Bruce Lindgren

Sequential therapy with sorafenib and sunitinib in renal cell carcinoma.

Sunitinib and sorafenib are small‐molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents.

Reduced small artery but not large artery elasticity is an independent risk marker for cardiovascular events

BACKGROUND Atherosclerosis begins in the arterial wall, with endothelial dysfunction accompanied by functional and structural changes that influence arterial stiffness. Pulse contour analysis provides an assessment of compliance or elasticity of the large conduit arteries (C(1)) and small microcirculatory arteries (C(2)). In this study, the predictive value of reduced elasticity of these arteries was evaluated by follow-up of subjects who underwent pulse contour analysis at the University of Minnesota. METHODS Questionnaires were sent to 870 subjects who had radial artery pulse wave analysis performed between 1993 and 1999 using a noninvasive sensor, parameter estimating algorithm and modified Windkessel model of the circulation. Responses from 419 subjects >19 years of age reported on any cardiovascular events including death, myocardial infarction, stroke, transient ischemic attacks, angina, or coronary or peripheral vascular interventional procedures. RESULTS Of the subjects, 168 (41%) reported one or more cardiovascular events. Events were more common in those with elevated blood pressure, elevated cholesterol, diabetes, and family history of events. Age, reduced C(1), and reduced C(2) were univariate predictors of events. After adjusting for age, a 2-unit decrease in C(2) remained a significant predictor (odds ratio 1.50, P <.001), whereas C(1) was no longer predictive. CONCLUSION Reduced small artery elasticity, which is a measure of endothelial dysfunction, is significantly associated with cardiovascular events independent of age.

Repair of Tears of the Subscapularis

BACKGROUND Rotator cuff tears involving the subscapularis are less common than those involving the superior aspect of the rotator cuff. The purpose of the present study was to report the results of repair of isolated tears of the subscapularis. METHODS The records on eighty-four shoulders that had undergone open repair of the subscapularis tendon were reviewed. The mean age of the patients at the time of surgery was 53.2 years. The mean interval from the onset of symptoms to the time of surgery was 12.5 months. Fifty-seven tears were traumatic, and twenty-seven were degenerative. Twenty-three tears involved the superior one-third of the subscapularis tendon, forty-one tears involved the superior two-thirds, and twenty tears were complete. Fifty-four shoulders had a dislocation or subluxation of the long head of the biceps tendon, and ten shoulders had a rupture of the long head of the biceps tendon. Forty-eight shoulders underwent concomitant biceps tenodesis, thirteen shoulders underwent concomitant biceps tenotomy, and four shoulders underwent concomitant recentering of the biceps. Patients were evaluated clinically and radiographically at a mean of forty-five months (range, twenty-four to 132 months) postoperatively. RESULTS The mean Constant score increased from 55.0 points preoperatively to 79.5 points postoperatively. Seventy-five patients were satisfied or very satisfied with the result. Preoperatively, four shoulders had mild glenohumeral arthritis. Postoperatively, twenty-five shoulders had mild glenohumeral arthritis and two shoulders had moderate glenohumeral arthritis. Tenodesis or tenotomy of the biceps tendon at the time of subscapularis repair was associated with improved subjective and objective results, independent of the preoperative condition of the biceps tendon. CONCLUSIONS Repair of isolated subscapularis tears yields acceptable improvement in shoulder function in selected patients. Additionally, the results of the present study support routine tenodesis or tenotomy of the long head of the biceps tendon at the time of subscapularis repair.

Extubation failure in pediatric intensive care: A multiple-center study of risk factors and outcomes

