background: The standard surgical treatment of endometrial carcinoma (EC) consisting of total hysterectomy with bilateral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in EC in a multidisciplinary setting. While also addressing work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility sparing treatment. Objectives: To define recommendations for fertility-sparing treatment of patients with endometrial carcinoma. Materials and Methods: ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of EC (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives. Results: The multidisciplinary development group formulated 48 recommendations for fertility-sparing treatment of patients with endometrial carcinoma in four sections: patient selection, tumour clinicopathological characteristics, treatment and special issues. Conclusions: These recommendations provide guidance to professionals caring for women with endometrial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy, conservative surgery, and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario. What is new? A collaboration was set up between the ESGO, ESHRE and ESGE, aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

Survival Outcomes of Epithelial Ovarian Cancer Patients Following Dose-dense Versus 3-Weekly Platinum-Paclitaxel Chemotherapy: A Meta-Analysis.

AIMS: Dose-dense chemotherapy has proven its value in several cancer fields. The purpose of the present systematic review is to evaluate the impact of dose-dense chemotherapy on survival outcomes of epithelial ovarian cancer patients. MATERIALS AND METHODS: Medline, Scopus, the Cochrane Central Register of Controlled Trials CENTRAL, Google Scholar and Clinicaltrials.gov databases were searched for relevant articles. Effect sizes were calculated in Rstudio using the meta and metafor functions. A sensitivity analysis was carried out to evaluate the possibility of small study effects and P-hacking. The methodological quality of the included studies was assessed using Risk of Bias 2 (RoB2) and Risk of Bias in non-Randomized Trials (RoBINS) tools. RESULTS: Overall, 12 studies were included in the present systematic review, involving 4979 epithelial ovarian cancer patients. The risk of recurrence was substantially improved in patients receiving dose-dense chemotherapy (hazard ratio 0.82, 95% confidence interval 0.70, 0.96); however, the result of the meta-analysis may be attributed to the effect size of smaller studies as following adjustment for small study effects the outcome becomes non-significant (hazard ratio 0.91, 95% confidence interval 0.81, 1.02, P = 0.123). Overall survival rates were not improved by dose-dense chemotherapy (hazard ratio 0.79, 95% confidence interval 0.60, 1.04). Thirty-five types of adverse effect were identified following retrieval of data from the original studies. Dose-dense chemotherapy did not increase significantly the rates of severe adverse effects, although thrombosis, severe diarrhoea and severe nausea were more prevalent in this group of patients. CONCLUSION: Dose-dense chemotherapy is associated with comparable side-effects to those of standard chemotherapy; however, data related to survival outcomes are not positive; hence, its use outside the setting of clinical trials should be discouraged.

Ocular metastasis of primary gynecological malignancies, a rare but not insignificant entity: A systematic review.

The genital system remains one of the most common sites of carcinogenesis in women. Advances in surgery, radiation treatment, and chemotherapy have increased their efficacy and many patients survive for many years after their initial diagnosis. The eye is a rare site of metastasis from gynecological cancer due to its distant location from the genitalia. In this systematic review, we retrieved all case reports of patients with ocular metastasis from gynecological neoplasms. The demographic, clinical, and treatment characteristics were retrieved and analyzed. A total of 70 case reports were included. Forty-eight of these reports concerned patients with a known malignancy that recurred in the eye and in 22 patients' ocular symptomatology accompanied the initial diagnosis of the gynecologic malignancy. 73.9% of these patients exhibited concomitant metastasis to other organs. The mean disease-free interval was found at 25.7 months and mean survival time after the eye metastasis was 13.5 months. Refractory disease was identified as the most important risk factor associated with mortality. Because eye metastasis has such a dismal prognosis, all gynecologists who treat oncological patients should be highly suspicious for reported eye complaints.

