Sexual and Psychosexual Consequences of Treatment for Gynaecological Cancers.

Modern multimodality cancer treatment has led to a rise in cancer survivors, and by 2030 the survival rate is estimated to increase by 31.4%. This is an impressive survival statistic on which clinicians and services continue to build. One of the less well-acknowledged consequences of survivorship among health professionals and patients alike is female sexual dysfunction, despite it occurring in more than 60% of women diagnosed with cancer. The systematic assessment and management of late effects from cancer lack integration within current models of oncology follow-up. Although highly prevalent, issues linked to sexual health are often not addressed among survivors. This overview aims to focus on the sexual impact of gynaecological cancer treatment. Clinicians should raise the topic of the sexual consequences of cancer treatment as a legitimate aspect of survivorship and service provision. Increased focus on the sexual consequences of treatment and cancer survivorship may in time lead to greater clinical recognition, service development and, most importantly, increase research focused on the effective management of what remains a neglected aspect of cancer care.

Vaginal epithelioid angiosarcoma: A literature review of a rare entity in an unusual site.

We describe an extremely rare case of a 66-year-old woman with a vaginal epithelioid angiosarcoma. She presented with constitutional symptoms, pelvic pain, vaginal bleeding, and a violaceous vaginal lesion. A thorough gynaecological examination, tissue biopsy and imaging were crucial to establish an accurate diagnosis. With only 3 other cases reported in the literature, epithelioid angiosarcoma of the vagina seem to present late due to their nonspecific presentation and secluded location. Once diagnosed, optimal treatment is difficult to determine and together with the overly aggressive behaviour of these tumours, they are associated with a poor prognosis. To our knowledge, our case study and systematic literature review is the first to compare the management outcomes of epithelioid subtype angiosarcomas of the vagina. The rarity of this pathology contributes to diagnostic difficulties and lack of consensus regarding treatment of angiosarcomas of the vagina.

The association between diabetes, comorbidities, body mass index and all-cause and cause-specific mortality among women with endometrial cancer.

OBJECTIVE: Although endometrial cancer (EC) is associated with relatively good survival rates overall, women diagnosed with high-risk subtypes have poor outcomes. We examined the relationship between lifestyle factors and subsequent all-cause, cancer-specific and non-cancer related survival. METHODS: In a cohort of 1359 Australian women diagnosed with incident EC between 2005 and 2007 pre-diagnostic information was collected by interview at recruitment. Clinical and survival information was abstracted from women's medical records, supplemented by linkage to the Australian National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific survival (EC death vs. non-EC death) associated with each exposure, overall and by risk group (low-grade endometrioid vs. high-grade endometrioid and non-endometrioid). RESULTS: After a median follow-up of 7.1 years, 179 (13%) women had died, with 123 (69%) deaths from EC. As expected, elevated body mass index (BMI), diabetes and the presence of other co-morbidities were associated with a significantly increased risk of all-cause and non-cancer related death. Women with diabetes had higher cancer-specific mortality rates (HR 2.09, 95% CI 1.31-3.35), particularly those who had were not obese (HR 4.13, 95% CI 2.20-7.76). The presence of ≥2 other co-morbidities (excluding diabetes) was also associated with increased risk of cancer-specific mortality (HR 3.09, 95% CI 1.21-7.89). The patterns were generally similar for women with low-grade and high-grade endometrioid/non-endometrioid EC. CONCLUSION: Our findings demonstrate the importance of diabetes, other co-morbidities and obesity as negative predictors of mortality among women with EC but that the risks differ for cancer-specific and non-cancer related mortality.

The value of local registry data for describing cervical cancer management and outcomes over three decades in Australia.