ObjectiveTo determine a contemporary failed extubation rate, risk factors, and consequences of extubation failure in pediatric intensive care units (PICUs). Three hypotheses were investigated: a) Extubation failure is in part disease specific; b) preexisting respiratory conditions predispose to extubation failure; and c) admission acuity scoring does not affect extubation failure. DesignTwelve-month prospective, observational, clinical study. SettingSixteen diverse PICUs in the United States. PatientsPatients were 2,794 patients from the newborn period to 18 yrs of age experiencing a planned extubation trial. InterventionsNone. Measurements and Main ResultsA descriptive statistical analysis was performed, and outcome differences of the failed extubation population were determined. The extubation failure rate was 6.2% (174 of 2,794; 95% confidence interval, 5.3–7.1). Patient features associated with extubation failure (p < .05) included age ≤24 months; dysgenetic condition; syndromic condition; chronic respiratory disorder; chronic neurologic condition; medical or surgical airway condition; chronic noninvasive positive pressure ventilation; the need to replace the endotracheal tube on admission to the PICU; and the use of racemic epinephrine, steroids, helium-oxygen therapy (heliox), or noninvasive positive pressure ventilation within 24 hrs of extubation. Patients failing extubation had longer pre-extubation intubation time (failed, 148.7 hrs, sd ± 207.8 vs. success, 107.9 hrs, sd ± 171.3; p < .001), longer PICU length of stay (17.5 days, sd ± 15.6 vs. 7.6 days, sd ± 11.1; p < .001), and a higher mortality rate than patients not failing extubation (4.0% vs. 0.8%; p < .001). Failure was found to be in part disease specific, and preexisting respiratory conditions were found to predispose to failure whereas admission acuity did not. ConclusionA variety of patient features are associated with an increase in extubation failure rate, and serious outcome consequences characterize the extubation failure population in PICUs.

Epidemiology of otitis media onset by six months of age.

Objective. Although early otitis media (OM) onset predicts later recurrent and chronic OM, little research has been directed at illuminating the role of prenatal exposures in early OM. This prospective study examined prenatal, innate, and early environmental exposures associated with acute otitis media (AOM) onset and recurrent OM (ROM) by age 6 months. Design and Methods. Prospective study of 596 infants from a health maintenance organization followed from birth to 6 months. Mothers completed monthly forms on prenatal exposures (diet, medications, and illnesses) and infant risk factors (eg, smoke exposure and child care) during pregnancy and until infants were 6 months old. Urine samples were collected when infants were 2 months of age and analyzed for cotinine and creatinine. Physicians and nurse practitioners examined infants at each clinic visit and completed standard ear examination forms. Results. Thirty-nine percent had an episode of AOM and 20% had ROM by age 6 months. Using Coxs regression models to control for confounding, respiratory tract infection (relative risk [RR] 7.5), day care (RR 1.7), >1 sibling (RR 1.4), maternal, paternal, and sibling OM history (RR 1.6, 1.5, and 1.7, respectively) were significantly related to early OM onset. ROM was related to respiratory tract infection (RR 9.5), day care (RR 1.9), conjunctivitis (RR 2.0), maternal OM history (RR 1.9), and birth in the fall (RR 2.6). Among prenatal exposures, only high prenatal dietary vitamin C intake was significantly inversely related to early AOM with univariate but not multivariate analysis. Conclusion. Prenatal factors were not linked to early AOM onset with multivariate analysis, but environmental and innate factors play an important role in early AOM onset. Strategies to reduce exposure to environmental variables could reduce rates of early AOM, which could potentially result in declining rates of ROM and chronic OME.

In utero or ex utero cord blood collection: which is better?

BACKGROUND : The relative nucleated cell count of umbilical cord blood (CB) correlates with improved engraftment and survival. This study compares two collection methods to assess CB content, including cell numbers.

Chronic and Recurrent Otitis Media: A Genome Scan for Susceptibility Loci

Otitis media (OM) is the most common childhood disease. Almost all children experience at least one episode, but morbidity is greatest in children who experience chronic/recurrent OM (COME/ROM). There is mounting evidence that COME/ROM clusters in families and exhibits substantial heritability. Subjects who had tympanostomy tube surgery for COME/ROM (probands) and their families were recruited for the present study, and an ear examination was performed, without knowledge of the subjects history, to determine presence of OM sequelae. In addition, tympanometric testing was performed at three frequencies (226, 630 or 710, and 1,400 Hz) to detect abnormal middle-ear mechanics, and hearing was screened at 20 dB for the speech frequencies. Of these families, 121 had at least two individuals who had received the diagnosis of COME/ROM (364 affected and genotyped individuals), of whom 238 affected and informative relative pairs were used for analyses. Single-point nonparametric linkage analysis provided evidence of linkage of COME/ROM to chromosome 10q at marker D10S212 (LOD 3.78; P=3.0 x 10(-5)) and to chromosome 19q at marker D19S254 (LOD 2.61; P=5.3 x 10(-4)). Analyses conditional on support for linkage at chromosomes 10q and 19q resulted in a significant increase in LOD score support on chromosome 3p (between markers D3S4545 and D3S1259). These results suggest that risk of COME/ROM is determined by interactions between genes that reside in several candidate regions of the genome and are probably modulated by other environmental risk factors.

