Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033377 (prolapse)
 11,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the last ten years, progress in evidence-based medicine coupled with technological and surgical breakthroughs have deeply changed the management of our patients. Uterine bleeding is the first cause of gynaecological consultation and the intrauterine progestin delivery system as well as new hysteroscopic procedures have optimized the therapeutic approach to this problem. Introduction of magnetic resonance imaging and interventional procedures have improved breast disease diagnosis and management; likewise sentinel node localization, introduction of aromatase and growth factors inhibitors, new radiotherapy procedures and pharmacogenomics, have helped to ameliorate breast cancer treatment. Pelvic surgery has been switching more and more towards laparoscopic procedures not only in the field of benign lesions (eg endometriosis), of surgery of prolapse and incontinence with new prosthetic materials, but also for an improved management of gynaecological cancers.
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PMID:[Therapeutic progress in gynecology: organic diseases]. 1772 16

Germline knockout studies in female mice demonstrated an essential role for forkhead box L2 (FOXL2) in early follicle development, whereas an inducible granulosa cell (GC)-specific deletion of Foxl2 in adults has shown ovary-to-testis somatic sex reprogramming. In women, over 120 different germline mutations in the FOXL2 gene have been shown to cause blepharophimosis/ptosis/epicantus inversus syndrome associated with or without primary ovarian insufficiency. By contrast, a single somatic mutation (FOXL2C134W) accounts for almost all adult-type GC tumors (aGCTs). To test the hypothesis that FOXL2C134W differentially regulates the expression of aGCT markers, we investigated the effect of FOXL2C134W on inhibin B and P450 aromatase expression using a recently established human GC line (HGrC1), which we now show to bear two normal alleles of FOXL2. Neither FOXL2wt nor FOXL2C134W regulate INHBB messenger RNA (mRNA) expression. However, FOXL2C134W selectively displays a 50-fold induction of CYP19 mRNA expression dependent upon activin A. Mechanistically, the CYP19 promoter is activated in a similar way by FOXL2C134W interaction with SMAD3, but not by FOXL2wt. SMAD2 had no effect. Moreover, FOXL2C134W interactions with SMAD3 and with the FOX binding element located at -199 bp upstream of the ATG initiation codon of CYP19 are more sustainable than FOXL2wt. Thus, FOXL2C134W potentiates CYP19 expression in HGrC1 cells via enhanced recruitment of SMAD3 to a proximal FOX binding element. These findings may explain the pathophysiology of estrogen excess in patients with aGCT.
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PMID:FOXL2C134W-Induced CYP19 Expression via Cooperation With SMAD3 in HGrC1 Cells. 2947 25

Aim of this paper is to allows to analyze a topic of great relevance and media interest such as the role of prophylactic mastectomy in healthy women with BRCA mutation proposing to the surgeons some useful informations for decision-making. Less than 15% of all breast cancers are associated with germline genetic mutations. The majority of hereditary breast tumors are due to mutations in BRCA1 and BRCA2 genes that are responsible for only one third of hereditary cases. The risk estimates are extremely heterogeneous with a mean cumulative lifetime breast cancer risk of approximately 72% in BRCA1 and 69% in BRCA2 by age 80. The breast cancer is often bilateral and multicentric in BRCA mutation carriers. BRCA1 carriers have earlier-onset disease, particularly before age 50 and are more likely to develop aggressive triple-negative breast cancer than BRCA2 carriers or those who are BRCA mutation negative 1. Multiple strategies are effective in managing the risk of breast cancer in these women, including surveillance, chemoprevention, bilateral salpingo-oophorectomy and risk-reducing mastectomy. More intensive surveillance, including annual mammography and breast magnetic resonance imaging screening (commonly alternated every six months) beginning at age 25 or individualized based upon the earliest age of onset in the family, have significantly improved early detection of breast cancer among patients with deleterious BRCA mutations 1. The risk-reducing benefit of chemoprevention is not as well defined; chemopreventive strategies to reduce the risk of breast cancer have focused exclusively on prevention in high-risk women and involve the use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors for breast cancer prevention. Only limited data are available regarding the preventive benefit of tamoxifene in BRCA mutations carriers 1. Risk-reducing bilateral salpingo-oophorectomy is recommended for BRCA mutation carriers by 35 to 40 or when childbearing is completed, or individualized based on age of onset of ovarian cancer in the family; bilateral salpingo-oophorectomy decreases the risk of both breast cancer and ovarian cancer in BRCA1 and BRCA2 mutation carriers and has also been associated with reduced all cause, breast cancer-specific, and ovarian cancer- specific mortality; risk-reducing bilateral salpingooophorectomy seems to offer an approximate 50% relative reduction in breast cancer risk 1. Prophylactic mastectomy provides the greatest reduction in risk of breast cancer development. In both retrospective and prospective observational studies, bilateral prophylactic mastectomy decreases the incidence of breast cancer by 90 