Registry data on invasive cervical cancers (n = 1,274) from four major hospitals (1984-2012) were analysed to determine their value for informing local service delivery in Australia. The methodology comprised disease-specific survival analyses using Kaplan-Meier product-limit estimates and Cox proportional hazards models and treatment analyses using logistic regression. Five- and 10-year survivals were 72% and 68%, respectively, equating with relative survival estimates for Australia and the USA. Most common treatments were surgery and radiotherapy. Systemic therapies increased in recent years, generally with radiotherapy, but were less common for residents from less accessible areas. Surgery was more common for younger women and early-stage disease, and radiotherapy for older women and regional and more advanced disease. The proportion of glandular cancers increased in-step with national trends. Little evidence of variation in risk-adjusted survival presented over time or by Local Health District. The study illustrates the value of local registry data for describing local treatment and outcomes. They show the lower use of systemic therapies among residents of less accessible areas which warrants further investigation. Risk-adjusted treatment and outcomes did not vary by socio-economic status, suggesting equity in service delivery. These data are important for local evaluation and were not available from other sources.

WOMEN IN CANCER THEMATIC REVIEW: Ovarian cancer-peritoneal cell interactions promote extracellular matrix processing.

Ovarian cancer has a distinct tendency for metastasising via shedding of cancerous cells into the peritoneal cavity and implanting onto the peritoneum that lines the pelvic organs. Once ovarian cancer cells adhere to the peritoneal cells, they migrate through the peritoneal layer and invade the local organs. Alterations in the extracellular environment are critical for tumour initiation, progression and intra-peritoneal dissemination. To increase our understanding of the molecular mechanisms involved in ovarian cancer metastasis and to identify novel therapeutic targets, we recently studied the interaction of ovarian cancer and peritoneal cells using a proteomic approach. We identified several extracellular matrix (ECM) proteins including, fibronectin, TGFBI, periostin, annexin A2 and PAI-1 that were processed as a result of the ovarian cancer-peritoneal cell interaction. This review focuses on the functional role of these proteins in ovarian cancer metastasis. Our findings together with published literature support the notion that ECM processing via the plasminogen-plasmin pathway promotes the colonisation and attachment of ovarian cancer cells to the peritoneum and actively contributes to the early steps of ovarian cancer metastasis.

The role of ABC transporters in ovarian cancer progression and chemoresistance.

Over 80% of ovarian cancer patients develop chemoresistance which results in a lethal course of the disease. A well-established cause of chemoresistance involves the family of ATP-binding cassette transporters, or ABC transporters that transport a wide range of substrates including metabolic products, nutrients, lipids, and drugs across extra- and intra-cellular membranes. Expressions of various ABC transporters, shown to reduce the intracellular accumulation of chemotherapy drugs, are increased following chemotherapy and impact on ovarian cancer survival. Although clinical trials to date using ABC transporter inhibitors have been disappointing, ABC transporter inhibition remains an attractive potential adjuvant to chemotherapy. A greater understanding of their physiological functions and role in ovarian cancer chemoresistance will be important for the development of more effective targeted therapies. This article will review the role of the ABC transporter family in ovarian cancer progression and chemoresistance as well as the clinical attempts used to date to reverse chemoresistance.

Antibody-based immunotherapy for ovarian cancer: where are we at?

Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM×anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I-III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimens.

Impact of weight change and weight cycling on risk of different subtypes of endometrial cancer.

AIM: Obesity is an established risk factor for endometrial cancer. Associations tend to be stronger for the endometrioid subtype. The role of adult weight change and weight cycling is uncertain. Our study aimed to determine whether there is an association between different adult weight trajectories, weight cycling and risk of endometrial cancer overall, and by subtype. METHODS: We analysed data from the Australian National Endometrial Cancer study, a population-based case-control study that collected self-reported information on height, weight at three time points (age 20, maximum and 1 year prior to diagnosis [recent]), intentional weight loss/regain (weight cycling) from 1398 women with endometrial cancer and 1538 controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression analysis. RESULTS: Relative to women who maintained a stable weight during adulthood, greater weight gain after the age of 20 was associated with increased risk of endometrial cancer (OR for gain 40+kg all subtypes 5.3, 95% CI 3.9-7.3; endometrioid 6.5, 95% CI 4.7-9.0). The strongest associations were observed among women who were continually overweight from the age of 20 (all subtypes OR 3.6, 95% CI 2.6-5.0). Weight cycling was associated with increased risk, particularly among women who had ever been obese (OR 2.9 95% CI 1.8-4.7), with ~3-fold risks seen for both endometrioid and non-endometrioid tumour subtypes. Women who had intentionally lost weight and maintained that weight loss were not at increased risk. CONCLUSION: These results suggest that higher adult weight gain, and perhaps weight cycling, independently increase the risk of endometrial cancer, however women who lost weight and kept that weight off were not at increased risk.

