Left Ureterocalycostomy With Ileal Interposition for Retroperitoneal Fibrosis in Patient With Erdheim-Chester Disease.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare progressive non-Langerhans' cell histiocytic multisystem disorder with a broad spectrum of clinical manifestations, including infiltrative perinephric with ureteral involvement resulting in hydronephrosis, renal atrophy, and eventual renal failure. OBJECTIVE: To present a patient with ECD with bilateral renal/ureteral involvement managed with bilateral percutaneous nephrostomy tubes (PCNT) and trametinib who underwent bilateral robotic upper tract reconstruction, the first such published report. The video demonstrates only the left-sided repair, which posed specific challenges and demonstrates reconstructive techniques useful in complex upper tract repairs with limited tissue availability. MATERIALS AND METHODS: A 35-year-old male initially presented with baseline creatinine of 1.62 and split renal function; 30% right and 70% left by Lasix renogram. Extra-genitourinary manifestations of disease included cardiac hypertrophy and skin ulcers/lesions. Bilateral retrograde pyeloureterography showed proximal ureteral obliteration ∼4 cm bilaterally. Multiple management options were discussed including PCNTs, but patient elected for definitive repair. He was seen by Cardiology and Anesthesia and deemed to be optimized. He held his trametinib for 1week before surgery. We demonstrate a difficult ureteral dissection with fibrotic hilum preventing separation. Simultaneous ureteroscopy identified the distal extent of stricture which was excised, leaving a ∼15 cm gap. Downward nephropexy was performed with ultrasound guidance to identify an inferior calyx. Partial nephrectomy was then performed without vascular control due to hilar fibrosis. Ileal interposition was chosen to bridge the remaining ∼8 cm gap. Proximal ileo-calyceal and distal ileo-ureteral anastomoses were performed. We then placed a 30 cm × 7 Fr double-J ureteral stent in standard fashion. The ileum was secured to the renal pelvis to maintain a straight lie and an omental flap was secured in place. RESULTS: Immediate postoperative course was complicated by partial small bowel obstruction leading to a negative exploratory laparotomy and a subsequent episode of urosepsis. The patient is now voiding well without stents or PCNTs, without infections and with improving renal function, now with GFR (glomerular filtration rate) of 62 from 43 preoperatively. With aggressive hydration, patient has had no obstruction of the distal ureter with mucus. MRI Abdomen/Pelvis 6months later showed irregularity of the calyces with stable mild hydronephrosis. The patient continues to be medically managed on trametinib for his underlying disease, with surveillance for recurrent fibrosis and obstruction which has not yet occurred. CONCLUSION: Robotic ureterolysis and ureterocalycostomy with possible bowel interposition is a reasonable option for upper tract reconstruction in select patients with ECD.

A career exploration didactic and simulation-based session increases student knowledge in and exposure to urology.

INTRODUCTION: Though urology attracts well-qualified applicants, students are not typically provided exposure to this smaller specialty until later in their medical education. While simulation-based training continues to supplement medical education, there is a lack of programming to teach specialty-specific procedural skills to medical students and those outside the specialty. We report a half-day simulation and didactic-based approach to increase exposure to urology to interested second-year medical students. METHODS: A half-day didactic- and simulation-based session was offered to second-year medical students (N=57). After a didactic-based overview of the specialty performed by urology providers and a surgical educator, the students participated in small-group simulations, including hands-on simulations. The students completed a post-curriculum survey measuring knowledge gains and soliciting feedback on the session. RESULTS: Students were 57.1% Caucasian, 66.7% female, with a mean age of 24.2 years; 80% stated they were potentially interested in pursuing a surgical specialty such as urology prior to the start of the session. Students reported pre- to post-curriculum gains in knowledge (mean=37%) about a career in urology and basic urologic procedures (p<0.001). Participants were also likely to recommend the curriculum to their peers (p<0.001). CONCLUSIONS: Given that exposure to urology in medical school is usually limited and offered later in training, a half-day didactic- and simulation-based experience for second-year students provides an early introduction and experience within the specialty and its common bedside procedures.

