The combination of antagonists of LHRH with antagonists of GHRH improves inhibition of androgen sensitive MDA-PCa-2b and LuCaP-35 prostate cancers

BACKGROUND: Antagonists of growth hormone-releasing hormone (GHRH) could extend the duration of response of androgen sensitive prostate cancers to androgen deprivation. METHODS: We investigated the effect of new GHRH antagonists MZ-J-7-118 and MZ-J-7-138 and luteinizing hormone-releasing hormone (LHRH) antagonist Cetrorelix or castration on androgen sensitive MDA-PCa-2b and LuCaP-35 prostate cancer models xenografted into nude mice. Animals bearing androgen-independent LuCaP-35V prostatic cancer model were also treated with MZ-J-7-118. RESULTS: Receptors for LHRH and GHRH were present in MDA-PCA-2b, LuCaP-35, and LuCaP-35V tumors. GHRH antagonists increased the inhibitory effect of surgical castration and LHRH antagonists on androgen sensitive MDA-PCa-2b and LuCaP-35 tumors. The time to relapse of androgen-dependent LuCaP-35 tumors was extended by GHRH antagonists. Growth of androgen-independent LuCaP-35V xenografts was also significantly inhibited by MZ-J-7-118. In MDA-PCa-2b tumors treatment with MZ-J-7-118 caused a significant decrease of VEGF and Cetrorelix or its combination with MZ-J-7-118 reduced EGF. The B(max) of EGF receptors was significantly reduced by Cetrorelix, MZ-J-7-118 and their combination. CONCLUSIONS: Our findings suggest that the use of a combination of antagonists of GHRH and LHRH could improve the therapy for androgen sensitive prostate cancer. Antagonists of GHRH could be also considered for treatment of androgen-independent prostate cancers.     

Predicting the outcome of physeal fractures of the distal femur

BACKGROUND:: Distal femoral epiphyseal fractures are uncommon but have a high incidence rate of complications. It is not clear whether there are any reliable predictor factors and whether the type of fracture, displacement (degree and direction), and treatment method alter the outcome. METHODS:: We retrospectively reviewed the medical charts and images of all patients who sustained a distal femoral epiphyseal fracture and were treated at 2 large level I pediatric centers during the past 10 years. RESULTS:: The selected group included 73 patients (boys, 59; mean age, 10 years). On the basis of the Salter-Harris classification (SH), 43 fractures (59%) were of type II. Fifty-nine percent of the fractures were displaced; 36 fractures were managed conservatively with long leg cast (with or without pelvic band) in 33 patients, cylinder cast in 2, and posterior splint in 1. Thirty-seven patients underwent surgery, and 34 underwent closed reduction followed by percutaneous fixation (crossed Steinman pins, 20; cannulated screws, 13; open reduction, 3; external fixation, 1). The overall complication rate was 40% (29/73), and growth arrest was the most frequent. The SH classification significantly correlated with the incidence of complications (P = 0.031). There was also a significantly higher (P < 0.0001) incidence rate of complications among displaced fractures (48.8% vs 26.6%); the amount and direction of displacement did not correlate with the outcome (P > 0.05). The group treated conservatively had a lower incidence rate of complications (25%) than did the surgical group (54%) (P < 0.05). Among the surgical group, a higher incidence rate of complications occurred when the physis was violated by hardware (65% vs 30%; P = 0.06). CONCLUSIONS:: Both SH classification and displacement of the fracture are significant predictors of the final outcome. The degree and the direction of displacement do not statistically correlate with outcome. The treatment method may influence the final outcome.     

Ventricular remodeling and mitral valve modifications in dilated cardiomyopathy: new insights from anatomic study

OBJECTIVE: The purpose of this study was to analyze the behavior of the mitral valve ring and the left ventricle in dilated cardiomyopathy. METHODS: We analyzed 68 fixed adult human hearts, divided into 48 hearts with dilated cardiomyopathy of ischemic or idiopathic origin and 20 hearts free of pathologic heart conditions. Digital images of the mitral ring perimeter, attachment of the anterior and posterior leaflets, and fibrous and muscular portions were collected. We also measured the internal perimeter of the left ventricle, the distance from the septum to the anterior and posterior papillary muscles, the distance between the papillary muscles, and the extension of interventricular septum. RESULTS: The analysis of the results showed proportional distribution of the ring's fibrous portion (r2 = 0.98) and muscular portion (r2 = 0.99) according to the degree of mitral valve dilation. Linear regression revealed that the perimeters of anterior and posterior leaflet attachments (r2 = 0.96 and r2 = 0.98, respectively) also had a proportional relation. We did not observe proportionality between the degree of dilation of the mitral ring and the left ventricle. It was observed that dilation of the left ventricle takes place globally in its segments. CONCLUSION: Differently from what was thought, in ischemic or idiopathic dilated cardiomyopathy, dilation of mitral ring is proportional and does not exclusively affect the posterior portion. The degree of left ventricular dilation does not determine the degree of dilation of the mitral ring because they are independent processes. These observations shed new light on the techniques used to correct mitral valve insufficiency in dilated cardiomyopathy.     

