Dysregulation of Vascular Endothelial Growth Factor Receptor-2 by Multiple miRNAs in Endothelial Colony-Forming Cells of Coronary Artery Disease.

BACKGROUND/AIMS: Endothelial colony-forming cells (ECFCs) have the potential to be used in regenerative medicine. Dysfunction of ECFCs is correlated with the onset of cardiovascular disorders, especially coronary artery disease (CAD). Binding of vascular endothelial growth factor A (VEGFA) to vascular endothelial growth factor receptor-2 (VEGFR2) triggers cell motility and angiogenesis of ECFCs, which are crucial to vascular repair. METHODS: To identify the miRNA-VEGFR2-dependent regulation of ECFC functions, ECFCs isolated from peripheral blood of disease-free and CAD individuals were subjected to small RNA sequencing for identification of anti-VEGFR2 miRNAs. The angiogenic activities of the miRNAs were determined in both in vitro and in vivo mice models. RESULTS: Three miRNAs, namely miR-410-3p, miR-497-5p, and miR-2355-5p, were identified to be upregulated in CAD-ECFCs, and VEGFR2 was their common target gene. Knockdown of these miRNAs not only restored the expression of VEGFR2 and increased angiogenic activities of CAD-ECFCs in vitro, but also promoted blood flow recovery in ischemic limbs in vivo. miR-410-3p, miR-497-5p, and miR-2355-5p could serve as potential biomarkers for CAD detection as they are highly expressed in the plasma of CAD patients. CONCLUSIONS: This modulation could help develop new therapeutic modalities for cardiovascular diseases and other vascular dysregulated diseases, especially tumor angiogenesis.

Effect of Recombinant Human Growth Hormone and Rosiglitazone for HIV-Associated Abdominal Fat Accumulation on Adiponectin and other Markers of Inflammation.

BACKGROUND/OBJECTIVE: In a previous report of HIV-infected patients with fat redistribution, we found that recombinant human growth hormone (rhGH) therapy reduced visceral adipose tissue (VAT) but increased insulin resistance, and that the addition of rosiglitazone reversed the negative effects of rhGH on insulin sensitivity. In this study, we sought to determine the effects of rhGH and rosiglitazone therapy on an array of inflammatory and fibrinolytic markers. METHODS: 72 patients with HIV-associated abdominal obesity and insulin resistance were randomized to treatment with rhGH, rosiglitazone, the combination of rhGH and rosiglitazone, or placebo for 12 weeks. Subjects with plasma and serum samples available at weeks 0 (n=63) and 12 (n=46-48) were assessed for adiponectin, C-reactive protein, homocysteine, interleukin-1, interleukin-6, tumor necrosis factor alpha, interferon gamma, fibrinogen, plasminogen activator inhibitor-1 antigen, and tissue plasminogen activator antigen. RESULTS: Treatment with both rosiglitazone alone and the combination of rosiglitazone and rhGH for 12 weeks resulted in significant increases in adiponectin levels from baseline. Adiponectin levels did not change significantly in the rhGH arm alone . There were no significant changes in the other biomarkers among the different treatment groups. DISCUSSION: In this study of HIV-infected patients with altered fat distribution, treatment with rosiglitazone had beneficial effects on adiponectin concentrations, an effect that was also seen with a combination of rosiglitazone and rhGH. RhGH administration alone, however, did not demonstrate any significant impact on adiponectin levels despite reductions in VAT.

Does the Presence of Endometriosis Affect Prognosis of Ovarian Cancer?

Ovarian cancers diagnosed between 2000 and 2013 were examined and cases with and without endometriosis compared. Among 139 epithelial ovarian, there were 49 (35%) with endometriosis and 90 (65%) without endometriosis. Endometriosis associated ovarian cancers were more likely to be confined to the pelvis (54% vs. 9%, p < 0.0001) and lower grade (51% vs. 29%, p = 0.014). Younger age and earlier stage independently predicted the presence of endometriosis (p = 0.0011 and p < 0.0001, respectively). Ovarian cancer patients with endometriosis had improved PFS and OS [(HR = 0.20; 95% CI, 0.09-0.43), (HR = 0.18; 95% CI, 0.04-0.81)], compared to patients without endometriosis; however, endometriosis had no independent prognostic significance.