Empire-CF study: A phase 2 clinical trial of leukotriene A4 hydrolase inhibitor acebilustat in adult subjects with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is characterized by neutrophilic inflammation in the airways. Leukotriene B4 (LTB4) is a neutrophil chemoattractant and has been implicated in CF pathogenesis. Acebilustat, a novel, synthetic, small-molecule leukotriene A4 hydrolase inhibitor, reduces LTB4 production. We report findings from a randomized placebo-controlled trial of acebilustat in adult subjects with mild-to-moderate lung disease. METHODS: Subjects were randomized (1:1:1) to once-daily acebilustat 50 mg, 100 mg or placebo for 48 weeks, concomitantly with their current therapeutic regimen. Subjects were stratified by use of concomitant CF transmembrane conductance regulator (CFTR) modulators, baseline percent predicted forced expiratory volume in 1 second (ppFEV1) 50-75 and >75, and number of pulmonary exacerbations in the past year (1 or >1). Primary endpoints were the change from baseline in ppFEV1 and safety. Secondary endpoints included the rate of pulmonary exacerbations. RESULTS: Overall, 199 subjects were randomized and dosed (acebilustat 50 mg, n=67; acebilustat 100 mg, n=66; placebo, n=66). Baseline demographics and disease profile were well balanced among treatment groups. Acebilustat had no statistically significant effect on the primary endpoint of change in ppFEV1 at week 48 or the secondary endpoint pulmonary exacerbations. There was a trend towards reduced pulmonary exacerbations in subjects receiving acebilustat in pre-specified populations with ppFEV1>75 (35% rate reduction) and those on concomitant CFTR modulator therapy (20% rate reduction). Acebilustat was well tolerated. CONCLUSIONS: Acebilustat did not improve lung function. A trend towards reduced pulmonary exacerbations in subjects with an earlier stage of lung disease suggests a potential effect in this population.

EMPIRE-CF: A phase II randomized placebo-controlled trial of once-daily, oral acebilustat in adult patients with cystic fibrosis - Study design and patient demographics.

Inflammation causes irreparable damage in the cystic fibrosis (CF) lung. Despite high standards of care and the advent of new therapies, inflammation continues to cause significant loss of lung function and morbidity. Acebilustat is a once-daily, oral molecule with anti-inflammatory activity through the inhibition of LTA4 hydrolase and modulation of LTB4. It has potential to reduce lung function decline and pulmonary exacerbations in patients with CF and is currently being tested in a Phase II multicenter, randomized, double-blind, placebo-controlled, parallel-group study (EMPIRE-CF). Strict inclusion criteria based on modeling of the Cystic Fibrosis Foundation Patient Registry data were selected to enrich the trial with patients most likely to benefit from chronic anti-inflammatory therapy that reduces lung function decline. 200 patients between 18 and 30 years of age, with an FEV1 percent predicted (pp) ≥50%, and ≥1 exacerbation in the past year have been enrolled. Patients are randomized 1:1:1 to placebo, acebilustat 50 mg or 100 mg for 48 weeks, taken concomitantly with their current standard of care, and stratified based on concomitant CFTR modulator use, baseline FEV1pp (50% to 75% and >75%), and number of exacerbations in the past year (1 or >1). The primary endpoints are absolute change from baseline in FEV1pp and safety outcomes. Secondary endpoints include rate of pulmonary exacerbations and time to first pulmonary exacerbation. Biomarkers of inflammation will also be assessed. EMPIRE-CF is expected to identify the optimal patient population, dose, duration and endpoints for future acebilustat trials, and widen understanding of the drug's efficacy in patients with CF.

Molecular and biological characterization of ϕRs551, a filamentous bacteriophage isolated from a race 3 biovar 2 strain of Ralstonia solanacearum.