Proteins' promise--progress and challenges in ovarian cancer proteomics.

Ovarian cancer is the leading cause of gynaecological cancer death. The mortality rate of ovarian cancer could be greatly decreased if there were a screening test which was able to detect the disease at an early stage, resulting in an increased probability of cure. The most promising prospect for the early detection of ovarian cancer comes from the rapidly advancing field of clinical proteomics. An increasing number of reports on the potential clinical application of proteomics research for early detection as well as risk assessment and management of ovarian cancer are being published. Although the research is very promising, major technical challenges are still preventing new discoveries in ovarian cancer proteomics from being translated into clinical practice.

Does retention of the ovaries improve long-term survival after hysterectomy? A gynecological oncological perspective.

Ovarian cancer is, in most cases, a lethal disease as it is virtually impossible to diagnose at an early stage and almost impossible to treat successfully when detected at an advanced stage. In postmenopausal women, there is no prevention for ovarian cancer but oophorectomy. Therefore, from the gynecological oncological perspective, where benign gynecological pathology requires surgery in postmenopausal women, oophorectomy should be the preferred option.

Tissue and plasma expression of the angiogenic peptide adrenomedullin in breast cancer.

Adrenomedullin (ADM) is an angiogenic factor that has also been shown to be a mitogen and a hypoxia survival factor for tumour cells. These properties point to ADM as a potential promoter of human malignancies, but little data are available concerning the expression of ADM in human breast cancer. In the present work, we have examined ADM peptide expression in a series of malignant breast tumours by immunohistochemistry using a newly developed anti-ADM monoclonal antibody. In addition, ADM plasma concentrations in breast cancer patients and healthy controls were determined by radioimmunoassay. Of the examined breast cancer samples, 27/33 (82%) showed a moderate to strong staining intensity. ADM-peptide expression in breast tumours was significantly correlated with axillary lymph node metastasis (P=0.030). Analysis of ADM plasma concentrations showed no significant difference between the circulating ADM levels of breast cancer patients and healthy controls. However, a significant positive correlation was found between tumour size and plasma ADM levels (r=0.641, P=0.017). Moreover, ADM levels in breast cancer patients correlated with the presence of lymph node metastasis (P=0.002). In conclusion, we have shown for the first time that ADM peptide is widely expressed in breast cancer and that the degree of expression is associated with lymph node metastasis. ADM peptide in plasma of breast cancer patients reflects the size of the primary tumour, but is unlikely to be a useful tumour marker for the detection of breast cancer. Plasma ADM might represent an independent predictor of lymph node metastasis. The clinical implications of these findings remain to be evaluated.

Menorrhagia: an update.

Menorrhagia is defined as a 'complaint of heavy cyclical menstrual bleeding occurring over several consecutive cycles'. Objectively it is a total menstrual blood loss equal to or greater than 80 ml per menstruation. It is estimated that approximately 30% of women complain of menorrhagia. Excessive bleeding is the main presenting complaint in women referred to gynecologists and it accounts for two-thirds of all hysterectomies, and most of endoscopic endometrial destructive surgery. Thus, menorrhagia is an important healthcare problem. Its etiology, investigation, medical and surgical management are described. In approximately 50% of cases of menorrhagia no pathology is found at hysterectomy. Abnormal levels of prostaglandins or the fibrinolytic system in the endometrium have been implicated. Effective medical treatments suitable for long-term use include intrauterine progestogens, antifibrinolytic agents (tranexamic acid) and nonsteroidal anti-inflammatory agents (mefenamic acid). Over the past decade there has been increasing use of endometrial destructive techniques as an alternative to hysterectomy. Their further refinement and the advent of fibroid embolization has increased the options available to women.

