Combined vascular endothelial growth factor and TP53 status predicts poor response to tamoxifen therapy in estrogen receptor-positive advanced breast cancer.

PURPOSE: In recent studies, we showed that TP53 gene mutation or high levels of cytosolic vascular endothelial growth factor (VEGF) in estrogen receptor (ER)-alpha-positive primary breast tumors predict a poor disease outcome for patients treated with first-line tamoxifen for advanced disease. Mutant TP53 may up-regulate VEGF, whereas, on the other hand, wild-type TP53 may decrease VEGF production. EXPERIMENTAL DESIGN: In the present study, we aimed to assess the combined predictive value of TP53 gene mutation and VEGF status of 160 advanced breast cancer patients with ER-positive tumors who were treated with tamoxifen (median follow-up from start of tamoxifen treatment, 64 months). To assess TP53 gene mutation status, the entire open reading frame was sequenced; for VEGF status, an ELISA was used. RESULTS: In univariate analysis, both TP53 gene mutation (28% of the tumors) and a VEGF level above the median value were significantly associated with a short progression-free survival, post-relapse overall survival, and a poor rate of response to tamoxifen. In Cox multivariate regression analysis including the traditional predictive factors, the addition of TP53 gene mutation and VEGF status, alone or in combination, significantly predicted a poor efficacy of tamoxifen treatment. When the two factors were combined, a significantly decreased odds ratio was seen for the rate of response (odds ratio, 0.27). Similarly, an increased hazard ratio (HR) was seen for progression-free survival (HR, 2.32) and post-relapse overall survival (HR, 1.68) in the group with mutant TP53 and high VEGF compared with the group with both risk factors absent. CONCLUSIONS: Combined TP53 gene mutation status and high VEGF levels of ER-positive primary breast tumors independently predict a poor course of the disease of patients with advanced breast cancer treated with tamoxifen. These patients, having unfavorable tumor characteristics, might benefit more from other types of (individualized) treatment protocols.     

Contraction-Relaxation Coupling and Impaired Left Ventricular Performance in Coronary Surgery Patients

Background: Dependence of left ventricular (LV) relaxation on cardiac systolic load is a function of myocardial contractility. The authors hypothesized that, if a tight coupling would exist between LV contraction and relaxation, the changes in relaxation rate with an increase in cardiac systolic load would be related to the changes in LV contraction.

Methods: Coronary surgery patients (n = 120) with preoperative ejection fraction > 40% were included. High-fidelity LV pressure tracings (n = 120) and transgastric transesophageal echocardiographic data (n = 40) were obtained. Hearts were paced at a fixed rate of 90 beats/min. Effects on contraction were evaluated by analysis of changes in dP/dtmax and stroke area. Effects on relaxation were assessed by analysis of R (slope of the relation between [small tau, Greek] and end-systolic pressure). Correlations were calculated with linear regression analysis using Pearson's coefficient r.

Results: Baseline LV end-diastolic pressure was 10 +/- 3 mmHg (mean +/- SD). During leg raising, systolic LV pressure increased from 93 +/- 9 to 107 +/- 11 mmHg. The change in dP/dtmax was variable and ranged from -181 to +254 mmHg/s. A similar variability was observed with the changes in stroke area, which ranged from -2.0 to +5.5 cm2. Changes in dP/dtmax and in stroke area were closely related to individual R values (r = 0.87, P < 0.001; and r = 0.81, P < 0.001, respectively) and to corresponding changes in LV end-diastolic pressure (r = 0.81, P < 0.001; and r = 0.74, P < 0.001, respectively).     

Bicuspid pulmonary valve with atrial septal defect leading to pulmonary aneurysm

Pulmonary artery aneurysms are rare. We describe 2 adult patients with pulmonary artery aneurysm with normal pulmonary pressure associated with bicuspid pulmonary valve and atrial septal defect. One patient presented with moderate pulmonary valve stenosis and was treated with open surgery; the other patient had a small atrial septal defect and mild pulmonary valve insufficiency and is periodically still being evaluated. Hemodynamic alterations associated with a pulmonary artery aneurysm are described; the influence of additional volume overload and intrinsic wall abnormalities in pulmonary valvular lesions as potential triggers for the development of these aneurysms are analyzed and therapeutic strategies are discussed.     

Impact of several histopathological prognosticators and local tumour extension on oncological outcome in pT3b/c N0M0 renal cell carcinoma

OBJECTIVE

To investigate the prognostic relevance of different histopathological features and local tumour extension in patients with pT3b/c N0M0 renal cell carcinoma (RCC), as recently new proposals of reclassifying tumour fat invasion in pT3b/c RCC have been made but the effect of other histopathological tumour characteristics and combinations thereof with tumour invasion has yet to be determined in these patients.

