Gynecological Cancers and Microbiota Dynamics: Insights into Pathogenesis and Therapy.

In recent years, the relationship between the microbiota and various aspects of health has become a focal point of scientific investigation. Although the most studied microbiota concern the gastrointestinal tract, recently, the interest has also been extended to other body districts. Female genital tract dysbiosis and its possible impact on pathologies such as endometriosis, polycystic ovary syndrome (PCOS), pelvic inflammatory disease (PID), and gynecological cancers have been unveiled. The incursion of pathogenic microbes alters the ecological equilibrium of the vagina, triggering inflammation and compromising immune defense, potentially fostering an environment conducive to cancer development. The most common types of gynecological cancer include cervical, endometrial, and ovarian cancer, which occur in women of any age but especially in postmenopausal women. Several studies highlighted that a low presence of lactobacilli at the vaginal level, and consequently, in related areas (such as the endometrium and ovary), correlates with a higher risk of gynecological pathology and likely contributes to increased incidence and worse prognosis of gynecological cancers. The complex interplay between microbial communities and the development, progression, and treatment of gynecologic malignancies is a burgeoning field not yet fully understood. The intricate crosstalk between the gut microbiota and systemic inflammation introduces a new dimension to our understanding of gynecologic cancers. The objective of this review is to focus attention on the association between vaginal microbiota and gynecological malignancies and provide detailed knowledge for future diagnostic and therapeutic strategies.

IMPROVE lifestyle in polycystic ovary syndrome: a systematic strategy.

Lifestyle change is the first-line of treatment for the management of women with PCOS, however obtaining long-term adherence is challenging. In order to improve adherence to advice on lifestyle, we propose a strategic systematic approach that could be easily remembered with the acronym I.M.P.R.O.V.E.: Inform, Motivate, Prescribe, Reward, Oversee, Visualize, Empower. Besides giving information and recommendations, it emphasizes the need to listen to PCOS patients in order to better motivate and to encourage to increase those physical activities they like the most. The reduction of calorie intake more than macronutrient changes may also be proposed. In the second phase the strategy aims to assess lifestyle changes, trying to visualize and quantify them so as to reinforce adherence and motivation or to find new motivations and rewards. The final goal is to empower the patient in order to maintain long term self-adherence. Lifestyle approach is not an alternative to pharmacological treatment of PCOS, but it is synergic with it as it can counterbalance some side effects or risks.

Vulvovaginal atrophy (VVA) in breast cancer survivors (BCS) is still an unmet medical need: results of an Italian Delphi Panel.

PURPOSE: VVA is a common disease, with approximately 50% of all postmenopausal women having related symptoms. VVA has a significant impact on the personal and sexual lives and on many aspects of women's self-esteem and emotional well-being. It is particularly frequent and severe in patients treated for BC, where it originates significant economic and social costs. Given the lack of published evidence on this subject, a Delphi Panel was carried out to evaluate:The epidemiology of VVA and of its risk-factors/comorbidities in ItalyThe present standard of care and unmet medical needsThe comparison between recent US epidemiological data and the Italian situationThe health resources used in VVA BC The burden of illnessDespite the considerable negative impact on quality of life, a disparity between the high prevalence of this condition and the infrequent clinical diagnosis is documented in medical practice and in surveys. This inaccuracy is thought to be primarily a consequence of patients' unwillingness and/or reluctance to report symptoms in the clinical setting and of health-care professional's difficulty in approaching this sensitive topic during routine consultations. METHODS: A Delphi Panel methodology was used: a first round of written questionnaires, followed by a plenary meeting with a facilitator and by two additional rounds of telephone interviews. RESULTS: The prevalence of the condition in Italy can be estimated in 115,000 cases out of 380,000 BC survivors. The Panel confirmed that the epidemiological findings of a recent pharmacoeconomic analysis of a US claims database can be applied to Italian patient population. The Panel confirmed also an estimate of 4.25 additional cases/100/yr of UTI (urinary tract infection) in VVA BC patients (vs. a non-VVA-matched population), of 3.68 additional cases of vulvovaginitis, of 6.97 cases of climacteric symptoms, and of 3.64 cases of bone and joint disorders. As far as the resource use is concerned, in the VVA BC populations, 33.4 additional gynecological visits/100/year can be expected, along with 22.8 additional cancer screenings, 7.07 additional outpatient visits and 5.04 screenings for HPV. CONCLUSIONS: Even in Italy, a diagnosis of VVA, especially in a BC population, is associated with a relevant increase in the burden of illness and social costs, compared to a control population matched for age without VVA. This is due essentially to an increase in comorbidities and resource utilization with the consequence that an adequate treatment could reduce the impact of the condition.