Neutrophil-to-lymphocyte ratio and chemotherapy response score as prognostic markers in ovarian cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is the recommended approach in patients with advanced epithelial ovarian cancer (EOC). However, most patients eventually relapse despite the initial high response rate to chemotherapy. Neutrophil-to-lymphocyte ratio is a well-known biomarker that reflects severe inflammation, critical illness, and mortality in various diseases. Chemotherapy response score (CRS) and neutrophil-to-lymphocyte ratio (NLR) have been identified as potential biomarkers of platinum resistance and disease prognosis. We retrospectively evaluated 132 patients with stage IIIc or IV ovarian/fallopian tube/primary peritoneal cancer who had received NACT followed by IDS from 01/01/2003 to 31/12/2018. CRS was assessed on omental specimens collected from IDS according to ICCR guidelines. RESULTS: Median age was 64.57 years (SD: 9.72; range 39.2-87.1). Most ovarian tumors were serous epithelial (90.9%; 120/132). An elevated NLR (defined as > 3) was observed in 72% (95/132) of patients in contrast with 28% (37/132) of patients characterized by low NLR status. Median PFS (mPFS) and median overall survival (mOS) were 13.05 months (95% CI: 11.42-14.67)) and 34.69 months (95% CI: 23.26-46.12) respectively. In univariate analysis, CRS3 score was significantly associated with prolonged mPFS (CRS1/2: 12.79 months vs CRS3: 17.7 months; P = 0.008). CRS score was not associated with mOS (P = 0.876). High NLR was not significantly associated with mPFS (P = 0.128), however it was significantly associated with poor mOS (P = 0.012). In multivariate analysis, only performance of surgery maintained its statistical significance with both PFS (P = 0.001) and OS (P = 0.008). CONCLUSION: NLR could serve as a useful predictor of OS but not PFS in ovarian cancer patients receiving NACT. In accordance with our previous study, CRS score at omentum was found to be associated with PFS but not OS in ovarian cancer patients treated with NACT and IDS.

Biomarkers that would predict response to neoadjuvant chemotherapy in advanced ovarian cancer patients are eagerly needed:• Neutrophil to Lymphocyte Ratio (NLR) is an indicator of systemic inflammatory response to the malignancy.• NLR was evaluated in 132 patients undergoing Neoadjuvant Chemotherapy for advanced ovarian cancer.• Elevated NLR was associated with worse prognosis.• No association between NLR and response to chemotherapy was noted.

A study protocol of vaginal laser therapy in gynecological cancer survivors.

Objectives: Sexual dysfunction and radiation cystitis are common adverse events following radiotherapy for gynecological cancer (GC). This study aims to assess the efficacy of intravaginal CO2 laser on GC survivors with dyspareunia following pelvic radiation and/or brachytherapy.Methods: This is the study protocol of a randomized double-blind placebo-controlled trial. All participants will receive five therapies (active or placebo) at monthly intervals. Outcomes will include a 10-cm visual analog scale measuring dyspareunia, vaginal dryness, and other symptom intensity, 3-day voiding diary, Day-to Day Impact of Vaginal Aging questionnaire, Female Sexual Function Index, European Organization for Research and Treatment of Cancer Quality of Life questionnaire cervical cancer module, Urogenital Distress Inventory short form, King's Health Questionnaire, International Consultation on Incontinence Questionnaire short form/female lower urinary tract symptoms, patient perception of improvement, sexual satisfaction of male partners, vaginal maturation value, and Vaginal Health Index. Differences between groups will be assessed at baseline and 1, 3, 6, 9, and 12 months following the five laser therapies.Results: As this is a study protocol, the study is ongoing with an expected end of recruitment and analysis date of 2021.Conclusion: Pelvic radiotherapy for GC increases the 5-year survival rate but with a negative impact on women's quality of life due to sexual dysfunction and radiation cystitis onset. With this study, CO2 laser therapy will be evaluated for the first time in GC survivors treated with radiotherapy. ClinicalTrials.gov registration number: NCT03714581.

Paving the way for changing perceptions in breast surgery: a systematic literature review focused on oncological and aesthetic outcomes of oncoplastic surgery for breast cancer.

BACKGROUND: The emphasis on aesthetic outcomes and quality of life after breast cancer surgery has motivated breast surgeons to develop oncoplastic breast conserving surgery (OPS). Training programs are still rare in most countries, and there is little standardization, which challenges the scientific evaluation of these techniques. This systematic review aims to assess oncological and cosmetic outcomes of OPS. METHODS: After a strict selection process with precise inclusion and exclusion criteria, oncologic and aesthetic outcomes of oncoplastic surgery were searched, using the MEDLINE database up to September 30th, 2017. Available published literature was classified in levels of evidence. After a thorough screening process, only studies with the best level of evidence were included on selection. Systematic reviews and meta-analyses were not included for methodological reasons. RESULTS: Titles and abstracts of 2.854 citations were identified and after screening 15 prospective studies including 1.391 patients were reviewed and scored in detail. Local relapse was found in 2.8% of cases with a wide range of follow-up (from 6 to 74 months). Close margins were retrieved in 11% of cases and positive margins in 9.4% of cases. Mastectomy was implemented in 6.9% of breast cancer patients to whom OPS was performed. Good cosmetic outcomes were detected in 90.2% of patients undergoing OPS, leaving open issues for who should perform cosmetic evaluation and which method should be used. CONCLUSION: Tumor margins, mastectomy rates, and cosmetic outcomes of OPS have to be further improved by standardizing various aspects of OPS. Research efforts should focus on level I evidence assessing both oncological and aesthetic outcomes of OPS and survival rates.