Wnt-7a is upregulated by norethisterone in human endometrial epithelial cells: a possible mechanism by which progestogens reduce the risk of estrogen-induced endometrial neoplasia.

Progestogens are added to oestrogen in hormone replacement therapy regimens to reduce the risk of endometrial cancer. We have performed in vitro studies analysing gene expression of isolated normal endometrial epithelia cells (NEE) treated with estradiol and the progestogen norethisterone acetate (NETA). We report here for the first time upregulation of the Wnt-7a gene by NETA in estrogen treated NEE. Wnt genes are a large family of developmental genes associated with cellular responses such as oncogenesis. We therefore suggest that upregulation of Wnt-7a may be associated with the antineoplastic effects of progestogens on the endometrium.

Tamoxifen induction of angiogenic factor expression in endometrium.

Tamoxifen is the current therapy of choice for patients with oestrogen receptor positive breast cancer, and it is currently under evaluation as a prophylactic for women at high risk of developing the disease. However, tamoxifen is also known to induce proliferative changes in the endometrium increasing the risk of developing endometrial hyperplasia, polyps and carcinoma. Angiogenesis is an intimate part of this process. For this reason, we have examined the expression of several well characterized angiogenic factors, namely, acidic and basic fibroblast growth factor, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin in both normal and tamoxifen exposed pre- and postmenopausal endometrium. Vascular density and endothelial proliferation index were also quantified. We found increased expression of acidic and basic fibroblast growth factor and adrenomedullin after treatment with tamoxifen mainly in premenopausal tissue. Vascular density was significantly increased in pre- but not post-menopausal endometrium (P=0.0018) following tamoxifen treatment. These results support the notion that angiogenesis is integral to the response to tamoxifen exposure, and is a potential target with which to block these side effects of tamoxifen.

Protease activated receptor-1 is down regulated by levonorgestrel in endometrial stromal cells.

Progestogens are used clinically for contraception, to control excessive menstrual bleeding and to oppose oestrogen in hormone replacement therapy. The use of intrauterine levonorgestrel (LNG) is however, associated with endometrial atrophy and decidualisation of the stroma. In this study, we aimed to identify genes whose expression is modulated by LNG either alone or in combination with progesterone. Thus endometrial stromal cells were stimulated with progesterone, LNG or LNG and progesterone. Poly-A RNA was isolated and used to probe expression arrays. The expression of a number of genes was altered on exposure to LNG or LNG and progesterone. Alteration of expression patterns was confirmed using semi-quantitative RT-PCR and western blot analysis. In particular, the protease activated receptor-1 (PAR-1) gene that encodes a receptor for thrombin was down regulated. This is the first demonstration that PAR-1 is down regulated by the progestogen LNG in human endometrium. Alteration in the expression levels of this receptor may affect both growth and haemostatic activity within the endometrium and may account for the observed morphological effects seen in users of intrauterine LNG delivery devices.

Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth.

Regions of hypoxia are a common feature of solid tumours. When tumour cells are exposed to hypoxic stress, transcription of a battery of genes is initiated. The angiogenic factor adrenomedullin (ADM) is a hypoxia regulated gene. ADM is thought to act through the G protein-coupled receptor calcitonin receptor-like receptor (CRLR), with specificity being conferred by the receptor associated modifying protein 2 (RAMP2). Here we report for the first time that ADM treated or stably transfected Ishikawa cells overexpressing ADM show increased resistance to hypoxia induced apoptosis. These cells also show an upregulation of the oncoprotein Bcl-2, which is protective against hypoxic cell death when transiently transfected into Ishikawa cells. Since Ishikawa cells express the putative ADM-receptor CRLR-RAMP2 the production and secretion of ADM with the consecutive upregulation of Bcl-2 could establish an autocrine/paracrine mechanism rescuing malignant cells from hypoxic cell death. These results, taken together with our previous findings that ADM is an angiogenic factor which is upregulated by the nonsteroidal antiestrogen tamoxifen (TAM) in endometrial cells, implicate this peptide as a promoter of tumour growth and a possible target for anticancer strategies.