MicroRNA-134 Contributes to Glucose-Induced Endothelial Cell Dysfunction and This Effect Can Be Reversed by Far-Infrared Irradiation.

Diabetes mellitus (DM) is a metabolic disease that is increasing worldwide. Furthermore, it is associated with the deregulation of vascular-related functions, which can develop into major complications among DM patients. Endothelial colony forming cells (ECFCs) have the potential to bring about medical repairs because of their post-natal angiogenic activities; however, such activities are impaired by high glucose- (HG) and the DM-associated conditions. Far-infrared radiation (FIR) transfers energy as heat that is perceived by the thermoreceptors in human skin. Several studies have revealed that FIR improves vascular endothelial functioning and boost angiogenesis. FIR has been used as anti-inflammatory therapy and as a clinical treatment for peripheral circulation improvement. In addition to vascular repair, there is increasing evidence to show that FIR can be applied to a variety of diseases, including cardiovascular disorders, hypertension and arthritis. Yet mechanism of action of FIR and the biomarkers that indicate FIR effects remain unclear. MicroRNA-134 (miR-134-5p) was identified by small RNA sequencing as being increased in high glucose (HG) treated dfECFCs (HG-dfECFCs). Highly expressed miR-134 was also validated in dmECFCs by RT-qPCR and it is associated with impaired angiogenic activities of ECFCs. The functioning of ECFCs is improved by FIR treatment and this occurs via a reduction in the level of miR-134 and an increase in the NRIP1 transcript, a direct target of miR-134. Using a mouse ischemic hindlimb model, the recovery of impaired blood flow in the presence of HG-dfECFCs was improved by FIR pretreatment and this enhanced functionality was decreased when there was miR-134 overexpression in the FIR pretreated HG-dfECFCs. In conclusion, our results reveal that the deregulation of miR-134 is involved in angiogenic defects found in DM patients. FIR treatment improves the angiogenic activity of HG-dfECFCs and dmECFCs and FIR has potential as a treatment for DM. Detection of miR-134 expression in FIR-treated ECFCs should help us to explore further the effectiveness of FIR therapy.

Lipid profile changes in the severely obese after laparoscopic sleeve gastrectomy (LSG), 1, 3, and 5 years after surgery.

BACKGROUND: Since there is an increasing acceptance of the laparoscopic sleeve gastrectomy (LSG) and limited information regarding its effect on cardiac risk factors, we assessed lipid profiles. METHODS: A retrospective review of patient records pre and post LSG was performed. Analysis of variance evaluated group differences and paired t tests compared variable changes. RESULTS: Eighty two patients (67 % female, age 46.4 ± 13.9) had presurgery lipid profiles and follow-up (43 at 1 year, 28 at 3 years, and 26 at 5 years). Groups were not different in gender distribution. The presurgery mean body mass index (BMI) was 55.7 kg/m(2); 65.9 % of the subjects were super obese. After surgery, percentage of excess BMI loss was 58.1 % year (yr) 1, 61.3 % yr 3, and 39.0 % yr 5. Lipids were within the normal ranges for all parameters at all times; however, at baseline 77 % had at least one abnormality. At 1 year, triglycerides decreased significantly from baseline (adjusted p value (adj-p) = 0.004) and high-density lipoprotein (HDL) increased (adj-p = 0.025). Year 3 HDL was significantly different from baseline, adj-p = 0.0001. Yr 3 cholesterol increased from baseline, (adj-p = 0.027). Negative linear correlations with weight loss were present for low-density lipoprotein (LDL) at yr 3(r = 0.46, p = 0.02) and triglyceride change at year 5 (r = 0.48, p = 0.02). The percentage of patients with dyslipidemia or medicated did not change significantly during these 5 years. CONCLUSIONS: For this population electing LSG, mean lipid profiles were within normal ranges for all parameters before surgery. However, 77 % showed at least one abnormality presurgery. Weight change correlated with some changes of triglycerides, HDL, and LDL over time, but the impact was limited.

Screening for type 2 diabetes mellitus in patients with mental illness: application of a self-assessment score for diabetes mellitus risk.

