Current and Emerging Strategies for Tubo-Ovarian Cancer Diagnostics.

Tubo-ovarian cancer is the most lethal gynaecological cancer. More than 75% of patients are diagnosed at an advanced stage, which is associated with poorer overall survival. Symptoms at presentation are vague and non-specific, contributing to late diagnosis. Multimodal risk models have improved the diagnostic accuracy of adnexal mass assessment based on patient risk factors, coupled with findings on imaging and serum-based biomarker tests. Newly developed ultrasonographic assessment algorithms have standardised documentation and enable stratification of care between local hospitals and cancer centres. So far, no screening test has proven to reduce ovarian cancer mortality in the general population. This review is an update on the evidence behind ovarian cancer diagnostic strategies.

Pulmonary benign metastasizing uterine leiomyoma (PBML): a case report and review of the literature.

Benign metastasizing leiomyoma (BML) is a rare disorder characterized by the presence of benign smooth muscle tumours in extrauterine sites, typically the lungs. It classically involves perimenopausal women with a history of uterine surgery. The condition follows an indolent course but may cause clinical symptoms with large or widespread lesions. Case presentation: The authors report the case of a 47-year-old female who presented with a 6-month history of irregular vaginal bleeding and severe hot flushes. The patient had no previous history of gynaecological surgery. Ultrasonography and subsequent MRI identified a suspicious 105×65 mm mass involving the right uterine cornu and broad ligament. Computed tomography identified bilateral lung nodules, suspicious for metastases. Histological assessment of the final uterine surgical specimen identified a benign dissecting leiomyoma involving the broad ligament and cervix. BML was diagnosed after thoracoscopic resection of a lung lesion which revealed a histologically identical tumour with entrapped normal lung alveoli. Clinical discussion: This case shows that there is a minority of patients without previous uterine surgery who still go on to develop pulmonary BML. In our case, a combined treatment approach was adopted, involving substitution of hormone replacement therapy to a non-hormonal alternative, thoracoscopic resection of lung lesions and interval surveillance imaging of the chest. Conclusions: BML is a rare condition but should be considered as a differential in women with pulmonary nodules and a history of uterine leiomyomata. Its diagnosis and subsequent counselling can be challenging; therefore cases should be treated by multidisciplinary teams in tertiary specialized centres.

A review of the pathophysiology and evidence-based management of varicoceles and pelvic congestion syndrome.

Pelvic congestion syndrome (PCS) in females and varicoceles in males may be regarded as closely related conditions since the main pathophysiological cause for both processes is pelvic venous insufficiency. Varicoceles are more prevalent amongst sub-fertile males, with an approximate incidence of 15% in the general male population. PCS is commonly diagnosed amongst premenopausal multiparous women, representing one of the leading causes of chronic pelvic pain. Both conditions appear to be predominantly left-sided and are associated with oxidative stress and pro-inflammatory cascades with subsequent effects on fertility. Clinical examination and pelvic ultrasonography play an essential role in the assessment of varicoceles, PCS and chronic pelvic pain. Venography is generally considered as a gold-standard procedure for both conditions. There is still much debate on how these conditions should be managed. This review article provides a comparative analysis of the underlying pathophysiological mechanisms of both PCS and varicoceles, their impact on fertility, as well as their clinical management.

GYNOCARE Update: Modern Strategies to Improve Diagnosis and Treatment of Rare Gynecologic Tumors­Current Challenges and Future Directions