A filamentous bacteriophage, designated ϕRs551, was isolated and purified from the quarantine and select agent phytopathogen Ralstonia solanacearum race 3 biovar 2 strain UW551 (phylotype IIB sequevar 1) grown under normal culture conditions. Electron microscopy suggested that ϕRs551 is a member of the family Inoviridae, and is about 1200 nm long and 7 nm wide. ϕRs551 has a genome of 7929 nucleotides containing 14 open reading frames, and is the first isolated virion that contains a resolvase (ORF13) and putative type-2 phage repressor (ORF14). Unlike other R. solanacearum phages isolated from soil, the genome sequence of ϕRs551 is not only 100% identical to its prophage sequence in the deposited genome of R. solanacearum strain UW551 from which the phage was isolated, but is also surprisingly found with 100% identity in the deposited genomes of 10 other phylotype II sequevar 1 strains of R. solanacearum. Furthermore, it is homologous to genome RS-09-161, resulting in the identification of a new prophage, designated RSM10, in a R. solanacearum strain from India. When ORF13 and a core attP site of ϕRs551 were either deleted individually or in combination, phage integration was not observed, suggesting that similar to other filamentous R. solanacearum ϕRSM phages, ϕRs551 relies on its resolvase and the core att sequence for site-directed integration into its susceptible R. solanacearum strain. The integration occurred four hours after phage infection. Infection of a susceptible R. solanacearum strain RUN302 by ϕRs551 resulted in less fluidal colonies and EPS production, and reduced motilities of the bacterium. Interestingly, infection of RUN302 by ϕRs551 also resulted in reduced virulence, rather than enhanced or loss of virulence caused by other ϕRSM phages. Study of bacteriophages of R. solanacearum would contribute to a better understanding of the phage-bacterium-environment interactions in order to develop integrated management strategies to combat R. solanacearum.

Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data.

BACKGROUND: Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence. METHODS: We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat. RESULTS: We analysed data for 83,399 women with 306,617 women-years of follow-up. Median follow-up was 65 months (IQR 54-93). Overall, we noted a 38% reduction (hazard ratio [HR] 0·62, 95% CI 0·56-0·69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5-10 (42%, HR 0·58, 0·51-0·66; p<0·0001 vs 25%, 0·75, 0·61-0·93; p=0·007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1·73, 95% CI 1·47-2·05; p<0·0001). We recorded a significant reduction of 34% in vertebral fractures (0·66, 0·59-0·73), but only a small effect for non-vertebral fractures (0·93, 0·87-0·99). INTERPRETATION: For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs. FUNDING: Cancer Research UK.

Tibia shaft fractures: costly burden of nonunions.

BACKGROUND: Tibia shaft fractures (TSF) are common for men and women and cause substantial morbidity, healthcare use, and costs. The impact of nonunions on healthcare use and costs is poorly described. Our goal was to investigate patient characteristics and healthcare use and costs associated with TSF in patients with and without nonunion. METHODS: We retrospectively analyzed medical claims in large U.S. managed care claims databases (Thomson Reuters MarketScan®, 16 million lives). We studied patients ≥ 18 years old with a TSF diagnosis (ICD-9 codes: 823.20, 823.22, 823.30, 823.32) in 2006 with continuous pharmaceutical and medical benefit enrollment 1 year prior and 2 years post-fracture. Nonunion was defined by ICD-9 code 733.82 (after the TSF date). RESULTS: Among the 853 patients with TSF, 99 (12%) had nonunion. Patients with nonunion had more comorbidities (30 vs. 21, pre-fracture) and were more likely to have their TSF open (87% vs. 70%) than those without nonunion. Patients with nonunion were more likely to have additional fractures during the 2-year follow-up (of lower limb [88.9% vs. 69.5%, P < 0.001], spine or trunk [16.2% vs. 7.2%, P = 0.002], and skull [5.1% vs. 1.3%, P = 0.008]) than those without nonunion. Nonunion patients were more likely to use various types of surgical care, inpatient care (tibia and non-tibia related: 65% vs. 40%, P < 0.001) and outpatient physical therapy (tibia-related: 60% vs. 42%, P < 0.001) than those without nonunion. All categories of care (except emergency room costs) were more expensive in nonunion patients than in those without nonunion: median total care cost $25,556 vs. $11,686, P < 0.001. Nonunion patients were much more likely to be prescribed pain medications (99% vs. 92%, P = 0.009), especially strong opioids (90% vs. 76.4%, P = 0.002) and had longer length of opioid therapy (5.4 months vs. 2.8 months, P < 0.001) than patients without nonunion. Tibia fracture patterns in men differed from those in women. CONCLUSIONS: Nonunions in TSF's are associated with substantial healthcare resource use, common use of strong opioids, and high per-patient costs. Open fractures are associated with higher likelihood of nonunion than closed ones. Effective screening of nonunion risk may decrease this morbidity and subsequent healthcare resource use and costs.

