UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2.

Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2 and MSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1, PALB2, RAD51D and RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and RAD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1, PALB2, RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting.

Clinicians' views on low-lying intrauterine devices or systems.

BACKGROUND: There is a lack of consensus and very little published guidance on the management of a low-lying or malpositioned intrauterine contraceptive device (IUD) or system (IUS). METHODS AND RESULTS: A short e-mail questionnaire sent to senior medical staff working in contraceptive services confirmed the variation in views and management of this clinical area. Almost all respondents would replace an IUD/IUS lying either totally or partially in the cervical canal. The nearer the device was to the fundus the more likely respondents were to leave it in situ and there was less concern if the device was an IUS, presumably in view of the hormonal action. In the presence of abnormal bleeding or pain, most respondents would look for other causes rather than assume that the low-lying device was to blame. Respondents expressed uncertainty as to whether low-lying devices were more likely to fail or not and around half the respondents felt that low-lying devices could migrate upwards within the cavity. CONCLUSION: This survey highlighted the need for accurate evidence-based guidance to assist in this area of clinical contraceptive practice.

Low-lying or malpositioned intrauterine devices and systems.

INTRODUCTION: The intrauterine device (IUD) and intrauterine system (IUS) are widely used forms of long-acting reversible contraception. Occasionally, IUD/IUS users have an ultrasound scan that shows a low-lying IUD/IUS or an IUD/IUS is found incidentally on scan to be low-lying within the uterus. No formal guidelines exist on the clinical implications of this scenario or the most appropriate management. We report here on a systematic review of the literature. METHODS: A search of the online database PubMed was performed to identify articles relating to low-lying or malpositioned IUD/IUS. RESULTS: A total of 1101 articles was identified, and 15 were determined to be relevant to the research question. DISCUSSION: There is little published evidence to determine the nature and extent of the clinical relevance of a low-lying IUD. We recommend individualised management of these women, with particular caution in younger women and those with a history of previous IUD/IUS expulsion. Consideration may be given to attempting to readjust the IUD/IUS position, but if removal is performed, immediate replacement is essential if provision of alternative effective contraception has not been established.

A role for lipoxin A4 as anti-inflammatory and proresolution mediator in human parturition.

The purpose of this study was to investigate the role of lipoxin A(4), an anti-inflammatory and proresolution modulator, during human parturition. We measured serum levels of lipoxin A(4) and myometrial protein release using ELISA, quantified lipoxin receptor (FPR2/ALX) mRNA expression using qRT-PCR, and localized protein expression using immunohistochemstry in myometrial biopsies from pregnant women. In addition, we compared the effects of lipoxin A(4) (100 nM) with vehicle on basal and LPS-stimulated expression of proinflammatory cytokines from samples of myometrium from pregnant women. Mean ± SE circulating level of lipoxin A(4) was 5.89 ± 0.63 nM at 24-wk gestation, with a further modest increase during pregnancy (P<0.05), but no differences in gestation matched women before and after labor (P>0.05). Levels of lipoxin A(4) in nonpregnant women were 0.48 ± 0.04 nM, significantly lower than in pregnant women (P<0.001). FPR2/ALX localized to myocytes and neutrophils, with a 9-fold increase in mRNA expression in labor (P<0.001). Lipoxin A(4) significantly reduced LPS-induced but not basal expression of the proinflammatory cytokines IL-6 and IL-8 in cultured myometrium (P<0.05), compared to vehicle-treated controls. We demonstrate for the first time a potential role for lipoxin A(4) and its receptor in the resolution of the inflammatory events of both physiological and pathological labor.