More than 50% of all gynecologic tumors can be classified as rare (defined as an incidence of ≤6 per 100,000 women) and usually have a poor prognosis owing to delayed diagnosis and treatment. In contrast to almost all other common solid tumors, the treatment of rare gynecologic tumors (RGT) is often based on expert opinion, retrospective studies, or extrapolation from other tumor sites with similar histology, leading to difficulty in developing guidelines for clinical practice. Currently, gynecologic cancer research, due to distinct scientific and technological challenges, is lagging behind. Moreover, the overall efforts for addressing these challenges are fragmented across different European countries and indeed, worldwide. The GYNOCARE, COST Action CA18117 (European Network for Gynecological Rare Cancer Research) programme aims to address these challenges through the creation of a unique network between key stakeholders covering distinct domains from concept to cure: basic research on RGT, biobanking, bridging with industry, and setting up the legal and regulatory requirements for international innovative clinical trials. On this basis, members of this COST Action, (Working Group 1, "Basic and Translational Research on Rare Gynecological Cancer") have decided to focus their future efforts on the development of new approaches to improve the diagnosis and treatment of RGT. Here, we provide a brief overview of the current state-of-the-art and describe the goals of this COST Action and its future challenges with the aim to stimulate discussion and promote synergy across scientists engaged in the fight against this rare cancer worldwide.

Purified and specific cytoplasmic pollen extract: a non-hormonal alternative for the treatment of menopausal symptoms.

Research into non-hormonal, alternative therapies is necessary for women for whom menopausal hormone therapy is contraindicated or for women who do not wish to take hormones. This review focuses on one such non-hormonal option, namely, purified and specific cytoplasmic pollen extract, or PureCyTonin®. This extract has been evaluated in several preclinical and clinical studies, where it demonstrated its value as a safe and non-estrogenic alternative for menopause. This review presents the beneficial effects of PureCyTonin® in the treatment of menopausal symptoms (e.g. hot flushes) in healthy women, as well as in premenstrual syndrome. We discuss the mechanism of action of PureCyTonin®, an SSRI-'like' therapy. The lack of estrogenic effect demonstrated in preclinical studies suggests that PureCyTonin® may also be a suitable option for the management of menopausal symptoms in women with breast cancer.

MiRNA influences in mesenchymal stem cell commitment to neuroblast lineage development.

Mesenchymal Stem Cells (MSCs) are widely used in therapeutic applications. Their plasticity and predisposition to differentiate into a variety of cell types, including those of the neuronal lineage, makes them ideal to study whether a selection of miRNAs may direct the differentiation of MSCs into neuroblasts or neuroblastoma to mature neurons. Following a short-listing, miR-107, 124 and 381 were selected as the most promising candidates for this differentiation. MSCs differentiated into cells of the neural lineage (Conditioned Cells) upon addition of conditioned medium (rich in microvesicles containing miRNAs) obtained from cultured SH-SY5Y neuroblastoma cells. Characterisation of stemness (including SOX2, OCT4, Nanog and HCG) and neural markers (including Nestin, MASH1, TUBB3 and NeuN1) provided insight regarding the neuronal state of each cell type. This was followed by transfection of the three miRNA antagonists and mimics, and quantification of their respective target genes. MiRNA target gene expression following transfection of MSCs with miRNA inhibitors and mimics demonstrated that these three miRNAs were not sufficient to induce differentiation. In conditioned cells the marginal changes in the miRNA target expression levels reflected potential for the modulation of intermediate neural progenitors and immature neuron cell types. Transfection of various combinations of miRNA inhibitors and/or mimics revealed more promise. Undoubtedly, a mix of biomolecules is being released by the SH-SY5Y in culture that induce MSCs to differentiate. Screening for those biomolecules acting synergistically with specific miRNAs will allow further combinatorial testing to elucidate the role of miRNA modulation.

Religious attitudes to gamete donation.

Religious teachings encourage fertility. The rapid progress of reproductive science has proved a challenge to interpret and adapt to assisted reproductive techniques which were not even dreamed of in ancient scriptures. The clash between religion and science has produced separate laws for each religion and reproductive practitioners are often at a loss to understand and accept them. Four lay members of different religions have set out the thinking of their religion regarding assisted reproductive techniques, concentrating in particular on gamete donation. Similarities rather than differences seem to dominate in the attitudes of the orthodox Catholic, Hindu, Jewish and Muslim beliefs and doctrines. The knowledge of these various religious beliefs and attitudes, as well as promoting a greater understanding, should help reproductive practitioners to accept and abide by the religious wishes of their patients.