Compliance with mammography and bone mineral density screening in women at least 50 years old.

OBJECTIVE: The aim of this study was to examine the utilization of mammography and bone mineral density (BMD) screenings and factors associated with compliance according to the recommended clinical practice guidelines. METHODS: Mammography and BMD were assessed using employer's administrative claims data for eligible women identified between January 2004 and December 2006. Women were categorized into five cohorts based on mammography- and BMD-recommended screening guidelines. Logistic regression modeling was used to examine the covariates associated with compliance. RESULTS: Mammography and BMD screening utilization were low in relation to recommendations, with 21%, 27%, and 16% of women complying with mammography, age-motivated BMD, and fracture-motivated BMD screening guidelines, respectively. BMD screening use (odds ratio [OR], 7.19; 95% CI, 7.08-7.31) was associated with compliance in the mammogram cohort. Mammogram use was associated with compliance in both the age-motivated BMD cohort (OR, 6.01; 95% CI, 5.28-6.85) and the fracture-motivated BMD cohort (OR, 2.20; 95% CI, 2.07-2.33). Having a Papanicolaou test was strongly associated with compliance in the combined mammogram plus age-motivated BMD cohort (OR, 16.83; 95% CI, 14.01-20.22) and the combined mammogram plus fracture-motivated BMD cohort (OR, 10.46; 95% CI 9.26-11.81). CONCLUSIONS: Postmenopausal women with employer-sponsored health insurance had low utilization of mammography and BMD screening relative to clinical guidelines. Use of other health screening services was associated with compliance with guidelines. Methods to improve adherence to mammography and BMD screening guidelines should be explored, which could possibly leverage the increased likelihood that women who receive one screening service will receive another.

Patient characteristics and utilization of breast cancer screening or diagnostic procedures prior to initiation of raloxifene, bisphosphonates and calcitonin.

OBJECTIVE: This study evaluated the characteristics of postmenopausal women who initiated on raloxifene, bisphosphonates, and calcitonin, specifically evaluating the use of breast cancer screening or diagnostic procedures prior to initiation of therapy. RESEARCH DESIGN AND METHODS: Women 50 years and older with at least one claim for raloxifene (RLX), bisphosphonates (BIS), or calcitonin (CT) in 2005 or 2006 and continuous enrollment (with consecutive gaps in enrollment of no more than 1 month) from January 2004 to December 2007 were identified in a large national commercial and Medicare claims database. Treatment-naïve postmenopausal women initiating on raloxifene, bisphosphonates, and calcitonin were compared in terms of breast cancer screening or diagnostic procedures (i.e., mammogram, breast MRI, ultrasound, and biopsy) as well as age, provider specialty, fractures, bone mineral density screening, Chronic Disease Scores, and comorbidities. RESULTS: Treatment-naïve patients initiated on raloxifene were younger than those initiated on bisphosphonates and calcitonin (mean age 63 years [RLX], 66 years [BIS], 72 years [CT]; p < 0.05). Treatment-naïve patients initiated on raloxifene were more likely to have had breast cancer screening or diagnostic procedures in the 12 months prior to therapy initiation than treatment-naïve bisphosphonate or calcitonin patients (RLX 61%, BIS 57%, CT 41%; p < 0.05), and were more likely to have an increased frequency of mammograms in the 12 months after therapy initiation (RLX 18%, BIS 16%, CT 15%; p < 0.05). Calcitonin patients were the most likely to have had a fracture in the pre-period followed by bisphosphonates then raloxifene patients. CONCLUSION: These data suggest that there are differences in the clinical characteristics of postmenopausal women who initiate osteoporosis medications specifically in regards to age, pre-period fractures and breast cancer screening or diagnostic procedure use prior to initiation. Key limitations include general claims database limitations, lack of ability to assess behavior change, and lack of information on therapy initiation rationale.