Approach to sexual dysfunction in women with cancer.

Sexual dysfunction in female cancer patients remains under-diagnosed and under-treated. As sexual dysfunction is becoming an increasingly common side effect of cancer treatments, it is imperative for healthcare providers and especially gynecologic oncologists to include a comprehensive evaluation of sexual health as a routine part of the workup of such patients. Although most oncologists are not experienced in treating sexual dysfunctions, simple tools can be incorporated into clinical practice to improve the management of these conditions. In this review, we propose a practical approach to selecting proper treatment for sexual dysfunctions in female cancer patients. This includes three main steps: knowledge, diagnosis, and sexual counseling. Knowledge can be acquired through a specific updating about sexual issues in female cancers, and with a medical training in female sexual dysfunctions. Diagnosis requires a comprehensive history and physical examination. Sexual counseling is one of the most important interventions to consider and, in some cases, it may be the only intervention needed to help cancer patients tolerate their symptoms. Sexual counseling should be addressed by oncologists; however, select patients should be referred for qualified psychological or sexological interventions where appropriate. Finally, a multidisciplinary team approach may be the best way to address this challenging issue.

HE4, CA125 and risk of ovarian malignancy algorithm (ROMA) as diagnostic tools for ovarian cancer in patients with a pelvic mass: An Italian multicenter study.

OBJECTIVE: This multicenter study aims to evaluate HE4, CA125 and risk of ovarian malignancy algorithm (ROMA) performance in the differential diagnosis of epithelial ovarian cancer (EOC). METHODS: A total of 405 patients referred to gynecological oncologist with suspicious pelvic mass requiring a surgery for identification of EOC were consecutively enrolled; 387 patients satisfied inclusion criteria: 290 benign diseases; 15 borderline neoplasia and 82 tumors (73 EOC). RESULTS: Good diagnostic performance in discriminating benign from EOC patients was obtained for CA125, HE4 and ROMA when calculating optimal cut-off values: premenopause, specificity (SP) >86.6, sensitivity (SN) >82.6, area under the curves (AUC)≥0.894; postmenopause, SP>93.2, SN>82, AUC≥0.928. Fixing SP at 98%, performance indicators obtained for benign vs EOC patients were: premenopause, SN:65.2%, positive predictive value (+PV): 75%, positive likelihood ratio (+LR): 26.4 for CA125; SN:69.6%, +PV:76.2%, +LR:28.1 for HE4; SN:69.6%, +PV: 80%; +LR:35.1 for ROMA; postmenopause, SN:88%, +PV: 95.7%, +LR:38.7 for CA125; SN:78%, +PV:95.1%, +LR:34.3 for HE4; SN:88%, +PV:97.8%, +LR:77.4 for ROMA. When using routine cut-off thresholds, ROMA showed better well-balanced values of both SP and SN (premenopause, SN:87%, SP:86.1%; postmenopause, SN:90%; SP:94.3%). CONCLUSIONS: Overall, ROMA showed well balanced diagnostic performance to differentiate EOC from benign diseases. Meaningful differences of +PVs and +LRs between HE4 and CA125 suggest that the two markers may play at least in part different roles in EOC diagnosis, with HE4 seeming to be more efficient than CA125 in ruling in EOC patients in the disease group, also in early stages tumors, both in pre and postmenopause.

Gonadal agenesis with hypoplastic paramesonephric ducts (PMNDs) derivatives in dizygotic twins.

The co-occurrence of gonadal agenesis alongside hypoplastic derivatives of the paramesonephric ducts has rarely been observed. PATIENT(S): 16-year-old dizygotic twin sisters were referred to our department because of primary amenorrhea. X-ray, bone densitometry, ultrasonography, pelvic MRI and measurement of pituitary, ovary, and thyroid hormones were performed. Both twins showed hypergonadotropic hypogonadism, bilateral gonadal agenesis, fallopian tube, uterus, and vaginal hypoplasia but normal kidney and urinary tract structures and skeletal system. Analysis of Q-banded chromosomes in peripheral blood for the search for centromeric X-chromosome DNA and SRY gene was normal as well as the molecular analysis of FMR1, GDF9, and BMP15 genes. Estradiol gel was administered for one year followed by estroprogestin treatment. Both twins growth increased; breast development was stimulated and first menses occurred. Deregulation in the expression of the various HOX genes along the axis of the developing reproductive tract in a determinate time of development may be one of the mechanisms involved in the origin of this complex and rare association.

