A prospective multicentre phase III validation study of AZGP1 as a biomarker in localized prostate cancer.

BACKGROUND: Prostate cancers (PCs) with similar characteristics at the time of diagnosis can have very different disease outcomes. Conventional biomarkers of PC still lack precision in identifying individuals at high risk of PC recurrence. While many candidate biomarkers are proposed in the literature, few are in clinical practice as they lack rigorous validation. This study prospectively enrolled an independent phase III cohort to evaluate the clinical utility of zinc-alpha 2-glycoprotein (AZGP1) as a prognostic biomarker in localized PC. PATIENTS AND METHODS: In our multicentre, prospective phase III study, AZGP1 status in 347 radical prostatectomy specimens was assayed by immunohistochemistry in a NATA-accredited laboratory. The AZGP1 score was assessed in a multivariable model incorporating established prognostic factors. We also report extended outcomes from our previous phase II study. The primary endpoint was biochemical relapse-free survival (BRFS). Secondary endpoints were metastasis-free survival (MFS) and PC-specific survival (PCSS). RESULTS: In the phase II cohort, with a median follow-up of 15.8 years, low/absent AZGP1 expression was an independent predictor of poor BRFS (HR, 1.4; 95% CI, 1.1-1.9; P = 0.03), MFS (HR, 2.8; 95% CI, 1.2-6.6; P = 0.02) and PCSS (HR, 3.8; 95% CI, 1.5-9.5; P = 0.005). These results were validated in our prospective phase III cohort. Low/absent AZGP1 expression independently predicted for BRFS (HR, 1.9; 95% CI, 1.1-3.3; P = 0.02), with shorter MFS (HR, 2.0; 95% CI, 1.1-3.4; P = 0.02). AZGP1 improved the discriminatory value when incorporated into existing prognostic risk models. CONCLUSION: Our study provides prospective phase III validation that absent/low AZGP1 expression provides independent prognostic value in PC. This study provides robust evidence for the incorporation of this biomarker into clinical practice.

Effects of verapamil in the prevention of warm ischaemia induced acute renal failure in dogs.

Acute renal failure in the immediate postoperative period remains a significant complication of renal transplantation. A major factor in the pathogenesis may be warm ischaemia (WI). Recent evidence implicates a calcium mediated mechanism as a final common pathway in certain models of acute renal failure. This study was undertaken to evaluate the effects of Verapamil, a calcium antagonist, in the prevention of warm ischaemia-induced acute renal failure following renal autotransplantation in the dog. Twenty-one mongrel dogs were randomly allocated to three groups. Group 1 (control, 8 dogs) received 20 ml normal saline before a standardized 60 min warm ischaemic insult to the left kidney. Group 2 (6 dogs) received Verapamil (0.3 mg/kg) by intravenous injection and Group 3 (7 dogs) received Verapamil (0.3 mg/kg) by intra-arterial injection into the left renal artery prior to the same ischaemic insult. The left kidney was heterotopically grafted to the right iliac fossa in the warm ischaemic period. Contralateral nephrectomy was performed. The dogs were followed up to 7 days after operation by serial creatinine estimation. Histological examination of some autografts was performed. Of the eight controls, six showed marked renal impairment (serum creatinine greater than 800, or death in renal failure). Three of the six dogs given intravenous Verapamil showed marked renal impairment. None of the seven dogs receiving intra-arterial Verapamil showed marked renal impairment (P = 0.013, chi 2 test). The mean rate of serum creatinine rise for each group was analysed by multivariate analyses of variance.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the effects of cyclosporin A and standard agents on primary wound healing in the rat.

Eighty-six Sprague-Dawley rats were randomly allocated to three treatment groups given tap water (control group), cyclosporin A (CSA group) and azathioprine and prednisone (AP group). Two incisions, one skin and one musculofascial, were made in each rat with a standardized technique. The healed incisions were subjected to tensiometery at days eight and 15 after operation. Histologic examination was undertaken on some wounds. The results indicate that cyclosporin A in clinical doses does not inhibit skin or musculofascial healing in the rat. Azathioprine and prednisone immunosuppression significantly retarded skin healing on day eight postoperatively although this had returned to control levels on day 15. Azathioprine and prednisone did not affect musculofascial healing at the administered dose. In the sections available for study, there were no qualitative histologic differences between groups at both days eight and 15 postoperatively.