Various methods for diabetes risk assessment have been developed over a decade, but they were not evaluated in patients with mental illness. This study examined the feasibility and utility of a self-assessment score for type 2 diabetes mellitus (DM2) risk among patients with mental illness. DM2 risk was assessed by patients with mental illness as well as clinicians via a self-assessment questionnaire, and the resulting scores were compared to each other as well as with actual diagnosis. Of 100 patients, nine patients were newly revealed to have DM2 and 34 patients have pre-DM2. Patients tended to underreport risk factors - obesity and physical activity - so perceived to have lower risk. Sensitivity of the self-assessment score was different when used by patients and by clinicians despite correlation coefficient of 0.82. Based on positive predictive values, we may expect one out of two patients who have high scores actually have DM2 or pre-DM2. Also, the discrimination capability was reasonably high (AUC=0.79), comparable to its performance observed in general populations. The self-assessment score has potential as a simple and adjunct tool to identify a high risk group of DM2/pre-DM2 among persons with mental illness, especially, when used together with health care providers.

miRNome traits analysis on endothelial lineage cells discloses biomarker potential circulating microRNAs which affect progenitor activities.

BACKGROUND: Endothelial progenitor cells (EPCs) play a fundamental role in not only blood vessel development but also post-natal vascular repair. Currently EPCs are defined as early and late EPCs based on their biological properties and their time of appearance during in vitro culture. Both EPC types assist angiogenesis and have been linked to ischemia-related disorders, including coronary artery disease (CAD). RESULTS: We found late EPCs are more mobile than early EPCs and matured endothelial cells (ECs). To pinpoint the mechanism, microRNA profiles of early EPCs late EPCs, and ECs were deciphered by small RNA sequencing. Obtained signatures made up of both novel and known microRNAs, in which anti-angiogenic microRNAs such as miR-221 and miR-222 are more abundant in matured ECs than in late EPCs. Overexpression of miR-221 and miR-222 resulted in the reduction of genes involved in hypoxia response, metabolism, TGF-beta signalling, and cell motion. Not only hamper late EPC activities in vitro, both microRNAs (especially miR-222) also hindered in vivo vasculogenesis in a zebrafish model. Reporter assays showed that miR-222, but not miR-221, targets the angiogenic factor ETS1. In contrast, PIK3R1 is the target of miR-221, but not miR-222 in late EPCs. Clinically, both miR-221-PIK3R1 and miR-222-ETS1 pairs are deregulated in late EPCs of CAD patients. CONCLUSIONS: Our results illustrate EPCs and ECs exploit unique miRNA modalities to regulate angiogenic features, and explain why late EPC levels and activities are reduced in CAD patients. These data will further help to develop new plasma biomarkers and therapeutic approaches for ischemia-related diseases or tumor angiogenesis.

A comparison of same setting versus delayed vitrectomy in the management of retained lens fragments after cataract surgery.

PURPOSE: Intravitreal retained lens fragments are a rare but potentially serious complication of phacoemulsification. The purpose of this study was to compare same setting ("no wait") vitrectomy with delayed surgery in the management of retained lens fragments in a single academic setting. METHODS: This study is a retrospective nonrandomized study of all patients undergoing pars plana vitrectomy for retained lens fragments after cataract surgery from 2007 to 2012. Outcomes included visual acuity and the development of various complications such as retinal detachment, elevated intraocular pressure >30 mmHg, and cystoid macular edema. Multivariate analysis was performed to adjust for potentially confounding variables such as age and preoperative visual acuity. RESULTS: Twenty-eight consecutive eyes (13 same setting, 15 delayed setting) were included in the analysis. Patients in the same setting group were older than in the delayed group (81.00 vs. 72.87 years, P = 0.053). No other preoperative differences existed between the groups (axial length, preoperative vision, and intraocular pressure). The mean time to pars plana vitrectomy in the delayed group was 26.6 days (range, 1-91 days). The mean follow-up time was 363 days (same setting) and 643 days (delayed). At the most recent follow-up, no significant difference existed in mean vision between the same setting (logMAR, 0.42) and the delayed group (logMAR, 0.57) (P = 0.132). Multivariate analysis showed no difference in final vision when adjusting for age and preoperative vision. Although there was a trend for eyes in the same setting group to obtain good vision (≥ 20/40) faster, a higher percentage of eyes in the delayed group obtained good vision at the most recent follow-up (66.7 vs. 23.1%, P = 0.02). More eyes in the delayed group had an intraocular pressure >30 at any point (P = 0.055). There was no significant difference between the groups in any other complications such as retinal detachment, choroidal detachment, and cystoid macular edema during the follow-up. CONCLUSION: In this cohort, same setting pars plana vitrectomy offers no significant visual acuity advantage over delayed pars plana vitrectomy in patients with retained lens fragments. Fewer eyes in the same setting group "ever" had an intraocular pressure ≥ 30 during follow-up, whereas no other complication differences were seen between the groups.