Nomegestrol acetate/estradiol hormonal oral contraceptive and breast cancer risk.

Combined hormonal contraceptives (CHCs) contain estrogen and progestin, which can stimulate estrogen-sensitive and/or progesterone-sensitive breast cancer growth. Until recently, ethinylestradiol had been almost the only estrogen used for decades, and its dose has been greatly reduced over time. The first generations of birth control pills contained approximately five times more estrogen and four times more progestin than the latest contraceptives. Newer CHCs also contain steroids that more closely mimic the physiological estradiol (E2) and progesterone effects. The newer CHC formulations are thus expected to have less influence on the breast, although it is very difficult to demonstrate any difference among the recent available preparations in human studies. Recently, nomegestrol acetate (NOMAC), a neutral, nonandrogenic, progesterone-like profile progestin, has become available in combination with the 'natural' estrogen, E2. According to the literature, NOMAC/E2 is expected to have either a lesser stimulating effect or a neutral effect on estrogen-sensitive breast cancers. We performed an analysis of the available studies and a bibliographical review. The endocrine and metabolic effects of NOMAC/E2 formulation might lead to a lesser breast tissue stimulation. The data reported, confirmed through clinical studies, should be considered when choosing a hormonal contraceptive, especially when breast stimulation is a concern.

Promestriene, a specific topic estrogen. Review of 40 years of vaginal atrophy treatment: is it safe even in cancer patients?

Urogenital symptoms resulting from estrogen deficiency are common problems that impair quality of life and sexuality. Potentially, one out of three postmenopausal women could benefit from a vaginal estrogen therapy, but the fear of systemic absorption limits its use. Promestriene used vaginally to relieve vaginal atrophy is a locally effective estrogen that has not shown systemic estrogenic effects. Thus, it could be a first-line option for those who necessitate a minimal or ideally no vaginal absorption, particularly in symptomatic cancer patients. There are little data available in the literature, mostly consisting of small, open-label, short duration studies, and few randomized-controlled studies. After a long-term market experience (almost 40 years), in 34 countries, and millions of pieces prescribed, the side effects were very rarely reported in pharmacovigilance data, whereas the effectiveness to relieve atrophy was good. To further improve promestriene safety, especially in estrogen-sensitive cancer patients, a very low dose is used from the beginning, starting from half or less of the usual dose, and then gradually increased till the minimum effective dose, which could further reduce its already minimal vaginal absorption.

The Impact of the Female Genital Microbiota on the Outcome of Assisted Reproduction Treatments.

The vaginal microbiota plays a critical role in the health of the female genital tract, and its composition contributes to gynecological disorders and infertility. Lactobacilli are the dominant species in the female genital tract: their production of lactic acid, hydrogen peroxide, and bacteriocins prevents the invasion and growth of pathogenic microorganisms. Several factors such as hormonal changes, age of reproduction, sexual practices, menstrual cycle, pregnancy, and antimicrobial drugs use can cause imbalance and dysbiosis of the vaginal microbiota. This review aims to highlight the impact of the vaginal microbiota in Assisted Reproductive Technology techniques (ART) and it examines the factors that influence the vaginal microbiota, the consequences of dysbiosis, and potential interventions to restore a healthy female genital tract.

Management of vaginal dryness and dyspareunia in estrogen sensitive cancer patients.

Cancer patients suffer from vaginal dryness and dyspareunia earlier and longer than the general population, with more severe and distressing symptoms. Life-style advices are the first step and vaginal lubricants can be tried, but they can't completely relieve atrophic symptoms. The most effective therapy is use of vaginal estrogens, but compliance and management are particularly difficult in estrogen sensitive cancer patients because of their systemic absorption. Compliance can be improved if they are begun at a very low dose and gradually increased until the lowest effective dose is reached. Promestriene only possesses an intramucosal effect, it can be used at very low doses in cancer patients suffering from urogenital symptoms.

Breast cancer risk of hormonal contraception: Counselling considering new evidence.