PATIENTS AND METHODS

Between 1990 and 2006, 1943 patients underwent surgical treatment for renal tumours in our institution, of which 175 patients (8.7%) had pT3b/c RCC. After exclusion of 57 patients (32.6%) with lymph node and/or distant metastases at the time of diagnosis, 118 (67.4%) remained for retrospective analysis. Different histopathological features and local tumour extension were studied for their association with cancer‐specific‐survival (CSS) and progression‐free‐survival (PFS) by univariate and multivariate analyses. Histopathology was reviewed and revised according to the 2002 Tumour‐Nodes‐Metastasis (TNM) classification system by one pathologist (S.B.). CSS and PFS were estimated by the Kaplan–Meier method.

RESULTS

Follow‐up data were obtained from 110 patients at a median (range) of 3.2 (0.3–16.1) years. In univariate analysis, microvascular invasion (MVI) and capsular invasion increased the risk of tumour progression by 2.05‐ and 2.72‐times (P = 0.037 and P < 0.001). Overall, tumour fat invasion (TFI) and the presence of areas composed by cells with eosinophilic cytoplasm were associated with a higher risk of progression (P = 0.001 and P = 0.011) and reduced CSS (P = 0.037 and P = 0.017). In multivariate analysis, MVI and capsular invasion were associated with a two‐fold increased risk of dying from cancer (hazard risk ratio, HR 2.22, P = 0.045 and HR 2.31, P = 0.011). TFI in general (P = 0.004) and specifically coexistent perirenal fat invasion (PFI) and renal sinus fat invasion (RSFI) were associated with a three‐fold increased risk of developing tumour progression (HR 3.36, P = 0.001). The 10‐year CSS and PFS rates were 39% and 36% for all patients, 47% and 45% for pT3b/c RCC with no PFI or RSFI, and 25% and 10% for PFI + RSFI.

CONCLUSION

Patients with pT3b/c RCC with MVI, capsular invasion, TFI and especially PFI + RSFI, have a markedly reduced prognosis compared with patients with pT3b/c RCC without these features. When these results are corroborated by additional studies and external validation, modification of the TNM classification system would be a sensible consequence.     

Preservation of Muscular and Elastic Artery Distensibility After an Intercontinental Cryoconserved Exchange: Theoretical Advances in Arterial Homograft Generation and Utilization

While the situation of tissue donation and transplantation differs between Latin American and European countries, a common problem is tissue deficiency. Hence, at present, there is a pressing need to generate alternatives so as to increase the possibilities of obtaining the requested materials. Consequently, it would be of significant interest to establish an intercontinental network for tissue exchange, to improve international cooperation, and to help patients that need tissue transplantation, and to evaluate the feasibility of using an intercontinental network for the exchange of cryopreserved arteries (cryografts), preserving the arterial distensibility and ensuring a reduced native artery–cryograft biomechanical mismatch. Distensibility was studied in ovine arteries divided into three groups: intact (in vivo tests, conscious animals), fresh control (in vitro tests immediately after the artery excision, Uruguay), and cryografts (in vitro tests of cryopreserved-transported-defrosted arteries, Spain). Histological studies were performed so as to analyze changes in the endothelial layer and elastic components. The comparison between fresh control and cryografts showed that neither the cryopreservation nor the exchange network impaired the distensibility, despite the expected histological changes found in the cryografts. The comparison between intact and cryografts showed that the cryografts would be capable of ensuring a reduced biomechanical mismatch. The cryopreservation and the intercontinental network designed for artery exchange preserved the arterial distensibility. It could be possible to transfer cryografts between Latin America and Europe to be used in cardiovascular surgeries and/or for tissue banking reprocessing, with basic biomechanical properties similar to those of the fresh and/or native arteries.     

alpha-Galactosidase A deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease.

INTRODUCTION: Fabry disease or alpha-galactosidase A (alpha-Gal A) deficiency is an X-linked lysosomal storage disorder that often leads to renal insufficiency in males and occasionally in females. The disease is rare, but its prevalence may be underestimated due to its variable clinical picture. Enzyme supplementation therapy with rHu-alphaGal A is currently available. Limited experience has so far shown that therapy may at best stabilize renal function. Despite these preliminary findings, much effort is being put into screening high-risk groups for undiagnosed alpha-Gal A deficiency. We studied the prevalence of alpha-Gal A deficiency in a Dutch dialysis cohort to establish possible underdiagnosis. We discuss the benefits of screening for Fabry disease. METHODS: Activity of alpha-Gal A in whole blood was measured in a group of 508 male Dutch dialysis patients. RESULTS: Of the 508 patients studied only one patient, already known with Fabry disease, had a alpha-Gal A deficiency, a prevalence of 0.22% (95 CI 0-1.1%). CONCLUSIONS: No undiagnosed Fabry patients were found, indicating that in our studied cohort there is no large-scale underestimation of its prevalence. Even though screening of dialysis patients for Fabry disease might identify patients who remain otherwise unrecognized, screening of high-risk populations for alpha-Gal A deficiency should be carried out with caution since long-term efficacy of treatment is currently unknown.