Dysregulated miR-361-5p/VEGF axis in the plasma and endothelial progenitor cells of patients with coronary artery disease.

Dysfunction and reduction of circulating endothelial progenitor cell (EPC) is correlated with the onset of cardiovascular disorders including coronary artery disease (CAD). VEGF is a known mitogen for EPC to migrate out of bone marrow to possess angiogenic activities, and the plasma levels of VEGF are inversely correlated to the progression of CAD. Circulating microRNAs (miRNAs) in patient body fluids have recently been considered to hold the potential of being novel disease biomarkers and drug targets. However, how miRNAs and VEGF cooperate to regulate CAD progression is still unclear. Through the small RNA sequencing (smRNA-seq), we deciphered the miRNome patterns of EPCs with different angiogenic activities, hypothesizing that miRNAs targeting VEGF must be more abundant in EPCs with lower angiogenic activities. Candidates of anti-VEGF miRNAs, including miR-361-5p and miR-484, were enriched in not only diseased EPCs but also the plasma of CAD patients. However, we found out only miR-361-5p, but not miR-484, was able to suppress VEGF expression and EPC activities. Reporter assays confirmed the direct binding and repression of miR-361-5p to the 3'-UTR of VEGF mRNA. Knock down of miR-361-5p not only restored VEGF levels and angiogenic activities of diseased EPCs in vitro, but further promoted blood flow recovery in ischemic limbs of mice. Collectively, we discovered a miR-361-5p/VEGF-dependent regulation that could help to develop new therapeutic modalities not only for ischemia-related diseases but also for tumor angiogenesis.

SPOP mutations in prostate cancer across demographically diverse patient cohorts.

BACKGROUND: Recurrent mutations in the Speckle-Type POZ Protein (SPOP) gene occur in up to 15% of prostate cancers. However, the frequency and features of cancers with these mutations across different populations is unknown. OBJECTIVE: To investigate SPOP mutations across diverse cohorts and validate a series of assays employing high-resolution melting (HRM) analysis and Sanger sequencing for mutational analysis of formalin-fixed paraffin-embedded material. DESIGN SETTING AND PARTICIPANTS: 720 prostate cancer samples from six international cohorts spanning Caucasian, African American, and Asian patients, including both prostate-specific antigen-screened and unscreened populations, were screened for their SPOP mutation status. Status of SPOP was correlated to molecular features (ERG rearrangement, PTEN deletion, and CHD1 deletion) as well as clinical and pathologic features. RESULTS AND LIMITATIONS: Overall frequency of SPOP mutations was 8.1% (4.6% to 14.4%), SPOP mutation was inversely associated with ERG rearrangement (P<.01), and SPOP mutant (SPOPmut) cancers had higher rates of CHD1 deletions (P<.01). There were no significant differences in biochemical recurrence in SPOPmut cancers. Limitations of this study include missing mutational data due to sample quality and lack of power to identify a difference in clinical outcomes. CONCLUSION: SPOP is mutated in 4.6% to 14.4% of patients with prostate cancer across different ethnic and demographic backgrounds. There was no significant association between SPOP mutations with ethnicity, clinical, or pathologic parameters. Mutual exclusivity of SPOP mutation with ERG rearrangement as well as a high association with CHD1 deletion reinforces SPOP mutation as defining a distinct molecular subclass of prostate cancer.

Peripheral nerve blocks in shoulder arthroplasty: how do they influence complications and length of stay?