Sentinel Lymph Node Biopsy in the Management of Vulvar Carcinoma: An Evidence-Based Insight.

OBJECTIVE: Lymph node metastasis has been shown to represent the most significant prognostic factor in vulvar carcinoma. Because only 25% to 35% of patients with early stage disease have lymph node metastases, a significant 65% to 75% possibly do not benefit from elective inguinofemoral lymphadenectomy considering the related morbidities of wound infection, breakdown, and lower limb lymphedema. This review article aims to present and summarize the evidence available with regard to sentinel lymph node (SLN)-guided management of vulvar carcinoma. MATERIALS AND METHODS: A literature search was performed in MEDLINE resources using the subject headings "vulvar neoplasms," "sentinel lymph node," "sentinel lymph node biopsy," and "lymphatic metastasis." This search returned 886 articles that were published through January 2017. Prospective studies investigating sentinel node identification techniques and their impact on vulvar cancer management and prognosis were considered. Case reports were excluded from the review. RESULTS: Technetium-99-m-labeled nanocolloid with or without blue dye and more recently indocyanine green fluorescence have been the main techniques used for SLN identification in vulvar carcinoma. Radioisotope and near-infrared techniques have been shown to be superior to blue dye particularly with midline lesions that drain bilaterally or that drain directly to a deep pelvic node. Patients with a small unifocal primary tumor (<4 cm) and no obvious preoperative metastasis have been shown to have low groin recurrence rates and excellent disease-specific survival rates with minimal treatment-related morbidity when undergoing SLN biopsy-guided management. CONCLUSIONS: Sentinel lymph node biopsy-guided management seems to be safe when restricted to International Federation of Gynecology and Obstetrics IB to II cases where tumors are unifocal, less than 4 cm in size, and when there is no evidence of lymph node metastasis on clinical/radiological assessment. This reduces operative morbidity in this cohort of patients.

The role of vitamin D in osteoporosis.

It is known that circulating vitamin D predominantly originates from cutaneous synthesis and therefore should be considered as a hormone rather than a vitamin. Vitamin D deficiency (<50nmol/L) is a worldwide epidemic with multiple implications on human health, due to its role in various physiological systems. Various studies have shown that with higher serum 25 hydroxyvitamin D levels, there is a decrease in the incidence of non-vertebral and hip fractures. There is limited research data on the management of vitamin D deficiency using therapeutic doses. The majority of studies focus on lower physiological doses rather than high pharmacological doses. In order to reach serum levels of 75nmol/L from a deficiency state, higher doses than 800-1000IU/day are required. Future focus should be on the implications of a rise in systemic 25(OH)D3 levels from a deficiency state to 75nmol/L on bone density and fracture risk, and the use of high doses in cases of vitamin D deficiency. Vitamin D treatment and supplementation need to be re-evaluated in the light of new evidence suggesting that high pharmacological doses need to be used in order to obtain the desired effect in the prevention of osteoporosis and recurrence of osteoporotic fractures.

ISGE statement on oral emergency contraception.

Unintended pregnancy is an important public health problem worldwide. Unwanted pregnancies may end in induced abortion (legal or illegal, safe or unsafe) or in childbirth. In many parts of the world both can be life threatening. Even where both are safe, abortion is distressing for all concerned while unwanted births often lead to poor health and social outcomes for both the mother and her child.

Pre-operative pain sensitivity: A prediction of post-operative outcome in the obstetric population.