Attachment of Coxiella burnetii to the zona pellucida of in vitro produced goat embryos.

Previous work demonstrated that after infection of in vivo derived caprine embryos, Coxiella burnetti (C. burnetii) showed a strong tendency to adhere to the zona pellicida (ZP). To investigate the risk of C. burnetii transmission via embryo transfer of in vitro-produced goat embryos the aim of this study was, (i) to evaluate the ability of C. burnetii to adhere to the intact zona pellicida of in vitro-produced goat embryos and to determine by confocal microscopy the location of the bacteria, (ii) to test the efficacy of IETS recommended rules for the washing of bovine embryos to eliminate C. burnetii. One hundred ZP-intact caprine embryos, produced in vitro, at the 8 to 16 cell stage, were randomly divided into 11 batches of eight to nine embryos. Nine batches were incubated for 18 h with 109Coxiella/ml of CbB1 strain (IASP, INRA Tours). The embryos then were recovered and washed in batches in 10 successive baths following the IETS guidelines. In parallel, two batches of embryos were subjected to similar procedures but without exposure to C. burnetii, to serve as the control group. One of the nine batches of infected embryos and one of the two non-infected control batches were separated to perform immunolabeling to locate the bacteria. C. burnetii DNA was detected by C-PCR in all eight batches of infected embryos after 10 successive washings. However, bacterial DNA was not detected in the embryo control batch. The first five washing media of the infected group were consistently found to be positive and Coxiella DNA was detected in the wash bath up to the 10th wash for two batches. After immunolabeling, the observation of embryos under confocal microscopy allowed C. burnetti to be found on the external part of the zona pellucida without deep penetration. This study clearly demonstrates that C. burnetii, after in vitro infection at 109Coxiella/ml, stick strongly to the external part of the zona pellucida of in vitro produced caprine embryos without deap penetration and that the 10 washings protocol recommended by IETS to eliminate the pathogenic agents of bovine embryos is unable to eliminate these bacteria from in vitro-produced goat embryo.

Can Chlamydia abortus be transmitted by embryo transfer in goats?

The objectives of this study were to determine (i) whether Chlamydia abortus would adhere to or penetrate the intact zona pellucida (ZP-intact) of early in vivo-derived caprine embryos, after in vitro infection; and (ii) the efficacy of the International Embryo Transfer Society (IETS) washing protocol for bovine embryos. Fifty-two ZP-intact embryos (8-16 cells), obtained from 14 donors were used in this experiment. The embryos were randomly divided into 12 batches. Nine batches (ZP-intact) of five embryos were incubated in a medium containing 4 × 10(7)Chlamydia/mL of AB7 strain. After incubation for 18 hours at 37 °C in an atmosphere of 5% CO2, the embryos were washed in batches in 10 successive baths of a phosphate buffer saline and 5% fetal calf serum solution in accordance with IETS guidelines. In parallel, three batches of ZP-intact embryos were used as controls by being subjected to similar procedures but without exposure to C. abortus. The 10 wash baths were collected separately and centrifuged for 1 hour at 13,000 × g. The washed embryos and the pellets of the 10 centrifuged wash baths were frozen at -20 °C before examination for evidence of C. abortus using polymerase chain reaction. C. abortus DNA was found in all of the infected batches of ZP-intact embryos (9/9) after 10 successive washes. It was also detected in the 10th wash fluid for seven batches of embryos, whereas for the two other batches, the last positive wash bath was the eighth and the ninth, respectively. In contrast, none of the embryos or their washing fluids in the control batches were DNA positive. These results report that C. abortus adheres to and/or penetrates the ZP of in vivo caprine embryos after in vitro infection, and that the standard washing protocol recommended by the IETS for bovine embryos, failed to remove it. The persistence of these bacteria after washing makes the embryo a potential means of transmission of the bacterium during embryo transfer from infected donor goats to healthy recipients and/or their offspring. Nevertheless, the detection of C. abortus DNA by polymerase chain reaction does not prove that the bacteria found was infectious. Further studies are required to investigate whether enzymatic and/or antibiotic treatment of caprine embryos infected by C. abortus would eliminate the bacteria from the ZP.