BACKGROUND: Regional anesthesia has proven to be a highly effective technique for pain control after total shoulder arthroplasty. However, concerns have been raised about the safety of upper-extremity nerve blocks, particularly with respect to the incidence of perioperative respiratory and neurologic complications, and little is known about their influence, if any, on length of stay after surgery. QUESTIONS/PURPOSES: Using a large national cohort, we asked: (1) How frequently are upper-extremity peripheral nerve blocks added to general anesthesia in patients undergoing total shoulder arthroplasty? (2) Are there differences in the incidence of and adjusted risk for major perioperative complications and mortality between patients receiving general anesthesia with and without nerve blocks? And (3) does resource utilization (blood product transfusion, intensive care unit admission, length of stay) differ between groups? METHODS: We searched a nationwide discharge database for patients undergoing total shoulder arthroplasty under general anesthesia with or without addition of a nerve block. Groups were compared with regard to demographics, comorbidities, major perioperative complications, and length of stay. Multivariable logistic regressions were performed to measure complications and resource use. A negative binomial regression was fitted to measure length of stay. RESULTS: We identified 17,157 patients who underwent total shoulder arthroplasty between 2007 and 2011. Of those, approximately 21% received an upper-extremity peripheral nerve block in addition to general anesthesia. Patients receiving combined regional-general anesthesia had similar mean age (68.6 years [95% CI: 68.2-68.9 years] versus 69.1 years [95% CI: 68.9-69.3 years], p < 0.0043), a slightly lower mean Deyo (comorbidity) index (0.87 versus 0.93, p = 0.0052), and similar prevalence of individual comorbidities, compared to those patients receiving general anesthesia only. Addition of regional anesthesia was not associated with different odds ratios for complications, transfusion, and intensive care unit admission. Incident rates for length of stay were also similar between groups (incident rate ratio = 0.99; 95% CI: 0.97-1.02; p = 0.467) CONCLUSIONS: Addition of regional to general anesthesia was not associated with an increased complication profile or increased use of resources. In combination with improved pain control as known from previous research, regional anesthesia may represent a viable management option for shoulder arthroplasty. However, further research is necessary to better clarify the risk of neurologic complications. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Critical care in patients undergoing lumbar spine fusion: a population-based study.

BACKGROUND: Data on the utilization of critical care services (CCSs) among patients who underwent spine fusion are rare. Given the increasing popularity of this procedure, information regarding demographics and risk factors for the use of these advanced services is needed in order to appropriately allocate resources, educate clinical staff, and identify targets for future research. METHODS: We analyzed hospital discharge data of patients who underwent lumbar spine fusion in approximately 400 US hospitals between 2006 and 2010. Patient, procedure, and health care system-related demographics for those requiring CCS were compared to those who did not. Outcomes such as mortality, complications, disposition status, and hospital charges were compared among groups and risk factors for the utilization of CCS identified. RESULTS: A total of 95 434 entries of patients who underwent posterior lumbar spine fusion surgery between 2006 and 2010 were identified. Approximately 10% of the patients required CCS. On average, patients requiring CCS were older and had a higher comorbidity burden, developed more complications, had longer hospital stays and higher costs, and were less likely to be discharged home compared to non-CCS patients. Risk factors with increased odds for requiring CCS included advanced age, increasing comorbidity burden, increasing surgical invasiveness, and presence of postoperative complications, especially pulmonary. CONCLUSIONS: Approximately, 10% of the patients undergoing lumbar spine surgery require CCS. Utilizing the present data, critical care physicians and administrators can identify patients at risk, educate clinical staff, identify targets for intervention, and allocate resources to meet the needs of this particular patient population.

Pathologic upgrade rates on subsequent excision when lobular carcinoma in situ is the primary diagnosis in the needle core biopsy with special attention to the radiographic target.

