PROgesterone Therapy for Endometrial Cancer Prevention in Obese Women (PROTEC) Trial: A Feasibility Study.

Obesity is the major etiologic driver for endometrial cancer. The levonorgestrel intrauterine system (LNG-IUS) reduces the risk of endometrial cancer and its precursor, atypical hyperplasia. We assessed feasibility and uptake of the LNG-IUS for primary prevention of endometrial cancer in high-risk women and its impact on endometrial tissue biomarkers. Women with class-III obesity [body mass index (BMI) > 40 kg/m2] and histologically normal endometrium were invited to participate in a clinical trial of the LNG-IUS for endometrial protection. Recruitment, successful LNG-IUS insertion, and adherence to trial procedures were recorded. We measured impact of the LNG-IUS on circulating biomarkers of endometrial cancer risk, endometrial proliferation (Ki-67, pAKT, PTEN), endometrial hormone receptor status [estrogen receptor and progesterone receptor (PR)], mental wellbeing, and menstrual function. At 6 months, women chose to keep their LNG-IUS or have it removed. In total, 103 women were approached, 54 were offered a participant information sheet, 35 agreed to participate, and 25 received a LNG-IUS. Their median age and BMI were 54 years [interquartile range (IQR) 52-57] and 47 kg/m2 (IQR 44-51), respectively. Three women (3/35, 9%) were ineligible due to atypical hyperplasia/endometrial cancer on their baseline biopsy. The LNG-IUS was well tolerated and had a positive overall effect on bleeding patterns and mental wellbeing. The LNG-IUS was associated with endometrial morphologic change, reduced Ki-67, and PR expression, but circulating biomarkers of endometrial cancer risk were unchanged. All but one woman (96%) kept her LNG-IUS. The LNG-IUS appears to be acceptable to some women with class-III obesity for primary prevention of endometrial cancer, which could provide a strategy for a prevention trial.Prevention Relevance: Novel strategies are urgently needed to prevent the rise in endometrial cancer diagnoses predicted by escalating obesity rates. Here, we show that women with class III obesity are willing to engage in risk reduction with a levonorgestrel intrauterine system, which could provide a strategy for an endometrial cancer prevention trial.

Phenotypic differences in alpha 1 antitrypsin-deficient sibling pairs may relate to genetic variation.

Alpha-1-antitrypsin deficiency is associated with variable development of airflow obstruction and emphysema. Index patients have greater airflow obstruction than subjects detected by screening, but it is unclear if this reflects smoking differences and/or ascertainment bias, or is due to additional genetic factors. In this study 72 sibling pairs with alpha-1-antitrypsin deficiency were compared using lung function measurements and HRCT chest. Tag single nucleotide polymorphisms to cover all common variation in four genes involved in relevant inflammatory pathways (Tumour necrosis factor alpha, Transforming growth Factor beta, Surfactant protein B and Vitamin D binding protein) were genotyped using TaqMan technology and compared between pairs for their frequency and relationship to lung function. 63.5% of non-index siblings had airflow obstruction and 59.5% an FEV(1) < 80% predicted. Index siblings had lower FEV(1) and FEV(1)/FVC ratio, a higher incidence of emphysema (all P