Pulmonary hemodynamics as predictors of mortality in patients awaiting lung transplantation.

Lung transplantation (LTx) is a therapeutic option for patients with end-stage lung disease. However, the mortality rate of patients on the waiting list is high. The purpose of this study was to examine the prognostic value of cardio-pulmonary hemodynamics for death in patients awaiting LTx. Retrospectively, 177 patients with advanced lung disease accepted for LTx at Sahlgrenska University Hospital from January 1990 through December 2003 were studied. Patient demographics, pulmonary function tests, gas exchange and hemodynamic variables were included in the analysis. Death while awaiting LTx was the primary endpoint for all analyses. Mean age was 49 +/- 9 years. Main diagnoses were alpha 1 antitrypsin deficiency (n = 56), chronic obstructive pulmonary disease (n = 61), cystic fibrosis (n = 14) and interstitial lung disease (n = 46). Thirty patients died (17%). LTx was performed in 143 cases. By univariate analyses, forced vital capacity (FVC) % of predicted, pulmonary vascular resistance (PVR) and diagnosis were associated with risk for death. In multivariate analysis PVR (HR, 1.22; 95% CI, 1.06-1.41; P = 0.006) and FVC% of predicted (HR, 0.97; 95% CI, 0.94-0.99; P = 0.01) were independently associated with death. Patients with increased PVR and a lower FVC % of predicted awaiting LTx should be considered for a higher organ allocation priority. Assessment of pulmonary hemodynamics needs to be considered during evaluation for LTx.     

The prospects of estimating trabecular bone tissue properties from the combination of ultrasound, dual-energy X-ray absorptiometry, microcomputed tomography, and microfinite element analysis.

Osteoporosis commonly is assessed by bone quantity, using bone mineral density (BMD) measurements from dual-energy X-ray absorptiometry (DXA). However, such a measure gives neither information about the integrity of the trabecular architecture nor about the mechanical properties of the constituting trabeculae. We investigated the feasibility of deriving the elastic modulus of the trabeculae (the tissue modulus) from computer simulation of mechanical testing by microfinite element analysis (muFEA) in combination with measurements of ultrasound speed of sound (SOS) and BMD measurements. This approach was tested on 15 postmortem bovine bone cubes. The apparent elastic modulus of the specimens was estimated from SOS measurements in combination with BMD. Then the trabecular morphology was reconstructed using microcomputed tomography (muCT). From the reconstruction a mesh for muFEA was derived, used to simulate mechanical testing. The tissue modulus was found by correlating the apparent moduli of the specimens as assessed by ultrasound with the ones as determined with muFEA. A mean tissue modulus of 4.5 GPa (SD, 0.69) was found. When adjusting the muFEA-determined elastic moduli of the entire specimens with their calculated tissue modulus, an overall correlation of R2 = 96% with ultrasound-predicted values was obtained. We conclude that the apparent elastic stiffness characteristics as determined from ultrasound correlate linearly with those from muFEA. From both methods in combination, the elastic stiffness of the mineralized tissue can be determined as an estimator for mechanical tissue quality. This method can already be used for biopsy specimens, and potentially could be applicable in vivo as well, when clinical CT or magnetic resonance imaging (MRI) tools with adequate resolution reach the market. In this way, mechanical bone quality could be estimated more accurately in clinical practice.     

Androgen-insensitive prostate cancer cells transiently respond to castration treatment when growing in an androgen-dependent prostate environment

BACKGROUND: Castration-induced involution of the normal prostate is caused by primary effects in the prostate stroma and vasculature, but if this is the case also in tumors is unknown. METHODS: Androgen-independent AT-1 prostate tumor cells were therefore injected into the ventral prostate (VP) in Copenhagen rats. Seven days later when the growing tumor was surrounded by normal VP tissue the rats were castrated and the effect examined 3 and 7 days later. RESULTS: Castration reduced vascular density in the surrounding VP tissue and this was accompanied by tumor cell hypoxia, apoptosis, and temporarily retarded tumor growth. Castration-induced VP tissue regression occurred more rapidly in the contra-lateral than in the tumor-bearing lobe. CONCLUSIONS: Androgen-independent tumor cell respond to castration when growing in an androgen-dependent environment. The presence of a tumor influences the castration response in the surrounding normal tissue. The microenvironment determines how prostate epithelial cells respond to castration.     

Central mesenteric lymph node BER-Ep4+ cells in colorectal cancer: challenge to sentinel node concept?

BACKGROUND: The role of sentinel lymph nodes in colorectal cancer remains unclear. METHODS: Cryosections from central para-aortic mesenterial lymph nodes were stained using mAb BER-Ep4. Overall survival and distant recurrence were calculated using Kaplan-Meier plots. RESULTS: All patients (n = 48) were free of distant metastases and curatively resected (R0). 23 pN0, 13 pN1 and 12 pN2 stages were found. 21/48 patients (44%) showed BER-Ep4+ cells in their central lymph nodes (7/23 pN0, 8/13 pN1, 6/12 pN2). In 6/23 pN0 patients, BER-Ep4+ cells were also found in locoregional nodes (p = 0.03, Fisher's exact test). pN status predicted overall survival (p = 0.006, Kaplan-Meier curve, log-rank test). An impact was exerted by central mesenteric BER-Ep4+ cells on overall survival (p = 0.009 in pN0 patients, p = 0.07 for all pN) and distant recurrence-free survival (p = 0.001 in pN0 patients, p = 0.007 for all pN). Multivariate analysis showed an independent prognostic effect on overall survival in pN0 patients (p = 0.022). CONCLUSION: Central lymph nodes are sentinels of disease not amenable to extended lymphadenectomy and might identify patients at risk of distant organ recurrence.     