Incidence of invasive breast cancer in postmenopausal women after discontinuation of long-term raloxifene administration.

BACKGROUND: Postmenopausal women with osteoporosis had a 66% relative risk reduction for invasive breast cancer over 8 years of raloxifene therapy in the randomized, placebo-controlled 4-year MORE (Multiple Outcomes of Raloxifene Evaluation) trial and the CORE (Continuing Outcomes Relevant to Evista) trial, a 4-year follow-up to MORE. PATIENTS AND METHODS: The first post hoc analysis examined the effects of raloxifene on the cumulative incidence of invasive breast cancer on a yearly basis. Another analysis compared the incidence of invasive breast cancer in 3967 patients who continued raloxifene for 8 years (RLX-C, n = 2280), discontinued raloxifene after 4 years in MORE (RLX-D, n = 401), or took placebo (n = 1286) for a mean 2.9 years' treatment duration (57,338 patient-years). RESULTS: The unadjusted breast cancer incidence rate was 5.39 per 1000 patient-years in the placebo group compared with 2.26 in the RLX-C group (hazard ratio [HR], 0.41 [95% CI 0.21-0.81]) and 3.59 in the RLX-D group (HR, 0.69 [95% CI 0.23-2.01]). Because the choice of taking the study drug was not randomized in CORE, propensity scores were used to adjust for potential imbalances in baseline characteristics before CORE. Results after adjustment by the propensity score method were similar to the unadjusted results. CONCLUSION: This analysis suggests a persistent effect for breast cancer risk reduction in patients who discontinued raloxifene, although this conclusion is limited by the small sample size.

Raloxifene use in clinical practice: efficacy and safety.

OBJECTIVE AND METHODS: In this article, we provide an interdisciplinary concise review of the effects of raloxifene on breast, bone, and reproductive organs, as well as the adverse events that may be associated with its use. RESULTS: Raloxifene has been shown to prevent osteoporosis in postmenopausal women (PMW) with low bone mass and prevent vertebral fractures in those with osteoporosis/low bone mass; it has not been shown to reduce the risk of nonvertebral fractures. Raloxifene reduces the risk of invasive breast cancer in PMW with osteoporosis or at high risk of breast cancer. The risk of venous thromboembolism has been consistently shown to be increased with raloxifene, so it should not be used in women at high risk of venous thromboembolism. Although raloxifene does not increase, nor decrease, the risk of coronary or stroke events overall, in the raloxifene trial of PMW at increased risk of coronary events, the incidence of fatal stroke was higher in women assigned raloxifene versus placebo. CONCLUSIONS: Based on its approved indications, it is appropriate to prescribe raloxifene to prevent or treat osteoporosis, as well as to reduce the risk of invasive breast cancer in PMW with osteoporosis or at high risk of breast cancer. Women at increased risk of both fracture and invasive breast cancer are those most likely to receive a dual benefit with raloxifene. Decision making must involve the incorporation of the woman's personal feelings about the risks and benefits of raloxifene therapy, balanced with her interest in reducing risk of fractures and breast cancer through pharmacological intervention.

Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk.