CONTEXT: Experimental assessments can determine pain threshold and tolerance, which mirror sensitivity to pain. This, in turn, influences the post-operative experience. AIMS: The study intended to evaluate whether the pre-operative pressure and electrical pain tests can predict pain and opioid requirement following cesarean delivery. SETTINGS AND DESIGN: Research was conducted on females scheduled for cesarean section at a tertiary care hospital of the state. Twenty women were enrolled, after obtaining written informed consent. MATERIALS AND METHODS: PAIN ASSESSMENT WAS PERFORMED ON THE EVE OF CESAREAN SECTIONS USING THREE DEVICES: PainMatcher(;) determined electrical pain threshold while the algometers PainTest(™) FPN100 (manual) and PainTest(™) FPX 25 (digital) evaluated pressure pain threshold and tolerance. Post-operative pain relief included intravenous morphine administered by patient-controlled analgesia, diclofenac (100 mg, every 12 h, rectally, enforced) and paracetamol (1000 mg, every 4-6 h, orally, on patient request). Pain scores were reported on numerical rating scales at specified time intervals. STATISTICAL ANALYSIS USED: Correlational and regression statistics were computed using IBM SPSS Statistics 21 software (IBM Corporation, USA). RESULTS: A SIGNIFICANT CORRELATION WAS OBSERVED BETWEEN MORPHINE REQUIREMENT AND: (1) electrical pain threshold (r = -0.45, P = 0.025), (2) pressure pain threshold (r = -0.41 P = 0.036) and (3) pressure pain tolerance (r = -0.44, P = 0.026) measured by the digital algometer. The parsimonious regression model for morphine requirement consisted of electrical pain threshold (r(2)= 0.20, P = 0.049). The dose of morphine consumed within 48 h of surgery decreases by 0.9 mg for every unit increment in electrical pain threshold. CONCLUSIONS: The predictive power of pain sensitivity assessments, particularly electrical pain threshold, may portend post-cesarean outcomes, including opioid requirements.

Skin connective tissue and ageing.

Collagen atrophy is a major factor in skin ageing. A strong correlation exists between skin collagen loss and oestrogen deficiency caused by the menopause. Skin ageing is associated with a progressive increase in extensibility and a reduction in elasticity. With increasing age, the skin also becomes more fragile and susceptible to trauma, leading to more lacerations and bruising. Furthermore, wound healing is impaired in older women. Oestrogen use after the menopause increases collagen content, dermal thickness and elasticity, and it decreases the likelihood of senile dry skin. Large-scale clinical trials are necessary to help make informed recommendations about postmenopausal oestrogen use and its role in preventing skin ageing.

An unusual site for calciphylaxis: a case report.

BACKGROUND: Calciphylaxis is a rare condition characterized by calcification of the tunica media of small arteries with or without endovascular fibrosis, extravascular calcification and vascular thrombosis, leading to tissue ischemia and hence necrosis of tissues supplied by respective vessel. CASE REPORT: An 83-year-old lady presented with a 2-week history of rapidly progressing painful necrotic vulval lesion. This patient was being treated medically with bisphosphonates for mild hypercalcaemia secondary to a parathyroid adenoma. The diagnosis of calciphylaxis was made by biopsy of lesion, revealing extensive necrotic areas and multiple abscesses with numerous thrombosed and calcified blood vessels. CONCLUSIONS: This case shows an unusual presentation of calciphylaxis, in a patient with primary hyperparathyroidism, in the absence of end stage renal failure. The pathogenesis of the condition is still relatively unknown. Particularly of note in this case is the presentation of the lesion 9 months after the start of treatment with bisphosphonate after the relative decrease of serum parathyroid levels and serum calcium levels. This leads to the question of initiation of the pathology - did the bisphosphonate treatment have an input in initiation of the lesion? The case under review adds a new differential diagnosis to necrotic vulval lesions, other than malignancy.

Synergistic effect on the treatment of menorrhagia by endometrial biopsy followed by contemporaneous insertion of the levonorgestrel intrauterine system.

OBJECTIVE: To evaluate the efficacy of endometrial biopsy followed by intrauterine system-releasing levonorgestrel (LNG-IUS) insertion in the treatment of women with menorrhagia. METHOD: This was a retrospective, non-comparative study. Ninety-two patients who had menorrhagia due to non-malignant causes were sequentially recruited into the study over a 3-year period (age range 29-51 years). Patients with a uterine size more than 12 weeks were not included. A LNG-releasing intrauterine system was inserted during the mid-cycle immediately after an endometrial biopsy was taken. One year after the closure of the study period, the women recruited were then contacted by telephone or by direct questioning at the outpatient clinic as to the outcome of the above treatment. RESULTS: The most common (15%) complaint regarding bleeding patterns at 3-6 months after insertion was spotting and intermenstrual bleeding. Following the introduction of the LNG-IUS, six women required a hysterectomy for various reasons. The remaining 86 women (93.5%) continued the use of LNG-IUS. CONCLUSION: LNG-IUS following an endometrial biopsy is an effective treatment for menorrhagia due to benign causes and could be an alternative to other forms of medical and surgical treatments.