Expression of the hypoxically regulated angiogenic factor adrenomedullin correlates with uterine leiomyoma vascular density.

Uterine leiomyomas are the most prevalent benign tumor type in women of reproductive age and are one of the most common indications for hysterectomy. The expression of five angiogenic factors, adrenomedullin (ADM), vascular endothelial growth factor (VEGF), acidic fibroblast growth factor, basic fibroblast growth factor, and platelet-derived endothelial cell growth factor/thymidine phosphorylase, were examined in 91 uteri collected throughout the menstrual cycle; 52 of which contained leiomyomata, and the remainder were normal controls. The microvascular density and endothelial proliferative indices were then determined for each of the uterine sections. ADM and VEGF were the most widely expressed angiogenic factors in the leiomyomas. Furthermore, the expression of ADM and VEGF in the endometrium and myometrium was up-regulated in leiomyoma-bearing uteri compared with controls. Although acidic fibroblast growth factor and basic fibroblast growth factor were expressed in leiomyomas and endometrium in all of the uterine samples examined, they were only expressed in the myometrium of leiomyomata-bearing uteri. Endothelial proliferation in leiomyomas was statistically greater than that of the myometrium and endometrium, both within and between uteri (P < 0.05). The vascular density in the myometrium but not the endometrium was significantly increased in leiomyoma-containing uteri (P < 0.05). Expression of ADM alone correlated directly with vascular density and endothelial cell proliferation index in leiomyomas and myometrium and may account for the high vascularity found in leiomyomas and the myometrium of leiomyoma-bearing uteri. As such, ADM is identified as a novel target for antiangiogenic therapy of these benign, clinically problematic uterine tumors.

Androgen receptor gene mutations do not occur in ovarian cancer.

Genetic alterations have been frequently found in ovarian cancer. There is some indirect evidence indicating that mutation of the steroid receptor genes may play a role in the carcinogenesis of ovarian cancer. Human androgen receptor (hAR) gene mutations have been found in up to 50% of hormone-relapsed prostate cancer. The role of hAR mutation and its association with decreased expression in ovarian cancer has never been elucidated. In this study mutations of hAR gene in 38 human ovarian cancer cell lines with different AR expression pattern were studied using SSCP. No mutation of the hAR gene was found. Mutation of hAR gene is an infrequent event and therefore unlikely to be involved in the development of ovarian cancer. The decreased expression of hAR in advanced ovarian tumor is not due to genetic aberration of hAR. Mutation screening of hAR may not provide any information for risk assessment of developing ovarian cancer.

Steroids and the endometrium.

Steroids are commonly employed in current clinical practice. The benefits of steroids in hormone replacement therapy, contraception and prevention or treatment of breast cancer are limited by their side effects arising from disorders in endometrial function. These side effects are complex and enclose bleeding problems and endometrial proliferation during hormone replacement therapy and antioestrogen treatment or menstrual disturbances during oral contraception. Numerous reports have identified gene targets influenced by steroids and have implicated these products as contributors to endometrial physiology or pathology. The expression of estrogen and progesterone receptors is regulated by steroids. The new estrogen receptor (ER) subtype ERbeta with different functional characteristics from ERalpha was recently described in endometrium. In addition, there is now increasing evidence that the functionally distinct progesterone receptor (PR) isoforms A and B are differentially expressed in this tissue. The relative proportions of these steroid receptors and their interaction determine the expression of specific genes upon steroidal stimulation. Steroids induce endometrial expression of various growth and angiogenic factors. Dysregulations of this steroid modulated expression is believed to be involved in the pathogenesis of many endometrial diseases. Irregular bleeding induced by steroidal contraception, for example, is thought to involve aberrant endometrial vascular development and expression of angiogenic growth factors. The antioestrogen tamoxifen induces growth factors like vascular endothelial growth factor and adrenomedullin which may be key mediators of endometrial neoplastic effects. This review describes recent advances regarding the mechanism of action of steroids on endometrium. The expression of oestrogen and progesterone receptors as well as steroid hormone dependent growth factors and angiogenic modulators are going to be discussed.