BACKGROUND: In the Raloxifene Use for The Heart trial, 10 101 postmenopausal women with coronary heart disease (CHD) or multiple CHD risk factors were randomly assigned to 60 mg/d raloxifene or to placebo and followed for a median of 5.6 years. Raloxifene, a selective estrogen receptor modulator, was found to reduce the risk of invasive breast cancer and vertebral fractures but not the risk of cardiovascular events. Here, we provide further details about breast cancer incidence by tumor characteristics, duration of treatment, and subgroup. METHODS: Reported breast cancer was adjudicated by an independent committee based on medical records and pathology reports. The primary analyses used Cox proportional hazards models with time to first breast cancer as the outcome. Subgroup effects were analyzed using similar models with terms for treatment by subgroup. All statistical tests were two-sided. RESULTS: As previously reported, raloxifene reduced the incidence of invasive breast cancer by 44% (hazard ratio [HR] = 0.56; 95% confidence interval [CI] = 0.38 to 0.83; absolute risk reduction = 1.2 invasive breast cancers per 1000 women treated for 1 year). The lower incidence of invasive breast cancer reflected a 55% lower incidence of invasive estrogen receptor (ER)-positive tumors (HR = 0.45; 95% CI = 0.28 to 0.72). However, raloxifene treatment did not reduce the incidence of noninvasive breast cancer or of invasive ER-negative breast cancer. The reduced incidence of invasive breast cancer was similar across subgroups, including those defined by age, body mass index, family history of breast cancer, prior use of postmenopausal hormones, and 5-year estimated risk of invasive breast cancer. CONCLUSION: Raloxifene reduces risk of invasive ER-positive breast cancer regardless of a woman's baseline breast cancer risk but does not reduce risk of noninvasive or ER-negative breast cancers. These results confirm those of the Multiple Outcomes of Raloxifene Evaluation, a previous randomized trial among women with osteoporosis.

Relationship between bone mass, invasive breast cancer incidence and raloxifene therapy in postmenopausal women with low bone mass or osteoporosis.

OBJECTIVE: To evaluate the relationship between bone mass and risk of breast cancer and to determine the effect of raloxifene therapy on breast cancer incidence in women categorized by bone mass into low bone mass and osteoporosis subgroups. DESIGN: In this post hoc analysis, data were analyzed from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, enrolling postmenopausal women with low bone mass (N = 7705), and the Continuing Outcomes Relevant to Evista (CORE) trial, a follow-up to MORE enrolling 4011 MORE participants. Total follow-up was for up to 8 years. Women with a total hip bone mineral density (BMD) T-score < -1 to > -2.5 or T-score < or = -2.5 (referent, NHANES III database) were classified as having low bone mass or osteoporosis, respectively. Women with a pre-existing vertebral fracture were considered as having osteoporosis irrespective of BMD T-score. Analyses were performed for invasive breast cancers and invasive estrogen-receptor (ER) positive breast cancers. RESULTS: Women with low bone mass (N = 3829) had a twofold higher incidence of invasive ER-positive breast cancer than those with osteoporosis (N = 3836) (HR 2.13, 95% CI 1.12-4.03). The incidence of all invasive breast cancers did not differ significantly between the bone mass groups. The incidences of invasive and invasive ER-positive breast cancers were 65-78% lower in women assigned raloxifene versus placebo in both the low bone mass and osteoporosis groups (p < 0.05). CONCLUSIONS: In this post hoc analysis of postmenopausal women participating in MORE and CORE, bone mass was a predictor of invasive ER-positive breast cancer. Raloxifene treatment reduced the risk of invasive and invasive ER-positive breast cancers in women with low bone mass and those with osteoporosis. Since participants were older postmenopausal women with low bone mass, whether these findings can be generalized to other postmenopausal women is unclear.

Risk factors for breast cancer in older women: the relative contribution of bone mineral density and other established risk factors.