CONTEXT: Lobular carcinoma in situ (LCIS) as the primary pathologic diagnosis in a needle core biopsy is an infrequent finding, and the management of patients in this setting is controversial. OBJECTIVE: To determine the rate of pathologic upgrade (defined as the presence of a clinically more-significant lesion in the subsequent excision) in patients with a primary pathologic diagnosis of LCIS in the needle core biopsy. DESIGN: Patients with a primary diagnosis of LCIS in a needle core biopsy who underwent subsequent excision were identified. Core biopsies containing a concurrent high-risk lesion and cases with radiologic-pathologic discordance were excluded. The presence of selected microscopic features in the needle core biopsy was correlated with pathologic upgrade. Microscopic findings were correlated with the radiographic target in the needle core biopsy. RESULTS: Sixty-one women with primary LCIS in their needle core biopsy showed a 10% pathologic upgrade rate. The percentage of cores involved by LCIS was significantly associated with pathologic upgrade (P= .04), whereas the remaining measured parameters were not. When LCIS represented the radiographic target, the pathologic upgrade rate was 18%, whereas when it was an incidental finding, the pathologic upgrade rate was 4%. CONCLUSIONS: It may be reasonable for patients with primary, yet incidental, LCIS on needle core biopsy to be managed in a nonsurgical fashion. Larger studies are needed to confirm our findings.

V-ets erythroblastosis virus E26 oncogene homolog (avian)/Trefoil factor 3/high-molecular-weight cytokeratin triple immunostain: a novel tissue-based biomarker in prostate cancer with potential clinical application.

Trefoil factor 3 (TFF3) is associated with various cancers and overexpressed in a subset of prostate cancers. Functional studies suggest that v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) down-regulates TFF3 expression in hormone-naïve prostate cancer. To characterize this inverse relationship, we developed a triple immunostain encompassing ERG, TFF3, and high-molecular-weight cytokeratin. Triple stain was performed on 96 tumors and 52 benign cases represented in tissue microarrays. Distinct ERG and TFF3 protein was expressed in 45% (43/96) and 36% (35/96) of prostate cancers, respectively. Coexpression was observed in 5% (5/96) of tumor cases, and 24% (23/96) did not express ERG or TFF3. The inverse expression of ERG and TFF3 was significant (P < .0001), with 57% (30/53) of ERG-negative tumors demonstrating TFF3 expression. Sensitivity and specificity of combined ERG and TFF3 expression in detecting prostate cancer were 76% and 96%, respectively. The feasibility of triple immunostain protocol was validated in a set of 76 needle biopsies. The application of this multiplex in situ biomarker for molecular characterization of prostate cancer and as a supplemental diagnostic and prognostic tool in prostate needle biopsies should be further explored.

Long-term survival after lobectomy for non-small cell lung cancer by video-assisted thoracic surgery versus thoracotomy.

BACKGROUND: Video-assisted thoracic surgery (VATS) lobectomy for non-small cell lung cancer (NSCLC) is increasingly popular. However, the oncologic soundness of VATS for patients with NSCLC as measured by long-term survival has not been proven. The objective here is to determine the overall survival (OS) and disease-free survival (DFS) in two well-matched groups of patients with NSCLC resected by VATS or thoracotomy. METHODS: We conducted a retrospective review of a prospective database to identify patients who had a lobectomy for NSCLC. A propensity score-matched analysis was done with variables of age, sex, smoking history, Charlson comorbidity index, forced expiratory volume in 1 second, lung diffusing capacity for carbon monoxide, histology, and clinical T and N status. Medical records were reviewed and survival was analyzed. RESULTS: After matching, there were 208 patients in each group. Patient and tumor characteristics were similar. The VATS group had a shorter length of stay. More nodes (14.3 versus 11.3; p=0.001) and more nodal stations (3.8 versus 3.1; p<0.001) were removed by thoracotomy. No differences were seen in OS and DFS. Median follow-up was 36 months. More than 90% of patients had clinical stage I disease, with 3- and 5-year OS of 87.4% and 76.5%, respectively, for VATS, and 81.6% and 77.5%, respectively, for thoracotomy (p=0.672). Both the incidence and distribution of recurrence were similar. Multivariate Cox regression analyses of OS and DFS confirmed the noninferiority of VATS. CONCLUSIONS: For patients with clinical stage I NSCLC, VATS lobectomy offered similar OS and DFS compared with thoracotomy. Thoracotomy offers a more thorough lymph node evaluation, and may be appropriate for patients with more advanced clinical disease.

Perioperative comparative effectiveness of anesthetic technique in orthopedic patients.