The possibility that the use of hormonal contraceptives may increase the risk of breast cancer has been raised since many years. In the past this hypothesis has been dismissed on the basis that available data were generally derived from "old" studies in which relatively high hormone doses had been used. The recent publication of two studies that analysed data from women receiving low-dose hormonal contraception and showed a statistically significant increase in breast cancer contradicts this reassuring belief. The topic however is not settled, since different results were obtained in other studies and since hormonal contraception (HC) also has unquestionable positive effects such as a decrease in ovarian and in endometrial cancer. The aim of the present paper is to provide evidence that may help gynaecologists and oncologists in discussing with their patients the use of HC. Even if cancer phobia is a strong reason for not using or limiting HC, patients must be informed that notwithstanding the slightly increased breast cancer risk, the overall cancer risk may still be lower than non-users. Proper counselling may help the woman choose the most suitable contraception in the different phases of her life and on the basis of other conditions that may increase cancer risk such as overweight, smoking or family history.

Biology, staging, and treatment of breast cancer during pregnancy: reassessing the evidences.

Breast cancer is one of the most frequently diagnosed malignancies during pregnancy. Here, we review the management of women with breast cancer during pregnancy (BCP), focusing on biology, diagnosis and staging, local and systemic treatments, obstetric care and long-term follow-up of children with prenatal exposure to anticancer treatments.

Cancer Targeted Therapy Strategy: The Pathologist's Perspectives.

The effectiveness of new personalized treatment procedures in oncology is based on the fact that certain tumors exhibit specific molecular features. More in detail, neoplastic tissues of patients should display a specific biomarker, most often a specific genetic alteration and/or under/overexpression of a definite protein, that could be the target of its respective drug. Immunohistochemical and molecular analyses, which usually include examination of nucleic acids from either tissues or fluids, are common tests to define the status of a tumor. This review focuses on the pathologist's role in carefully controlling pre- analytic procedures and standard operating procedures that are a crucial prerequisite to reach reliable and reproducible results. Six paradigmatic applications of targeted therapy, for which pathological diagnosis plays a fundamental role, are summarized. Traditional and next-generation sequencing are also addressed from the pathologist's perspective as well as the importance pathologists have in this shift to more accurate definition of disease risk and prognostication of therapy response in the personalized medicine era.

Mechanisms of chemotherapy-induced ovarian damage in breast cancer patients.

Fertility preservation in breast cancer patients is an increasingly relevant topic. In the present paper we review available data on the mechanism of ovarian damage caused by anticancer agents currently used for the treatment of breast cancer. We also describe current methods to preserve fertility including oocytes or ovarian tissue freezing and administration of LH-RHa during chemotherapy. The aim of the paper is to provide clinical oncologists with an adequate knowledge of the subject to enable them to give a correct counselling to young women that must receive chemotherapy and want to increase their possibilities of maintaining fertility.

Coffee Decreases the Risk of Endometrial Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

AIM: The aim of this study was to perform a comprehensive meta-analysis of the association between coffee consumption and risk of endometrial cancer. METHODS: Eligible studies were identified by searching the PubMed and EMBASE databases. The dose-response relationship as well as the risk of endometrial cancer for the highest versus the lowest categories of coffee consumption were assessed. Subgroup analyses considering the menopausal and receptor statuses, the smoking status, and the BMI (Body Mass Index) were performed in order to identify potential confounders. RESULTS: We identified a total of 12 studies eligible for meta-analysis. A dose-response meta-analysis showed a decreased risk of endometrial cancer. Moreover, a subgroup analysis indicated that coffee consumption is significantly associated with a decreased risk of postmenopausal cancer. Increasing coffee consumption by four cups per day was associated with a 20% reduction in endometrial cancer risk (relative risk (RR) 0.80; 95% confidence interval (CI) 0.72 to 0.89) and with a 24% reduction in postmenopausal cancer risk (RR 0.76; 95% CI 0.69 to 0.83). CONCLUSIONS: Our findings suggest that increased coffee consumption is associated with decreased risk of endometrial cancer, and this association is observed also for postmenopausal cancer.

Use of Complementary and Alternative Medicine (CAM) in cancer patients: An Italian multicenter survey.