AIM: To determine the contribution of bone mineral density (BMD) to breast cancer risk relative to other established breast cancer risk factors in postmenopausal women with osteoporosis. METHODS: Data for this analysis comprised those collected from women randomized to placebo in the MORE and CORE trials (N = 2,576). Risk factors measured at baseline included age, family history of breast cancer, estradiol level, body mass index, prior hormone therapy, BMD and vertebral fracture status. Cox proportional hazards regression models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a total of 13,698 woman-years of follow-up, 65 incident breast cancers occurred. In univariate analyses, older age and family history of breast cancer were the strongest predictors of breast cancer risk, associated with a 2.4- and 2.6-fold increase in breast cancer incidence. A higher estradiol level was associated with a 1.9-fold increase in breast cancer incidence. The association between femoral neck BMD and breast cancer incidence was only significant after adjustment for age (P = 0.03). The final multivariable model included age, family history, estradiol, BMD, and the BMD-estradiol interaction since the effect of BMD on breast cancer varied by estradiol level (interaction P-value, 0.04); in those with a lower estradiol level, a higher BMD was associated with a 2.6-fold increased in breast cancer. CONCLUSION: Overall, BMD is a relatively weak predictor of breast cancer risk in these postmenopausal women with osteoporosis, after taking into consideration age, family history and endogenous estradiol level.

Effect of raloxifene on the incidence of invasive breast cancer in postmenopausal women with osteoporosis categorized by breast cancer risk.

PURPOSE: To assess the effect of raloxifene, indicated for osteoporosis treatment and prevention, on invasive breast cancer in subgroups of postmenopausal women defined by risk factors for breast cancer. EXPERIMENTAL DESIGN: Data from the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial (N=7,705) and a follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial (N=4,011), were analyzed. Prespecified subgroups were defined by age (>or=65 versus<65 years), age at menopause (>or=49 versus<49 years), body mass index (>or=25 versus<25 kg/m2), family history of breast cancer (yes/no), serum estradiol level (5-10 versus<5, >10 versus<5 pmol/L), prior estrogen therapy (yes/no), and bone mass at MORE baseline, and 5-year predicted risk, assessed using the modified Gail model (>or=1.67 versus<1.67%), at CORE baseline. Time-to-first invasive breast cancer was analyzed using Cox proportional hazards models. RESULTS: In the placebo group, older age, higher estradiol level, and a family history of breast cancer were associated with an increased breast cancer risk (P<0.05). Raloxifene therapy was associated with a reduced breast cancer risk in both women at lower and those at higher breast cancer risk. Hazard ratio point estimates were 0.11 to 0.67, corresponding to a 33% to 89% reduction in breast cancer risk with raloxifene versus placebo. The therapy by family history interaction was significant (P=0.04). CONCLUSIONS: Raloxifene therapy was associated with a reduced risk of invasive breast cancer in postmenopausal women irrespective of the presence/absence of risk factors; its effect was greater in women with a family history of breast cancer.

Hemodynamic effects of acute and repeated exposure to raloxifene in ovariectomized sheep.

We hypothesize that administration of acute and daily doses of raloxifene will have significant effects on ovine coronary and uterine hemodynamics and that these changes are estrogen receptor dependent. Eleven ovariectomized sheep were instrumented to measure mean arterial pressure, heart rate (HR), cardiac output (CO), and coronary (CBF) and uterine artery blood flows (UBF). A dose-response curve was generated for raloxifene (1, 3, and 10 microg/kg) and compared with a standard dose of estradiol-17beta (1 microg/kg) given intravenously. In a second group of animals, raloxifene (10 microg.kg-1.day-1) was administered intravenously for 14 consecutive days, and cardiovascular responses were compared with a group of animals administered estradiol-17beta (10 microg/kg) daily for the same period. To determine whether raloxifene-related vascular responses were estrogen receptor (ER) mediated, the animals were pretreated with estrogen antagonist ICI-182,780 given intravenously. Finally, RT-PCR was preformed to determine the presence of ERalpha and ERbeta mRNA in ovine coronary and uterine vessels. Raloxifene increased CBF and UBF dose dependently with a parallel decrease in the associated vascular resistances. Acute cardiovascular responses to daily doses of raloxifene and estradiol-17beta were sustainable. In contrast to estradiol-17beta, which significantly increases CO by increasing HR but not stroke volume, raloxifene significantly increased stroke volume without a significant parallel increase in HR. ICI-182,780 abolished raloxifene-induced hemodynamic responses, and ERalpha and ERbeta mRNA are present in both ovine coronary and uterine vessels. Hence, the hemodynamic effects of raloxifene are dose dependent, sustainable, and estrogen receptor mediated.