BACKGROUND: The impact of anesthetic technique on perioperative outcomes remains controversial. We studied a large national sample of primary joint arthroplasty recipients and hypothesized that neuraxial anesthesia favorably influences perioperative outcomes. METHODS: Data from approximately 400 hospitals between 2006 and 2010 were accessed. Patients who underwent primary hip or knee arthroplasty were identified and subgrouped by anesthesia technique: general, neuraxial, and combined neuraxial-general. Demographics, postoperative complications, 30-day mortality, length of stay, and patient cost were analyzed and compared. Multivariable analyses were conducted to identify the independent impact of choice of anesthetic on outcomes. RESULTS: Of 528,495 entries of patients undergoing primary hip or knee arthroplasty, information on anesthesia type was available for 382,236 (71.4%) records. Eleven percent were performed under neuraxial, 14.2% under combined neuraxial-general, and 74.8% under general anesthesia. Average age and comorbidity burden differed modestly between groups. When neuraxial anesthesia was used, 30-day mortality was significantly lower (0.10, 0.10, and 0.18%; P < 0.001), as was the incidence of prolonged (>75th percentile) length of stay, increased cost, and in-hospital complications. In the multivariable regression, neuraxial anesthesia was associated with the most favorable complication risk profile. Thirty-day mortality remained significantly higher in the general compared with the neuraxial or neuraxial-general group for total knee arthroplasty (adjusted odds ratio [OR] of 1.83, 95% CI 1.08-3.1, P = 0.02; OR of 1.70, 95% CI 1.06-2.74, P = 0.02, respectively). CONCLUSIONS: The utilization of neuraxial versus general anesthesia for primary joint arthroplasty is associated with superior perioperative outcomes. More research is needed to study potential mechanisms for these findings.

Sleep apnea and total joint arthroplasty under various types of anesthesia: a population-based study of perioperative outcomes.

BACKGROUND AND OBJECTIVES: The presence of sleep apnea (SA) among surgical patients has been associated with significantly increased risk of perioperative complications. Although regional anesthesia has been suggested as a means to reduce complication rates among SA patients undergoing surgery, no data are available to support this association. We studied the association of the type of anesthesia and perioperative outcomes in patients with SA undergoing joint arthroplasty. METHODS: Drawing on a large administrative database (Premier Inc), we analyzed data from approximately 400 hospitals in the United States. Patients with a diagnosis of SA who underwent primary hip or knee arthroplasty between 2006 and 2010 were identified. Perioperative outcomes were compared between patients receiving general, neuraxial, or combined neuraxial-general anesthesia. RESULTS: We identified 40,316 entries for unique patients with a diagnosis for SA undergoing primary hip or knee arthroplasty. Of those, 30,024 (74%) had anesthesia-type information available. Approximately 11% of cases were performed under neuraxial, 15% under combined neuraxial and general, and 74% under general anesthesia. Patients undergoing their procedure under neuraxial anesthesia had significantly lower rates of major complications than did patients who received combined neuraxial and general or general anesthesia (16.0%, 17.2%, and 18.1%, respectively; P = 0.0177). Adjusted risk of major complications for those undergoing surgery under neuraxial or combined neuraxial-general anesthesia compared with general anesthesia was also lower (odds ratio, 0.83 [95% confidence interval, 0.74-0.93; P = 0.001] vs odds ratio, 0.90 [95% confidence interval, 0.82-0.99; P = 0.03]). CONCLUSIONS: Barring contraindications, neuraxial anesthesia may convey benefits in the perioperative outcome of SA patients undergoing joint arthroplasty. Further research is needed to enhance an understanding of the mechanisms by which neuraxial anesthesia may exert comparatively beneficial effects.

Impact of a large breast separation on radiation dose delivery to the ipsilateral lung as result of respiratory motion quantified using free breathing and 4D CT-based planning in patients with locally advanced breast cancers: a potential for adverse clinical implications.