Molecular aspects and clinical methods for preserving ovarian reserves in women receiving cancer treatment.

Cancer prevalence is high, and of importance to cancer sufferers is the long term survival and normal activities resumption. Moreover, pregnancy is drawing interest for preserving ovarian reserves in post-chemotherapy affected women, especially of younger ages. The gonadotoxic effect of cancer treatment, involves mechanisms that are not fully understood, mainly due to the variety of molecular pathways triggered once therapeutic agents applied. Reported rates of premature ovarian failure after the treatment effect and the application of various treatment protocols, differ extensively due to the protocol itself but also due to the age of treated patients. Several options for preserving ovarian reserves are currently employed in the clinique, such as ovarian transposition, embryos cryopreservation and the use of gonadotropin-releasing hormone (GnRH) and its agonists/antagonists, but most of them are still under investigation. This paper reviews these methods and the molecular mechanisms that are possibly involved in the action of agents such as GnRH.

Chlamydiaceae and chlamydial infections in sheep or goats.

Chlamydiae induce a range of pathological syndromes in small ruminants. Abortion is the most common clinical expression of the infection that causes important economic losses and presents a risk to human health, particularly in pregnant women. The present paper gives an overview of chlamydial infections in sheep and goats, focusing specifically on abortion and on recent data brought by cellular and genomic approaches regarding genotyping, virulence of strains, epidemiology, diagnosis, pathogenesis and control of the disease.

MRI findings before and after abdominal radical trachelectomy (ART) for cervical cancer: a prospective study and review of the literature.

AIM: To report the authors' experience with dedicated pelvic magnetic resonance imaging (MRI) in young women with early-stage cervical cancer treated with abdominal radical trachelectomy (ART). MATERIALS AND METHODS: During a 5-year period, 21 patients, with biopsy-confirmed cervical carcinoma, International Federation of Gynaecology and Obstetrics (FIGO) stage ≤IB1, were considered for trachelectomy. All patients underwent pelvic MRI within 30 days prior to surgery. Tumour size, endocervical extension, extrauterine spread, and nodal status were noted. Postoperative MRI findings were reviewed in 16 patients. RESULTS: Nineteen of the 21 patients were treated with ART. In two patients, trachelectomy was aborted intraoperatively and radical hysterectomy was performed; preoperative MRI findings were consistent with surgicopathological examination in both patients. MRI correctly assessed tumour size in 18/21 patients, coming within 5 mm of the surgical specimen. Tumour size was underestimated in two cases because of circumferential growth (n = 1) or technical difficulties (n = 1). False-positive MRI result was due to post-biopsy inflammation (n = 1). MRI accurately identified absence of internal os involvement in 17/19 ART patients; false-positive MRI for internal os involvement were due to endocervical polyp (n = 1) and coexisting Nabothian cysts (n = 1). No trachelectomy patient had extrauterine disease or malignant nodes at MRI or final histology. Post-trachelectomy complications included hydrosalpinges (n = 3), lymphocysts (n = 2), isthmic stenosis (n = 1), and tumour relapse (n = 2). CONCLUSIONS: Dedicated pelvic MRI is helpful in assessing tumour size and endocervical extension in young women, candidates for ART. Hydrosalpinx may occur after ART and it may influence fertility potential.

Can Coxiella burnetii be transmitted by embryo transfer in goats?