percent or more in patients with BRCA mutation; it also is able to determine a variable gain in life expectancy compared to radiological surveillance; besides risk-reducing mastectomy allows to contain the strong anxiety and the fear of getting sick that often compromise the quality of life of BRCA mutation carriers 2. Prophylactic mastectomy could be technically performed in different ways. However, regarding the surgical technique, on the basis of current evidence, the gold standard seems to be represented by nipple-sparing mastectomy which, thanks to the preservation of the skin envelope and the nipple-areola complex, is able to optimize the oncological and aesthetic results. Nipple-sparing mastectomy provides superior cosmetic results. This procedure is usually performed through an inframmamary or radial or axillary incision where the skin is carefully dissected off the breast until all anatomic boundaries of the breast are reached and the gland in its entirety is excised. This technique does not seem to compromise the oncological/preventive efficacy compared to other types of mastectomy. In a multi-institution review of prophylactic 346 BRCA carriers undergoing either bilateral mastectomy or contralateral mastectomy with nipple- areola sparing there were no cases of breast cancer, whereas, based on models, 22 would have been expected 3. However nipple-sparing mastectomy must be carried out with technical skill and maximum attention not to leave macroscopic residues of mammary gland in particular in the axillary extension, peripheral extremities of the gland and the nipple-areola complex; it is necessary to perform an accurate dissection and a meticulous preparation of the skin flaps and of the areola-nipple complex which must be reasonably thin without however compromising its vitality. Whenever the patients opt to proceed with bilateral prophylactic mastectomy, an accurate preoperative radiological study should always be performed with mammography, ultrasound and magnetic resonance imaging to rule out the presence of suspicious breast lesions and minimize the risk of occult carcinomas by definitive histological examination. In the absence of contraindications, all patients should be candidates for breast reconstruction in order to minimize the negative physical and psychological impact of the mastectomy; the breast reconstruction should preferably be immediate, performed at the same time of the prophylactic mastectomy, by a team of dedicated plastic surgeons, or with permanent prosthesis or autologous tissues; the choice of the most appropriate reconstructive technique depends on various factors such as the physical/anatomical structure of the woman, the morphology/ degree of breast ptosis, the comorbidities but also the patient's wishes and preferences 1. However, in the discussion on the possibility of carrying out a prophylactic mastectomy, it is always necessary to consider a series of issues related to this procedure: - the possible oncological failure because risk-reducing mastectomy does not completely eliminate the risk of developing breast cancer; there is always a residual risk of about 5% to be related to the possible presence of residual glandular tissue or ectopic breast tissue 2; - the surgical morbidity with overall complication rates of 15-20% such as ischemia of the skin and/or of the areola-nipple complex, haematomas, infections, implant failure, partial/total autologous flap loss; in a considerable percentage of cases there is also the need to resort after the prophylactic mastectomy to further aesthetic/ plastic procedures to correct some imperfections or repair surgical complications 3-5; - the presence of sequelae such as the loss of sensitivity of the areola-nipple complex, possible paresthesias, painful sensations and the need for re-adaptation to a different body image 2; - the possible body image issues due to many factors, such as self-consciousness, feeling less sexually attractive and dissatisfaction with the scars 2,3. In addition to these issues we must add that most of the studies that show a gain in life expectancy thanks to prophylactic mastectomy, are based only on mathematical models and that the few prospective cohort studies often do not show a statistically significant improvement in terms of survival among women undergoing MP and intensive radiological surveillance 1,2. Therefore in consideration of the benefits but also of the problems that the prophylactic mastectomy involves, all the international guidelines highlight that this procedure must be considered, must be discussed with healthy BRCA women, however without giving an absolute recommendation to perform it 1. This discussion must take place, case by case, in specialized breast centers with a dedicated risk team. A personalized multidisciplinary path should guarantee an accurate genetic and clinical counselling, adequate psychological support and detailed information about all alternative risk management strategies. Clinical decision-making about strategies to pursue for breast cancer risk reduction should involve a tradeoff between life expectancy and quality of life. However if the patient and the medical team opt to proceed with prophylactic surgery, the cumulative evidence to date supports nipple sparing mastectomy with immediate reconstruction as an appropriate risk-reducing procedure to optimize the oncological and aesthetic results and improve quality of life.
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PMID:Bilateral prophylactic mastectomy in BRCA mutation carriers: what surgeons need to know. 3087 61