INTRODUCTION: Complementary and Alternative Medicine (CAM) include a wide range of products (herbs, vitamins, minerals, and probiotics) and medical practices, developed outside of the mainstream Western medicine. Patients with cancer are more likely to resort to CAM first or then in their disease history; the potential side effects as well as the costs of such practices are largely underestimated. PATIENTS AND METHOD: We conducted a descriptive survey in five Italian hospitals involving 468 patients with different malignancies. The survey consisted of a forty-two question questionnaire, patients were eligible if they were Italian-speaking and receiving an anticancer treatment at the time of the survey or had received an anticancer treatment no more than three years before participating in the survey. RESULTS: Of our patients, 48.9% said they use or have recently used CAM. The univariate analysis showed that female gender, high education, receiving treatment in a highly specialized institute and receiving chemotherapy are associated with CAM use; at the multivariate analysis high education (Odds Ratio, (OR): 1.96 95% Confidence Interval, CI, 1.27-3.05) and receiving treatment in a specialized cancer center (OR: 2.75 95% CI, 1.53-4.94) were confirmed as risk factors for CAM use. CONCLUSION: Roughly half of our patients receiving treatment for cancer use CAM. It is necessary that health professional explore the use of CAM with their cancer patients, educate them about potentially beneficial therapies in light of the limited available evidence of effectiveness, and work towards an integrated model of health-care provision.

Special issues in fertility preservation for gynecologic malignancies.

Gynecologic malignancies account for 1,09 million new cancer cases worldwide consisting of about 12% of tumors affecting female population. About 10% of all female cancer survivors are younger than 40 years of age. Since cancers affecting female genital organs are usually treated by radical surgery, chemotherapy or chemoradiation approaches that induce permanent damage of reproductive functions, the development of strategies for fertility preservation represent one of the most important goals for gynecologic oncology. In this scenario, the newly defined oncofertility discipline acquires increasing interest, offering patients maximal chances to make an adequate decision about future fertility, based on their oncologic diagnosis and prognosis. However, the majority of physicians do not pay particular attention to these issues, even if impressive progresses have been made in this field in the last decades. Possibly, it is due to the lack of strong evidences from clinical trials without an adequate number of cases to establish safety and efficacy of these procedures. In this review we will discuss the most recently debated options for fertility preservation in gynecologic oncology, highlighting issues and controversies related to oncofertility.

Carcinogenetic mechanisms of endocrine disruptors in female cancers (Review).

Endocrine disruptors (EDs) are pollutants that alter the endocrine system and are involved in carcinogenesis. EDs have multiple and complex levels of action. They can affect the synthesis, release and transport of natural hormones. In target tissues, EDs can reduce or increase the effects of natural hormones on their receptors and change signaling cascades. When ED exposure happens at critical periods of life, from embryo to puberty, they can act at doses considered safe for an adult. Furthermore, their epigenetic effects can also influence the cancer risk of future generations. The cancer mechanisms of known EDs are hereby reviewed, There are thousands of newly introduced substances whose potential endocrine-disrupting and cancer effects are completely unknown. Although there are still gaps in our knowledge, these data support the urgent need for health and environmental policies aimed at protecting the public and in particular, the developing fetus and women of reproductive age.

Endocrine disruptors and female cancer: Informing the patients (Review).

Pollutants altering the endocrine system, known as endocrine disruptors (ED), may modify the risk of female cancers. The carcinogenic effect of ED on humans has been confirmed by experimental studies for various substances including pesticides, DDT, dioxins, phthalates, bisphenol A, diethylstilbestrol, as well as heavy metals, but it is difficult to quantify precisely for several reasons hereby reviewed. Carcinogenesis is a complex and multifactorial mechanism that manifests itself over a long period of time, making difficult the detection of the specific contribution of the pollutants, whose absorbed dose is often unknown. The combined effect of various substances leads to complex interactions whose outcome is difficult to predict. These substances may accumulate and carry out their harmful effect on critical periods of life, probably also at doses considered harmless to an adult. ED can also have epigenetic adverse effects on the health of future generations. In conclusion, the carcinogenic effects of endocrine disruptors on female cancer types is plausible although additional studies are needed to clarify their mechanisms and entities. In the last part of the review we suggest ways to reduce ED exposure as it is mandatory to implement necessary measures to limit exposure, particularly during those periods of life most vulnerable to the impact of oncogenic environmental causes, such as the embryonic period and puberty.

Is effective and safe a radiochemotherapy approach in elderly cancer patients? A review.

Although more than 60% of all cancer patients in Europe and the USA are older than 65 years at the time of diagnosis, elderly patients are generally under-represented in clinical trials. A general consensus on how to treat elderly patients is still far from being achieved. In this review, we address some of the issues and challenges surrounding the treatment of older cancer patients and radiochemotherapy. We discuss the existing evidence related to radiochemotherapy in the elderly, focusing primarily on the malignancies most commonly seen in older patients and making general treatment recommendations where applicable.