The detection of significant bacterial loads of Coxiella burnetii in flushing media and tissue samples from the genital tracts of nonpregnant goats represents a risk factor for in utero infection and transmission during embryo transfer. The aim of this study was to investigate (1) whether cells of early goat embryos isolated from in vivo-fertilized goats interact with C. burnetii in vitro, (2) whether the embryonic zona pellucida (ZP) protects early embryo cells from infection, and (3) the efficacy of the International Embryo Transfer Society (IETS) washing protocol for bovine embryos. The study was performed in triple replicate: 12 donor goats, certified negative by ELISA and polymerase chain reaction, were synchronized, superovulated, and subsequently inseminated by Q fever-negative males. Sixty-eight embryos were collected 4 days later by laparotomy. Two-thirds of the resulting ZP-intact and ZP-free 8- to 16-cell embryos (9-9, 11-11, and 4-4 in replicates 1, 2, and 3, respectively) were placed in 1 mL minimum essential medium containing 10(9)C. burnetii CBC1 (IASP, INRA Tours). After overnight incubation at 37 °C and 5% CO2, the embryos were washed according to the IETS procedure. In parallel, the remaining third ZP-intact and ZP-free uninfected embryos (3-3, 5-5, and 2-2 in replicates 1, 2, and 3, respectively) were subjected to the same procedures, but without C. burnetii, thus serving as controls. The 10 washing fluids for all batches of each replicate were collected and centrifuged for 1 hour at 13,000 × g. The washed embryos and pellets were tested by polymerase chain reaction. Coxiella burnetii DNA was found in all batches of ZP-intact and ZP-free infected embryos after 10 successive washes. It was also detected in the first five washing fluids for ZP-intact embryos and in the first eight washing fluids for ZP-free embryos. None of the control batches (embryos and washing fluids) were found to contain bacterial DNA. These results clearly indicate that caprine early embryonic cells are susceptible to infection by C. burnetii. The bacterium shows a strong tendency to adhere to the ZP after in vitro infection, and the washing procedure recommended by the IETS for bovine embryos failed to remove it. The persistence of these bacteria makes the embryo a potential means of transmission to recipient goats. Further studies are needed to investigate whether the enzymatic treatment of caprine embryos infected by C. burnetii would eliminate the bacteria from the ZP.

Q fever in humans and farm animals in four European countries, 1982 to 2010.

Q fever is a disease of humans, caused by Coxiella burnetii, and a large range of animals can be infected. This paper presents a review of the epidemiology of Q fever in humans and farm animals between 1982 and 2010, using case studies from four European countries (Bulgaria, France, Germany and the Netherlands). The Netherlands had a large outbreak between 2007 and 2010, and the other countries a history of Q fever and Q fever research. Within all four countries, the serological prevalence of C. burnetii infection and reported incidence of Q fever varies broadly in both farm animals and humans. Proximity to farm animals and contact with infected animals or their birth products have been identified as the most important risk factors for human disease. Intrinsic farm factors, such as production systems and management, influence the number of outbreaks in an area. A number of disease control options have been used in these four countries, including measures to increase diagnostic accuracy and general awareness, and actions to reduce spillover (of infection from farm animals to humans) and human exposure. This study highlights gaps in knowledge, and future research needs.

VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2.

BACKGROUND: Vascular endothelial growth factor action in tumour angiogenesis is well characterised; nevertheless, it functions as a key element in the promotion of the immune system's evasion by tumours. We sought to investigate the possible direct effect of VEGF on T-cell activation and through which type of VEGF receptor it exerts this effect on cells isolated from ovarian cancer patients' ascites. METHODS: T cells isolated from the ascites of ovarian cancer patients were cultured with anti-CD3 and IL-2, with or without VEGF for 14 days and the number of viable T cells was counted. Cytotoxic activity of cultured T cells and expression of VEGF receptor-2 (VEGFR-2), was assayed. RESULTS: The addition of VEGF in cultures significantly reduced the number and proliferation rate of T cells in a dose-dependent manner and CD3(+) T cells expressed VEGFR-2 on their surface upon activation. Experiments with specific anti-VEGFR-2 antibodies revealed that the direct suppressive effect of VEGF on T-cell proliferation is mediated by VEGFR-2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells. CONCLUSION: Our study showed that ascites-derived T cells secrete VEGF and express VEGFR-2 upon activation. Vascular endothelial growth factor directly suppresses T-cell activation via VEGFR-2.

Safety of hormone replacement therapy in gynaecological cancer survivors.

Therapy for endometrial, ovarian and cervical cancer in young women can cause sudden onset of intense menopausal symptoms, such as hot flushes, emotional disorders and sexual dysfunction. In order to overcome these unpleasant and sometimes severe symptoms, hormone replacement therapy (HRT) has proven to be very effective. However, its safety remains controversial. We reviewed English literature and examined whether administration of HRT in this specific population is related with more recurrences and worse prognosis. Current scientific data, comprising mainly retrospective studies, suggest that recurrence rates and survival are comparable between HRT users and non-users. However, large randomised trials are missing and definitive conclusions cannot be drawn. Gynaecological cancer survivors using HRT, although they seem to have little if any risk for recurrence, should be correctly informed about the lack of strong evidence.

PRKAR1A gene analysis and protein kinase A activity in endometrial tumors.