PURPOSE: We examined the effects of large breast separation (BS) on dosimetric and positional differences of radiation treatment plans of locally advanced breast cancers during a free-breathing respiratory cycle. MATERIALS AND METHODS: Computed tomography (CT) datasets of 18 patients were acquired using 3D, 4D-0% (end-inspiration), and 4D-50% (end-exhalation). BS was examined in relation to the positional and dosimetric changes to organs-at-risk (OAR). Based on dosimetric analysis of all three plans, we compared 4D-0% and 4D-50% for V5, V10, and V20 to 3D for heart and ipsilateral lung. Using 4D-0% and 4D-50% CTs, we recorded positional variations of the organs' centroid (centers of mass) and their effects on dosimetry. RESULTS: Median BS was 23.95 cm (range: 16.86-29.48 cm). There was a strong positive correlation between BS and dose to the ipsilateral lung for V5, V10, and V20, with the greatest linearity observed at V20 (R(2) = 0.23). At BS ≥ 27 cm, the dose increased during inspiration at V5, V10 , and V20 (P < 0.05). When comparing 4D and 3D for the heart, V5 and V10, decreased by average of 0.94% and 0.96% (P < 0.008), respectively. CONCLUSIONS: This study offers the first evidence of the impact of a large BS on radiation dose to the ipsilateral lung.

Outcomes after lobectomy using thoracoscopy vs thoracotomy: a comparative effectiveness analysis utilizing the Nationwide Inpatient Sample database.

OBJECTIVES: We examined the Nationwide Inpatient Sample (NIS) database to compare short-term postoperative outcomes following open and thoracoscopic lobectomy. Thoracoscopic (video-assisted thoracic surgery) lobectomy has been demonstrated to be associated with fewer postoperative complications compared with open thoracotomy lobectomy in several large case series. However, as no randomized trial has been performed, there are many who question this. METHODS: We examined the NIS database for all patients undergoing lobectomy as their principal procedure either via thoracoscopic or open thoracotomy from 2007 to 08. We compared the postoperative outcomes of these two groups of patients after propensity matching these groups based on several preoperative variables. RESULTS: Over a 2-year-period, 68 350 patients underwent a lobectomy by either thoracoscopy [n = 10 554 (15%)] or thoracotomy [n = 57 796(85%)]. Thirty-two percent of thoracoscopic lobectomies (n = 3421) were performed in either rural or non-teaching urban centres. Although in propensity-matched cohorts there was no difference in operative mortality, thoracoscopic lobectomy was associated with a lower incidence of postoperative complications [n = 4146 (40.8%) vs n = 13 913 (45.1%), P < 0.001] and shorter length of stay (5.0 vs 7.0 days; P < 0.001) compared with open lobectomy. Specifically, the incidences of supraventricular arrhythmias, myocardial infarction, pulmonary embolism and empyema were lower. CONCLUSIONS: This large national database study demonstrates that thoracoscopic lobectomy is associated with fewer in-hospital postoperative complications compared with open lobectomy. Thoracoscopic lobectomy appears to be applicable to the wider general thoracic surgical community.

Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression.

Androgen receptor signaling plays a critical role in prostate cancer pathogenesis. Yet, the regulation of androgen receptor signaling remains elusive. Even with stringent androgen deprivation therapy, androgen receptor signaling persists. Here, our data suggest that there is a complex interaction between the expression of the tumor suppressor miRNA, miR-31, and androgen receptor signaling. We examined primary and metastatic prostate cancer and found that miR-31 expression was reduced as a result of promoter hypermethylation, and importantly, the levels of miR-31 expression were inversely correlated with the aggressiveness of the disease. As the expression of androgen receptor and miR-31 was inversely correlated in the cell lines, our study further suggested that miR-31 and androgen receptor could mutually repress each other. Upregulation of miR-31 effectively suppressed androgen receptor expression through multiple mechanisms and inhibited prostate cancer growth in vivo. Notably, we found that miR-31 targeted androgen receptor directly at a site located in the coding region, which was commonly mutated in prostate cancer. In addition, miR-31 suppressed cell-cycle regulators including E2F1, E2F2, EXO1, FOXM1, and MCM2. Together, our findings suggest a novel androgen receptor regulatory mechanism mediated through miR-31 expression. The downregulation of miR-31 may disrupt cellular homeostasis and contribute to the evolution and progression of prostate cancer. We provide implications for epigenetic treatment and support clinical development of detecting miR-31 promoter methylation as a novel biomarker.