Treatment with 3‐aminobenzamide during ex vivo lung perfusion of damaged rat lungs reduces graft injury and dysfunction after transplantation

Ex vivo lung perfusion (EVLP) with pharmacological reconditioning may increase donor lung utilization for transplantation (LTx). 3‐Aminobenzamide (3‐AB), an inhibitor of poly(ADP‐ribose) polymerase (PARP), reduces ex vivo lung injury in rat lungs damaged by warm ischemia (WI). Here we determined the effects of 3‐AB reconditioning on graft outcome after LTx. Three groups of donor lungs were studied: Control (Ctrl): 1 hour WI + 3 hours cold ischemia (CI) + LTx; EVLP: 1 hour WI + 3 hours EVLP + LTx; EVLP + 3‐AB: 1 hour WI + 3 hours EVLP + 3‐AB (1 mg^.mL^?1) + LTx. Two hours after LTx, we determined lung graft compliance, edema, histology, neutrophil counts in bronchoalveolar lavage (BAL), mRNA levels of adhesion molecules within the graft, as well as concentrations of interleukin‐6 and 10 (IL‐6, IL‐10) in BAL and plasma. 3‐AB reconditioning during EVLP improved compliance and reduced lung edema, neutrophil infiltration, and the expression of adhesion molecules within the transplanted lungs. 3‐AB also attenuated the IL‐6/IL‐10 ratio in BAL and plasma, supporting an improved balance between pro‐ and anti‐inflammatory mediators. Thus, 3‐AB reconditioning during EVLP of rat lung grafts damaged by WI markedly reduces inflammation, edema, and physiological deterioration after LTx, supporting the use of PARP inhibitors for the rehabilitation of damaged lungs during EVLP.     

基本药物今昔25年

二十世纪初 ,广为普及的现代药物只有一个 :乙酰水杨酸 (阿司匹林 )。二十世纪四十年代 ,人类发现第一种抗菌素、第一种批量生产的抗疟药和第一种抗痨药。五、六十年代 ,很快研制出口服避孕药 ,治疗糖尿病的药 ,及治疗精神疾病、各种感染疾病、心血管疾病和癌症的药物。到七十年代 ,几乎每大类疾病都能找到有效药物 ,尽管这些药物的效果不很理想。但全球约有一半的人口似乎依然生活在十九世纪。他们由于贫穷 ,得不到、买不起现代药物 ;因用法不当而不能正确发挥药物疗效。1 975年 ,世界卫生大会提出“基本药物”和“国家药品政策”的概念 ,…     

Customised osteotomy guides and endoprosthetic reconstruction for periacetabular tumours

Purpose

We sought to analyse clinical and oncological outcomes of patients after guided resection of periacetabular tumours and endoprosthetic reconstruction of the remaining defect.

Methods

From 1988 to 2008, we treated 56 consecutive patients (mean age 52.5 years, 41.1 % women). Patients were followed up either until death or February 2011 (mean follow up 5.5 years, range 0.1–22.5, standard deviation ± 5.3). Kaplan–Meier analysis was used to estimate survival rates.

Results

Disease-specific survival was 59.9 % at five years and 49.7 % at ten and 20 years, respectively. Wide resection margins were achieved in 38 patients, whereas 11 patients underwent marginal and seven intralesional resection. Survival was significantly better in patients with wide or marginal resection than in patients with intralesional resection (p = 0.022). Survival for patients with secondary tumours was significantly worse than for patients with primary tumours (p = 0.003). In 29 patients (51.8 %), at least one reoperation was necessary, resulting in a revision-free survival of 50.5 % at five years, 41.1 % at ten years and 30.6 % at 20 years. Implant survival was 77.0 % at five years, 68.6 % at ten years and 51.8 % at 20 years. A total of 35 patients (62.5 %) experienced one or more complications after surgery. Ten of 56 patients (17.9 %) experienced local recurrence after a mean of 8.9 months. The mean postoperative Musculoskeletal Tumor Society (MSTS) score was 18.1 (60.1 %).

Conclusion

The surgical approach assessed in this study simplifies the process of tumour resection and prosthesis implantation and leads to acceptable clinical and oncological outcomes.     

The Added Value of Percentage of Free to Total Prostate-specific Antigen,PCA3, and a Kallikrein Panel to the ERSPC Risk Calculator for Prostate Cancer in Prescreened Men

Background

Prostate-specific antigen (PSA) testing has limited accuracy for the early detection of prostate cancer (PCa).

Objective

To assess the value added by percentage of free to total PSA (%fPSA), prostate cancer antigen 3 (PCA3), and a kallikrein panel (4k-panel) to the European Randomised Study of Screening for Prostate Cancer (ERSPC) multivariable prediction models: risk calculator (RC) 4, including transrectal ultrasound, and RC 4 plus digital rectal examination (4+DRE) for prescreened men.

Design, setting, and participants

Participants were invited for rescreening between October 2007 and February 2009 within the Dutch part of the ERSPC study. Biopsies were taken in men with a PSA level ≥3.0 ng/ml or a PCA3 score ≥10. Additional analyses of the 4k-panel were done on serum samples.

Outcome measurements and statistical analysis

Outcome was defined as PCa detectable by sextant biopsy. Receiver operating characteristic curve and decision curve analyses were performed to compare the predictive capabilities of %fPSA, PCA3, 4k-panel, the ERSPC RCs, and their combinations in logistic regression models.

Results and limitations

PCa was detected in 119 of 708 men. The %fPSA did not perform better univariately or added to the RCs compared with the RCs alone. In 202 men with an elevated PSA, the 4k-panel discriminated better than PCA3 when modelled univariately (area under the curve [AUC]: 0.78 vs 0.62; p = 0.01). The multivariable models with PCA3 or the 4k-panel were equivalent (AUC: 0.80 for RC 4+DRE). In the total population, PCA3 discriminated better than the 4k-panel (univariate AUC: 0.63 vs 0.56; p = 0.05). There was no statistically significant difference between the multivariable model with PCA3 (AUC: 0.73) versus the model with the 4k-panel (AUC: 0.71; p = 0.18). The multivariable model with PCA3 performed better than the reference model (0.73 vs 0.70; p = 0.02). Decision curves confirmed these patterns, although numbers were small.

Conclusions

Both PCA3 and, to a lesser extent, a 4k-panel have added value to the DRE-based ERSPC RC in detecting PCa in prescreened men.

Patient summary

We studied the added value of novel biomarkers to previously developed risk prediction models for prostate cancer. We found that inclusion of these biomarkers resulted in an increase in predictive ability.