The impact of a cardioprotective protocol on the incidence of cardiac complications after aortic abdominal surgery

We analyzed a local database including 468 consecutive patients who underwent elective aortic abdominal surgery over an 8-yr period in a single institution. A new cardioprotective perioperative protocol was introduced in January 1997, and we questioned whether perioperative cardiac outcome could be favorably influenced by the application of a stepwise cardiovascular evaluation based on the American College of Cardiology/American Heart Association guidelines and by the use of antiadrenergic drugs. Clonidine was administered during surgery, and beta-blockers were titrated after surgery to achieve heart rates less than 80 bpm. We compared data of two consecutive 4-yr periods (1993-1996 [control period] versus 1997-2000 [intervention period]). Implementation of American College of Cardiology/American Heart Association guidelines was associated with increased preoperative myocardial scanning (44.3% vs 20.6%; P < 0.05) and coronary revascularization (7.7% vs 0.8%; P < 0.05). During the intervention period, there was a significant decrease in the incidence of cardiac complications (from 11.3% to 4.5%) and an increase in event-free survival at 1 yr after surgery (from 91.3% to 98.2%). Multivariate regression analysis showed that the combined administration of clonidine and beta-blockers was associated with a decreased risk of cardiovascular events (odds ratio, 0.3; 95% confidence interval, 0.1-0.8), whereas major bleeding, renal insufficiency, and chronic obstructive pulmonary disease were predictive of cardiac complications. In conclusion, cardiac testing was helpful to identify a small subset of high-risk patients who might benefit from coronary revascularization. Sequential and selective antiadrenergic treatments were associated with improved postoperative cardiac outcome. IMPLICATIONS: Implementation of American College of Cardiology/American Heart Association guidelines and use of antiadrenergic drugs were associated with better cardiac outcomes after major vascular surgery.     

Factors associated with moderate or severe left atrioventricular valve regurgitation within 30 days of repair of incomplete atrioventricular septal defect

Introduction

Left atrioventricular valve regurgitation is the most concerning residual lesion after surgical correction of atrioventricular septal defect.

Objective

To determine factors associated with moderate or greater left atrioventricular valve regurgitation within 30 days of surgical repair of incomplete atrioventricular septal defect.

Methods

We assessed the results of 51 consecutive patients 14 years-old and younger presenting with incomplete atrioventricular septal defect that were operated on at our practice between 2002 and 2010. The following variables were considered: age, weight, absence of Down syndrome, grade of preoperative left atrioventricular valve regurgitation, abnormalities on the left atrioventricular valve and the use of annuloplasty. The median age was 4.1 years; the median weight was 13.4 Kg; 37.2% had Down syndrome. At the time of preoperative evaluation, there were 23 cases with moderate or greater left atrioventricular valve regurgitation (45.1%). Abnormalities on the left atrioventricular valve were found in 17.6%; annuloplasty was performed in 21.6%.

Results

At the time of postoperative evaluation, there were 12 cases with moderate or greater left atrioventricular valve regurgitation (23.5%). The variation between pre- and postoperative grades of left atrioventricular valve regurgitation of patients with atrioventricular valve malformation did not reach significance (P=0.26), unlike patients without such abnormalities (P=0.016). During univariate analysis, only absence of Down syndrome was statistically significant (P=0.02). However, after a multivariate analysis, none of the factors reached significance.

Conclusion

None of the factors studied was determinant of a moderate or greater left atrioventricular valve regurgitation within the first 30 days of repair of incomplete atrioventricular septal defect in the sample. Patients without abnormalities on the left atrioventricular valve benefit more of the operation.     

Myocardial and Coronary Effects of Propofol in Rabbits with Compensated Cardiac Hypertrophy

Background: Myocardial effects of propofol have been previously investigated but most studies have been performed in healthy hearts. This study compared the cardiac effects of propofol on isolated normal and hypertrophic rabbits hearts.

Methods: The effects of propofol (10-1,000 [mu]m) on myocardial contractility, relaxation, coronary flow and oxygen consumption were investigated in hearts from rabbits with pressure overload-induced left ventricular hypertrophy (LVH group, n = 20) after aortic abdominal banding and from sham-operated control rabbits (SHAM group, n = 10), using an isolated and erythrocyte-perfused heart model. In addition, to assess the myocardial and coronary effects of propofol in more severe LVH, hearts with a degree of hypertrophy greater than 140% were selected (severe LVH group, n = 7).