Safety assessment of raloxifene over eight years in a clinical trial setting.

OBJECTIVE: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting. METHODS: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista (CORE) trial. MORE was an international, 4-year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4-year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test. RESULTS: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups (p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively (p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93-3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups (p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo (p = 0.028, p < 0.001, and p = 0.008, respectively). CONCLUSION: These 8-year data support the known clinical safety profile of raloxifene, established in the MORE trial.

Association of leptin with poor ovarian stimulation during in vitro fertilization.

OBJECTIVE: To evaluate whether serum leptin levels are predictive of in vitrofertilization (IVF) outcome. STUDY DESIGN: A nested, case-control study was performed on patients undergo-formed on patients undergoing IVF. Ovarian stimulation was performed with a set protocol. At the conclusion of the stimulation, patients were divided into 2 groups, poor stimulator (PS) and high stimulator (HS), based on the number of follicles seen on ultrasound. The PS group contained patients with < 12 follicles > 13 mm in diameter; the HS group contained patients with > or = 12 follicles > 13 mm. Blood from the start of the cycle in which human chorionic gonadotropin (hCG) was administered was assayed for leptin and estradiol. The number of follicles obtained, number of oocytes retrieved, quality of the oocytes and quality of the embryos were calculated. Mean leptin and estradiol levels were compared using Student's t test. Pearson correlation coefficients were calculated to assess the relationship between leptin and the other outcome variables. RESULTS: Mean leptin levels (+/- SEM) at the start of the cycle (21.5 +/- 2.9 ng/dL for PS and 34.6 +/- 14.0 ng/dL for HS) and on the day of hCG (53.2 +/- 5.37 ng/dL for PS and 50.4 +/- 9.1 ng/dL for HS) were not significantly different. CONCLUSION: Leptin levels obtained at the start of stimulation or on the day of hCG administration are not predictive of IVF outcome.

Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene.

BACKGROUND: The randomized, double-blind Multiple Outcomes of Raloxifene Evaluation (MORE) trial found that 4 years of raloxifene therapy decreased the incidence of invasive breast cancer among postmenopausal women with osteoporosis by 72% compared with placebo. We conducted the Continuing Outcomes Relevant to Evista (CORE) trial to examine the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer in women in MORE who agreed to continue in CORE. METHODS: Women who had been randomly assigned to receive raloxifene (either 60 or 120 mg/day) in MORE were assigned to receive raloxifene (60 mg/day) in CORE (n = 3510), and women who had been assigned to receive placebo in MORE continued on placebo in CORE (n = 1703). Breast cancer incidence was analyzed by a log-rank test, and a Cox proportional hazards model was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: During the CORE trial, the 4-year incidences of invasive breast cancer and estrogen receptor (ER)-positive invasive breast cancer were reduced by 59% (HR = 0.41; 95% CI = 0.24 to 0.71) and 66% (HR = 0.34; 95% CI = 0.18 to 0.66), respectively, in the raloxifene group compared with the placebo group. There was no difference between the two groups in incidence of ER-negative invasive breast cancer during CORE (P = .86). Over the 8 years of both trials, the incidences of invasive breast cancer and ER-positive invasive breast cancer were reduced by 66% (HR = 0.34; 95% CI = 0.22 to 0.50) and 76% (HR = 0.24; 95% CI = 0.15 to 0.40), respectively, in the raloxifene group compared with the placebo group. During the CORE trial, the relative risk of thromboembolism in the raloxifene group compared with that in the placebo group was 2.17 (95% CI = 0.83 to 5.70). This increased risk, also observed in the MORE trial, persisted over the 8 years of both trials. CONCLUSIONS: The reduction in invasive breast cancer incidence continues beyond 4 years of raloxifene treatment in postmenopausal women with osteoporosis. No new safety concerns related to raloxifene therapy were identified during CORE.