Multimodal assessment of estrogen receptor mRNA profiles to quantify estrogen pathway activity in breast tumors

Background Molecular markers have transformed our understanding of the heterogeneity of breast cancer and have allowed the identification of genomic profiles of estrogen receptor (ER)-α signaling. However, our understanding of the transcriptional profiles of ER signaling remains inadequate. Therefore, we sought to identify the genomic indicators of ER pathway activity that could supplement traditional immunohistochemical (IHC) assessments of ER status to better understand ER signaling in the breast tumors of individual patients. Materials and Methods We reduced ESR1 (gene encoding the ER-α protein) mRNA levels using small interfering RNA in ER+ MCF7 breast cancer cells and assayed for transcriptional changes using Affymetrix HG U133 Plus 2.0 arrays. We also compared 1034 ER+ and ER− breast tumors from publicly available microarray data. The principal components of ER activity generated from these analyses and from other published estrogen signatures were compared with ESR1 expression, ER-α IHC, and patient survival. Results Genes differentially expressed in both analyses were associated with ER-α IHC and ESR1 mRNA expression. They were also significantly enriched for estrogen-driven molecular pathways associated with ESR1, cyclin D1 (CCND1), MYC (v-myc avian myelocytomatosis viral oncogene homolog), and NFKB (nuclear factor kappa B). Despite their differing constituent genes, the principal components generated from these new analyses and from previously published ER-associated gene lists were all associated with each other and with the survival of patients with breast cancer treated with endocrine therapies. Conclusion A biomarker of ER-α pathway activity, generated using ESR1-responsive mRNAs in MCF7 cells, when used alongside ER-α IHC and ESR1 mRNA expression, could provide a method for further stratification of patients and add insight into ER pathway activity in these patients

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Clinical-decision taking in primary pelvic organ prolapse; the effects of diagnostic tests on treatment selection in comparison with a consensus meeting

INTRODUCTION AND HYPOTHESIS: The objective of the study was to establish the effects of additional diagnostic tests compared to a consensus outcome on treatment selection in primary pelvic organ prolapse. METHODS: Three expert gynecologists individually defined a management plan in 53 patients after magnetic resonance imaging, defecography, urodynamic, and anorectal function test information was provided. These management plans were compared with basic treatment advices in the absence of any test and with consensus advices (opinion-based references). The experts assigned a subjective score (assigned diagnostic value [ADV], 0-100%) to rate the test's relative importance. RESULTS: On average, additional diagnostic testing resulted in a revised initial management plan in 38% of the cases; 24% of the individual management plans did not meet the consensus reference. Overall defecography was regarded most valuable (ADV range 19-65%) vs. magnetic resonance imaging rated least (ADV range 0-37%). CONCLUSIONS: Although additional diagnostic tests frequently led to adaptations of basic treatment proposals, consensus was not reached in a fourth of the case

Surgery versus Physiotherapy for Stress Urinary Incontinence

<p>BackgroundPhysiotherapy involving pelvic-floor muscle training is advocated as first-line treatment for stress urinary incontinence; midurethral-sling surgery is generally recommended when physiotherapy is unsuccessful. Data are lacking from randomized trials comparing these two options as initial therapy.</p><p>MethodsWe performed a multicenter, randomized trial to compare physiotherapy and midurethral-sling surgery in women with stress urinary incontinence. Crossover between groups was allowed. The primary outcome was subjective improvement, measured by means of the Patient Global Impression of Improvement at 12 months.</p><p>ResultsWe randomly assigned 230 women to the surgery group and 230 women to the physiotherapy group. A total of 49.0% of women in the physiotherapy group and 11.2% of women in the surgery group crossed over to the alternative treatment. In an intention-to-treat analysis, subjective improvement was reported by 90.8% of women in the surgery group and 64.4% of women in the physiotherapy group (absolute difference, 26.4 percentage points; 95% confidence interval [CI], 18.1 to 34.5). The rates of subjective cure were 85.2% in the surgery group and 53.4% in the physiotherapy group (absolute difference, 31.8 percentage points; 95% CI, 22.6 to 40.3); rates of objective cure were 76.5% and 58.8%, respectively (absolute difference, 17.8 percentage points; 95% CI, 7.9 to 27.3). A post hoc per-protocol analysis showed that women who crossed over to the surgery group had outcomes similar to those of women initially assigned to surgery and that both these groups had outcomes superior to those of women who did not cross over to surgery.</p><p>ConclusionsFor women with stress urinary incontinence, initial midurethral-sling surgery, as compared with initial physiotherapy, results in higher rates of subjective improvement and subjective and objective cure at 1 year.</p>