EMAS clinical guide: selective estrogen receptor modulators for postmenopausal osteoporosis.

Osteoporosis and the resulting fractures are major public health issues as the world population is ageing. Various therapies such as bisphosphonates, strontium ranelate and more recently denosumab are available. This clinical guide provides the evidence for the clinical use of selective estrogen modulators (SERMs) in the management of osteoporosis in postmenopausal women.

Iliac vessel wall thickness in menstrual and hormone treated and untreated postmenopausal women.

OBJECTIVE: To assess iliac vessel wall thickness in different groups of women. METHOD: Three groups of women were menopausal and were classified by hormone replacement therapy (HRT) (n = 32), atherosclerotic risk factors (n = 14) and an untreated group of postmenopausal women (n = 29), two groups of menstrual women, above 35 years (N = 35) and below 35 years (n = 16). In these groups of women, a 3.5 MHz ultrasound was used to assess the combined vessel wall thickness of the right iliac artery inner wall and vein outer wall. RESULTS: The iliac vessel wall thickness was found significantly high in the menopausal group of women possessing high risk factors for atherosclerosis (4.3 ± 0.08 mm) and the untreated menopausal group of women (3.9 ± 0.08 mm) compared to the other three groups (p < 0.0001) (Mann-Whitney U test). The vessel wall thickness of the HRT group was 2.96 ± 0.09 mm, the older menstrual group 2.61 ± 0.07 mm, and 2.0 ± 0.06 mm in the young menstrual group. The HRT group had a significantly thicker iliac vessel wall compared to the young menstrual group (p < 0.001). CONCLUSION: These results confirm the significant impact of high risk factors, such as smoking, hyperlipidaemia and diabetes, on the vessel wall thickness due to accelerated atherosclerosis. This study also suggests that the oestrogenaemic state of a woman may affect the health of the vessel wall.

Anti-Müllerian hormone reduces follicle sensitivity to follicle-stimulating hormone in human granulosa cells.

OBJECTIVE: To determine that anti-Müllerian hormone (AMH) has been shown to inhibits E(2) production in rodents and in luteinized granulosa cells (GC). We determined whether this occurs in human cells most highly expressing AMH (i.e., from small antral follicles) and whether this is an effect on aromatase promoter activity. We also investigated the effects of AMH on other factors determining FSH sensitivity. DESIGN: Granulosa cells were exposed to AMH with and without gonadotropins for 48 hours. SETTING: University laboratory. PATIENT(S): Not applicable. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Aromatase and FSH receptor messenger RNA expression measured using real time quantitative polymerase chain reaction (PCR). Aromatase promoter II activity measured using a luciferase assay. Estradiol, inhibin A and B, and vascular endothelial growth factor production were measured in the conditioned medium. RESULT(S): The AMH decreased gonadotropin-stimulated aromatase expression and decreased forskolin-stimulated aromatase in KGN cells and this effect was through a dose-dependent inhibition of promoter II. Surprisingly, AMH also reduced FSH receptor mRNA expression. High AMH doses had no effect on inhibin B, whereas a low dose stimulated production. There was no effect on inhibin A or vascular endothelial growth factor. CONCLUSION(S): The AMH inhibits factors affecting FSH sensitivity. As AMH levels decrease with follicle growth, this inhibition would be removed. The AMH overproduction in anovulatory polycystic ovaries (PCO) may therefore restrict folliculogenesis by an inhibitory effect on FSH sensitivity, thereby contributing to anovulation.