PRKAR1A codes for the type 1a regulatory subunit (RIα) of the cAMP-dependent protein kinase A (PKA), an enzyme with an important role in cell cycle regulation and proliferation. PKA dysregulation has been found in various tumors, and PRKAR1A-inactivating mutations have been reported in mostly endocrine neoplasias. In this study, we investigated PKA activity and the PRKAR1A gene in normal and tumor endometrium. Specimens were collected from 31 patients with endometrial cancer. We used as controls 41 samples of endometrium that were collected from surrounding normal tissues or from women undergoing gynecological operations for other reasons. In all samples, we sequenced the PRKAR1A-coding sequence and studied PKA subunit expression; we also determined PKA activity and cAMP binding. PRKAR1A mutations were not found. However, PKA regulatory subunit protein levels, both RIα and those of regulatory subunit type 2b (RIIß), were lower in tumor samples; cAMP binding was also lower in tumors compared with normal endometrium (P<0.01). Free PKA activity was higher in tumor samples compared with that of control tissue (P<0.01). There are significant PKA enzymatic abnormalities in tumors of the endometrium compared with surrounding normal tissue; as these were not due to PRKAR1A mutations, other mechanisms affecting PKA function ought to be explored.

Three-dimensional power Doppler ultrasound for the study of cervical cancer and precancerous lesions.

OBJECTIVE: To evaluate the blood flow characteristics of the cervix in normal women and in women with cervical precancerous lesions or cervical cancer. METHODS: We studied 165 women with three-dimensional power Doppler ultrasound (3D-PDU), of whom 71 had cervical cancer, 61 had precancerous lesions and 33 were healthy controls. The cervix was manually traced in the stored volumes using 15° rotation steps and the following 3D-PDU indices were calculated: vascularization index (VI), flow index (FI) and vascularization flow index (VFI). These indices were compared among the study groups and were also correlated with features of the precancerous lesions group and cancer group. RESULTS: The three indices were all statistically significantly higher in the cervical cancer group and precancerous lesions group than in controls (P < 0.001). In addition, significantly higher values of all indices were found in the cervical cancer group than in the precancerous lesions group (P < 0.001). Further analysis according to patient characteristics in the cancer group showed that VI, FI and VFI were not significantly different in relation to grade, histology, presence of positive lymph nodes or lymphovascular space involvement (P > 0.05). However, VI was significantly higher in patients with Stages IIIB-IV cancer than in patients with less advanced disease (P = 0.045). In the cervical cancer group there was a significant positive correlation between 3D-PDU indices and cervical volume. CONCLUSION: 3D-PDU assessment of the cervix reveals significant differences in all indices studied between women with cervical precancerous lesions or cancer and healthy women. In women with cervical cancer, an advanced stage is associated with higher VI, but 3D-PDU indices are not related to other pathological characteristics.

Regeneration of uterine cervix at 6 months after large loop excision of the transformation zone for cervical intraepithelial neoplasia.

OBJECTIVE: To sonographically investigate cervical regeneration 6 months after large loop excision of the transformation zone (LLETZ) conisation for cervical intraepithelial neoplasia (CIN) pathology. DESIGN: Prospective observational study. SETTING: University Hospital setting. POPULATION: Women having LLETZ conisation for intraepithelial lesions in response to abnormal Papanicolaou smears or colposcopic findings. METHODS: Cervical dimensions were estimated before conisation and at 6 months with three-dimensional sonography and use of vocal™ software. Cone depth was measured using a ruler before fixation, and cone volume was measured using a volumetric tube and the fluid displacement technique. Cervical regeneration was sonographically estimated. MAIN OUTCOME MEASURES: Correlation of cervical volume regeneration with percentage of initial cervical volume excised and remaining cervical tissue immediately after conisation. RESULTS: A cohort of 112 women were initially recruited over a 2-year period and 73 women presented for ultrasound follow up at 6 months. Multivariate linear regression analysis showed that for women matched for age and initial cervical volume, if cervical volume excised was increased by 1% then regeneration of tissue deficit at the cervical crater was reduced by 1.37%. There also seemed to be a cutoff point suggesting that when >14% of initial cervical volume was excised, the tissue deficit at the cervical crater at 6 months was restored by <75% and there was >25% of remaining tissue deficit. CONCLUSIONS: Cervical regeneration at 6 months after excision is dependent on the percentage of initial cervical volume excised and on the remaining cervical tissue immediately after conisation. The greater the cone and the less cervical tissue remaining, the less the degree of cervical regeneration achieved.