Recurrent Disease After Esophageal Cancer Surgery: A Substudy of The Dutch Nationwide Ivory Study

OBJECTIVE: This study investigated the patterns, predictors, and survival of recurrent disease following esophageal cancer surgery. BACKGROUND: Survival of recurrent esophageal cancer is usually poor, with limited prospects of remission. METHODS: This nationwide cohort study included patients with distal esophageal and gastroesophageal junction adenocarcinoma and squamous cell carcinoma after curatively intended esophagectomy in 2007 to 2016 (follow-up until January 2020). Patients with distant metastases detected during surgery were excluded. Univariable and multivariable logistic regression were used to identify predictors of recurrent disease. Multivariable Cox regression was used to determine the association of recurrence site and treatment intent with postrecurrence survival. RESULTS: Among 4626 patients, 45.1% developed recurrent disease a median of 11 months postoperative, of whom most had solely distant metastases (59.8%). Disease recurrences were most frequently hepatic (26.2%) or pulmonary (25.1%). Factors significantly associated with disease recurrence included young age (≤65 y), male sex, adenocarcinoma, open surgery, transthoracic esophagectomy, nonradical resection, higher T-stage, and tumor positive lymph nodes. Overall, median postrecurrence survival was 4 months [95% confidence interval (95% CI): 3.6-4.4]. After curatively intended recurrence treatment, median survival was 20 months (95% CI: 16.4-23.7). Survival was more favorable after locoregional compared with distant recurrence (hazard ratio: 0.74, 95% CI: 0.65-0.84). CONCLUSIONS: This study provides important prognostic information assisting in the surveillance and counseling of patients after curatively intended esophageal cancer surgery. Nearly half the patients developed recurrent disease, with limited prospects of survival. The risk of recurrence was higher in patients with a higher tumor stage, nonradical resection and positive lymph node harvest

Recurrent Disease After Esophageal Cancer Surgery: A Substudy of The Dutch Nationwide Ivory Study

OBJECTIVE: This study investigated the patterns, predictors, and survival of recurrent disease following esophageal cancer surgery. BACKGROUND: Survival of recurrent esophageal cancer is usually poor, with limited prospects of remission. METHODS: This nationwide cohort study included patients with distal esophageal and gastroesophageal junction adenocarcinoma and squamous cell carcinoma after curatively intended esophagectomy in 2007 to 2016 (follow-up until January 2020). Patients with distant metastases detected during surgery were excluded. Univariable and multivariable logistic regression were used to identify predictors of recurrent disease. Multivariable Cox regression was used to determine the association of recurrence site and treatment intent with postrecurrence survival. RESULTS: Among 4626 patients, 45.1% developed recurrent disease a median of 11 months postoperative, of whom most had solely distant metastases (59.8%). Disease recurrences were most frequently hepatic (26.2%) or pulmonary (25.1%). Factors significantly associated with disease recurrence included young age (≤65 y), male sex, adenocarcinoma, open surgery, transthoracic esophagectomy, nonradical resection, higher T-stage, and tumor positive lymph nodes. Overall, median postrecurrence survival was 4 months [95% confidence interval (95% CI): 3.6-4.4]. After curatively intended recurrence treatment, median survival was 20 months (95% CI: 16.4-23.7). Survival was more favorable after locoregional compared with distant recurrence (hazard ratio: 0.74, 95% CI: 0.65-0.84). CONCLUSIONS: This study provides important prognostic information assisting in the surveillance and counseling of patients after curatively intended esophageal cancer surgery. Nearly half the patients developed recurrent disease, with limited prospects of survival. The risk of recurrence was higher in patients with a higher tumor stage, nonradical resection and positive lymph node harvest