Rodent Osteoblastic Cells Express Voltage-Sensitive Calcium Channels Lacking a γ Subunit

Voltage-sensitive calcium channels (VSCC) open in response to external stimuli, including calcitropic hormones, that alter plasma membrane calcium (Ca²⁺) permeability. Ca²⁺ that enters the cell through these channels serves a second messenger function, eliciting cellular responses that include secretion and changes in gene expression. In osteoblasts, VSCCs serve as key regulators of Ca²⁺ permeability and are a major class of calcitropic hormone-sensitive Ca²⁺ channels present in the plasma membrane. The members of the VSCC family exist as a complex of polypeptide subunits that are comprised of a pore-forming ₁ subunit, an intracellular subunit, a dimer of disulfide-linked ₂ and subunits, and in some tissues, a subunit. Previous studies in our laboratory have shown that the major functional ₁ subunit present in osteoblasts is the _1C (Ca_V1.2). To determine the complement of auxiliary subunits present in rodent osteoblastic cells, we employed RT-PCR using a battery of subunit specific primers and appropriate tissue controls. Immunohistochemistry also was performed, using available subunit specific antibodies, to measure protein expression and localization. Cell types examined included MC3T3-E1 at various stages of differentiation, ROS 17/2.8 osteosarcoma, and primary cultures of rat calvarial osteoblasts. The results indicate that all cells expressed multiple subunit classes and ₂ dimers, but no subunits, regardless of differentiation state. We propose a structure for the functional osteoblast VSCC that consists of ₁, , ₂ subunits and is devoid of a subunit.     

Reduced number of CD169+ macrophages in pre‐metastatic regional lymph nodes is associated with subsequent metastatic disease in an animal model and with poor outcome in prostate cancer patients

Background

Tumor‐derived antigens are captured by CD169⁺ (SIGLEC1⁺) sinus macrophages in regional lymph nodes (LNs), and are presented to effector cells inducing an anti‐tumor immune response. Reduced CD169 expression in pre‐metastatic regional LNs is associated with subsequent metastatic disease and a poor outcome in several tumor types, but if this is the case in prostate cancer has not been explored.

Methods

CD169 expression was measured with immunohistochemistry in metastasis‐free regional LNs from 109 prostate cancer patients treated with prostatectomy (January 1996 to April 2002). Possible associations of CD169 expression with PSA‐relapse, prostate cancer death, Gleason score, and other clinical data were assessed using Kaplan‐Meier survival‐ and Cox regression analysis. In addition, the Dunning rat prostate tumor model was used to examine CD169 expression in pre‐metastatic LNs draining either highly metastatic MatLyLu‐ or poorly metastatic AT1‐tumors.

Results

In patients with low CD169 immunostaining in metastasis‐free regional LNs, 8 of the 27 patients died from prostate cancer compared with only three of the 82 patients with high immunostaining (P < 0.001). CD169 expression in regional LNs was not associated with PSA‐relapse. Rats with highly metastatic tumors had decreased CD169 immunoreactivity in pre‐metastatic regional LNs compared with rats with poorly metastatic tumors.

Conclusion

Low expression of CD169 in metastasis‐free regional LNs indicates a reduced anti‐tumor immune response. If verified in other studies, CD169 expression in regional LNs could, in combination with other factors, potentially be used as a marker of prostate cancer aggressiveness.     

Neutrophil stimulation with granulocyte colony-stimulating factor worsens ventilator-induced lung injury and mortality in rats

BACKGROUND: Based on the association between the neutrophil and ventilator-induced lung injury, the authors hypothesized that neutrophil inhibition with fucoidin would be beneficial and stimulation with granulocyte colony-stimulating factor (G-CSF) would be harmful in a rat model of lethal ventilator-induced lung injury. METHODS: Animals (n = 111) were randomly assigned to be pretreated with fucoidin, G-CSF, or placebo (control) before 4 h of low-tidal-volume (10 ml/kg) or high-tidal-volume (40 ml/kg) mechanical ventilation. RESULTS: All low-volume animals survived. With high volumes, compared with controls, fucoidin did not improve survival (3 of 20 control animals and 5 of 20 fucoidin animals died; P = 0.51) but G-CSF significantly worsened it (18 of 22 animals died; P < 0.001). Circulating neutrophils were increased early with G-CSF and late with fucoidin with low and high tidal volumes (P < 0.05 for each treatment and tidal volume). Fucoidin decreased lung neutrophils, but these were only significant with high tidal volumes, whereas G-CSF increased lung neutrophils but only significantly with low tidal volumes (P < or = 0.01 for each). Fucoidin did not alter any cardiopulmonary measure significantly. Compared with control, G-CSF increased airway pressures with high tidal volumes and worsened lung edema and arterial oxygen with both tidal volumes (P < 0.05 for each). CONCLUSIONS: In this model, neutrophil stimulation by G-CSF increased lung dysfunction and with high tidal volumes worsened survival rates. Extrapolated clinically, neutrophil stimulation either by agents such as G-CSF or conditions such as sepsis may aggravate ventilator-induced lung injury.