Predictors of post-caesarean section pain and analgesic consumption.

BACKGROUND: Ideally, the intensity of postoperative pain should be predicted so as to customize analgesia. The objective of this study was to investigate whether preoperative electrical and pressure pain assessment can predict post-caesarean section pain and analgesic requirement. MATERIALS AND METHODS: A total of 65 subjects scheduled for elective caesarean section, who gave written informed consent, were studied. Preoperatively, PainMatcher(®) was used to evaluate electrical pain threshold, while manual PainTest™ FPN 100 Algometer and digital PainTest™ FPX 25 Algometer determined pressure pain threshold and tolerance. Postoperatively, numerical rating scales were used to assess pain at regular time intervals. Patients received intramuscular pethidine (100mg, 6 hourly), rectal diclofenac (100mg, 12 hourly), and oral paracetamol (1g, p.r.n.) for pain relief. Statistical analysis was conducted using PASW Statistics 18 software. RESULTS: Preoperative electrical pain threshold correlated significantly with post-caesarean pain scores at 6 and 24 hours (r = -0.26, P < 0.02; r = -0.23, P < 0.04, respectively), and with the quantity of paracetamol consumed by the patient within 48 hours of surgery (r = -0.33, P < 0.005). Preoperative pressure pain tolerance measured by PainTest™ FPX 25 Algometer was significantly correlated with pain scores 6 hours postsurgery (r = -0.21, P < 0.05). Pain scores 6 hours post-caesarean section correlated significantly with anesthesia-general or spinal (F = 4.22, v(1) = 1, v(2) = 63, P < 0.05). CONCLUSIONS: The predictive methods proposed may aid in identifying patients at greater risk for postoperative pain. Electrical pain threshold could be useful in personalizing the postoperative analgesic protocol.

Obstetric outcome and cytokine levels in threatened miscarriage.

OBJECTIVES: To evaluate the proportion of women with threatened miscarriage (TM) who proceed to miscarriage in a population of single ethnicity and to investigate prospectively their risk of adverse pregnancy outcome in relationship with the cytokines levels in their circulation. METHODS: We conducted a prospective observational study over a period of 1 year of 94 Maltese women presenting with TM at the same hospital and compared their clinical data with those of 564 age-matched controls from the National Obstetric Information System (NOIS) of Malta. Main outcome measures included gestational age and weight at delivery and incidence of adverse pregnancy outcomes. A pilot study was carried out, where in subgroups of 10 women with TM (n=10), non-pregnant women (n=12), normal pregnant controls (n=9) and women presenting with missed-miscarriage (n=11), the plasma levels of ß-human chorionic gonadotrophin (ß-hCG), tumour necrosis factor α (TNFα), interferon γ (IFNγ), interleukin-6 (IL-6), interleukin-10 (IL-10) and TNF-receptors 1 (R1) and 2 (R2) were measured. RESULTS: Of the women presenting with TM, 25 (26.6%) proceeded to complete miscarriage. The TM group had also a significantly higher incidence of antepartum haemorrhage (p<0.005), pre-eclampsia (p<0.05), foetal growth restriction (p<0.05), premature labour (p<0.001) and retained placenta (p<0.005). In the pilot biochemical analysis, significantly (p<0.05) higher levels of TNFα and lower levels of TNFR2 were found in the TM subgroup compared to non-pregnant controls. The ratio TNFα/IL-10 was significantly (p<0.05) higher and the ß-hCG levels was significantly lower (p<0.01) in missed-miscarriage and non-pregnant subgroups than in TM and normal pregnant controls. The IFNγ/1L-10 and IFNγ/1L-6 ratio were significantly (<0.001) different between the four subgroups with the lowest level found in TM. No similar gradient was found for the TNFα/1L-6 ratio. CONCLUSION: Women presenting with TM are at significantly increased risk of adverse pregnancy outcome and the pathophysiology of these conditions involves a change in the Th1/Th2 balance. Changes in levels of cytokines could help to predict and thus prevent the development of some of these complications.