Results: The cardiac hypertrophy model induced significant left ventricular hypertrophy (136 +/- 21%, P < 0.05). The pressure-volume relation showed normal systolic function but an altered diastolic compliance in hypertrophic hearts. Propofol only decreased myocardial contractility and relaxation at supratherapeutic concentrations (>= 300 [mu]m) in SHAM and LVH groups. The decrease in myocardial performances was not significantly different in SHAM and LVH groups. Propofol induced a significant increase in coronary blood flow which was not significantly different between groups. In severe LVH group, the degree of hypertrophy reached to 157 +/- 23%. Similarly, the effects of concentrations of propofol were not significantly different from the SHAM group.     

Instant Vertebral Assessment: A Noninvasive Dual X-ray Absorptiometry Technique to Avoid Misclassification and Clinical Mismanagement of Osteoporosis

The presence of a vertebral fracture significantly increases the risk of future fracture, classifies a patient with "clinical" osteoporosis, and usually results in treatment for osteoporosis. However, the majority of vertebral fractures are silent, and lateral X-rays (the standard method for identification) are not routinely obtained. Instant vertebral assessment (IVA), a technology that utilizes dual X-ray absorptiometry (DXA), provides rapid assessment of vertebral fractures and is highly correlated with vertebral fractures, as assessed on standard lateral spine X-rays. To assess the role of IVA in patient management, we examined standard bone mineral density (BMD) of the spine, total hip, and femoral neck and spine IVA by DXA in 482 participants screened for an osteoporosis study, who had no previous knowledge of vertebral fractures. Using World Health Organization (WHO) guidelines, subjects were classified using BMD at the spine, total hip, femoral neck, or any combination of these central sites. In addition, we considered subjects as osteoporotic if they had vertebral fractures independent of low bone density. We found that vertebral fractures assessed by IVA were present in 18.3% of asymptomatic postmenopausal women recruited for this study. The sensitivity of BMD alone to diagnose osteoporosis based on either a vertebral fracture or low BMD using WHO criteria ranged from 40 to 74%. This means that between 26 and 60% of osteoporotic individuals could have potentially been missed. Furthermore, 11.0-18.7% of clinically osteoporotic individuals would have been classified as normal by BMD criteria alone. We conclude that IVA is a useful adjunct in the clinical identification of osteoporosis and may prevent mismanagement of osteoporotic patients.     

Serum Isoform [−2]proPSA Derivatives Significantly Improve Prediction of Prostate Cancer at Initial Biopsy in a Total PSA Range of 2–10 ng/ml: A Multicentric European Study

Background

Strategies to reduce prostate-specific antigen (PSA)–driven prostate cancer (PCa) overdiagnosis and overtreatment seem to be necessary.

Objective

To test the accuracy of serum isoform [−2]proPSA (p2PSA) and its derivatives, percentage of p2PSA to free PSA (fPSA; %p2PSA) and the Prostate Health Index (PHI)—called index tests—in discriminating between patients with and without PCa.

Design, setting, and participants

This was an observational, prospective cohort study of patients from five European urologic centers with a total PSA (tPSA) range of 2–10 ng/ml who were subjected to initial prostate biopsy for suspected PCa.

Outcome measurements and statistical analysis

The primary end point was to evaluate the specificity, sensitivity, and diagnostic accuracy of index tests in determining the presence of PCa at prostate biopsy in comparison to tPSA, fPSA, and percentage of fPSA to tPSA (%fPSA) (standard tests) and the number of prostate biopsies that could be spared using these tests. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision curve analysis.

Results and limitations

Of >646 patients, PCa was diagnosed in 264 (40.1%). Median tPSA (5.7 vs 5.8 ng/ml; p = 0.942) and p2PSA (15.0 vs 14.7 pg/ml) did not differ between groups; conversely, median fPSA (0.7 vs 1 ng/ml; p < 0.001), %fPSA (0.14 vs 0.17; p < 0.001), %p2PSA (2.1 vs 1.6; p < 0.001), and PHI (48.2 vs 38; p < 0.001) did differ significantly between men with and without PCa. In multivariable logistic regression models, p2PSA, %p2PSA, and PHI significantly increased the accuracy of the base multivariable model by 6.4%, 5.6%, and 6.4%, respectively (all p < 0.001). At a PHI cut-off of 27.6, a total of 100 (15.5%) biopsies could have been avoided. The main limitation is that cases were selected on the basis of their initial tPSA values.

Conclusions

In patients with a tPSA range of 2–10 ng/ml, %p2PSA and PHI are the strongest predictors of PCa at initial biopsy and are significantly more accurate than tPSA and %fPSA.

Trial registration

The study is registered at http://www.controlled-trials.com, ref. ISRCTN04707454.