FOXO1 Inhibits Runx2 Transcriptional Activity and Prostate Cancer Cell Migration and Invasion

Prostate cancer patients with regional lymph node involvement at radical prostatectomy often experience disease progression to other organs, with the bone as the predominant site. The transcription factor Runx2 plays an important role in bone formation and prostate cancer cell migration, invasion, and metastasis. Here we showed that the forkhead box O (FOXO1) protein, a key downstream effector of the tumor suppressor PTEN, inhibits the transcriptional activity of Runx2 in prostate cancer cells. This inhibition was enhanced by PTEN but diminished by active Akt. FOXO1 bound to Runx2 in vitro and in vivo and suppressed Runx2s activity independent of its transcriptional function. FOXO1 inhibited Runx2-promoted migration of prostate cancer cells, whereas silencing of endogenous FOXO1 enhanced prostate cancer cell migration in a Runx2-dependent manner. Forced expression of FOXO1 also inhibited Runx2-promoted prostate cancer cell invasion. Finally, we found that expression of PTEN and the level of FOXO1 in the nucleus is inversely correlated with expression of Runx2 in a cohort of prostate cancer specimens from patients with lymph node and bone metastasis. These data reveal FOXO1 as a critical negative regulator of Runx2 in prostate cancer cells. Inactivation of FOXO1 due to frequent loss of PTEN in prostate cancer cells may leave the oncogenic activities of Runx2 unchecked, thereby driving promiscuous expression of Runx2 target genes involved in cell migration and invasion and favoring prostate cancer progression.

Chronic Disease Management for Tobacco Dependence: A Randomized, Controlled Trial

BACKGROUND Tobacco dependence disorder is a chronic relapsing condition, yet treatment is delivered in discrete episodes of care that yield disappointing long-term quit rates. METHODS We conducted a randomized controlled trial from June 1, 2004, through May 31, 2009, to compare telephone-based chronic disease management (1 year; longitudinal care [LC]) with evidence-based treatment (8 weeks; usual care [UC]) for tobacco dependence. A total of 443 smokers each received 5 telephone counseling calls and nicotine replacement therapy by mail for 4 weeks. They were then randomized to UC (2 additional calls) or LC (continued counseling and nicotine replacement therapy for an additional 48 weeks). Longitudinal care targeted repeat quit attempts and interim smoking reduction for relapsers. The primary outcome was 6 months of prolonged abstinence measured at 18 months of follow-up. RESULTS At 18 months, 30.2% of LC participants reported 6 months of abstinence from smoking, compared with 23.5% in UC (unadjusted, P = .13). Multivariate analysis showed that LC (adjusted odds ratio, 1.74; 95% CI, 1.08-2.80), quit attempts in past year (1.75; 1.06-2.89), baseline cigarettes per day (0.95; 0.92-0.99), and smoking in the 14- to 21-day interval post-quit (0.23; 0.14-0.38) predicted prolonged abstinence at 18 months. The LC participants who did not quit reduced smoking more than UC participants (significant only at 12 months). The LC participants received more counseling calls than UC participants (mean, 16.5 vs 5.8 calls; P < .001), longer total duration of counseling (283 vs 117 minutes; P < .001), and more nicotine replacement therapy (4.7 vs 2.4 boxes of patches; P < .001). CONCLUSION A chronic disease management approach increases both short- and long-term abstinence from smoking. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00309296.

Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer.

Preclinical studies show that opioids stimulate angiogenesis and tumor progression through the mu opioid receptor (MOR). Although MOR is overexpressed in several human malignancies, the effect of chronic opioid requirement on cancer progression or survival has not been examined in humans.