Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study

Study Type – Prognostic (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Previous studies used the decrease in PSA after 6 months of dutasteride treatment as a new ‘baseline’ PSA value from which subsequent rises may serve as a warning for prostate cancer; however, PSA tends to continue to decrease as dutasteride treatment continues. By comparing positive biopsy rates in the REDUCE study using any rise from nadir in the dutasteride arm and standard PSA decision criteria (NCCN) in the placebo arm, we demonstrated that the ability to detect prostate cancer and high grade prostate cancer is maintained with dutasteride treatment.

OBJECTIVES

? To determine if dutasteride‐treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. ? To analyse whether the use of treatment‐specific criteria for repeat biopsy maintains the usefulness of prostate‐specific antigen (PSA) level for detecting high grade cancers.

PATIENTS AND METHODS

? The REDUCE study was a randomized, double‐blind, placebo‐controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy‐detectable prostate cancer in men with a previous negative biopsy. ? The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. ? The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. ? Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds.

RESULTS

? Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. ? If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8–10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8–10 cancers would have been missed in the placebo group. ? In both groups, the incidence of Gleason 7 and Gleason 8–10 cancers generally increased with greater rises in PSA. ? Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7–10 cancers in men treated with dutasteride vs placebo. ? Men with Gleason 7 and Gleason 8–10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds.

CONCLUSION

? Using treatment‐specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. ? The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8–10) or higher than (Gleason 7–10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements.     

Credentialing for transvaginal mesh placement—a case for “added qualification” in competency

Introduction and hypothesis

A process of added qualification of transvaginal mesh (TVM) placement is desirable.

Methods

Through a physician-led partnership of specialty societies, centers of excellence, and industry, a core curriculum encompassing mesh/graft biology, technical skills, and safety can be coupled with current educational endeavors instructing surgeons in the use of TVM. A posttest process can verify a knowledge-based competency in mesh/graft safety. An auditing process after implementation would be optimal.

Results

We recommend implementation of a five-step process in order to accomplish these goals.

Conclusions

It is hoped through these efforts, the ultimate goal of patient safety may be reached.

     

Focal cryotherapy for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years

Background

Evolution of cryotherapy for prostate cancer is likely to result in parenchyma-sparing modifications adjacent to the urethra and neurovascular bundle. Results of initial series of focal therapy to minimize cryosurgery-related morbidity without compromising oncologic control have been encouraging, but limited in short-term outcomes.

Objective

To retrospectively report (1) median 3.7-yr follow-up experience of primary focal cryotherapy for clinically unilateral prostate cancer with oncologic and functional outcomes, and (2) matched-pair analysis with contemporaneous patients undergoing radical prostatectomy (RP).

Design, setting, and participants

Over 8.5 yr (September 2002 to March 2011), focal cryoablation (defined as ablation of one lobe) was performed in 73 carefully selected patients with biopsy-proven, clinically unilateral, low-intermediate risk prostate cancer. All patients underwent transrectal ultrasound (TRUS) and Doppler-guided sextant and targeted biopsies at entry.

Outcome measurements and statistical analysis

Post-therapy follow-up included measuring prostate-specific antigen (PSA) level every 3–6 mo; TRUS biopsies at 6–12 mo and yearly, as indicated; and validated symptom questionnaires. Matched-pair analysis compared oncologic outcomes of focal cryotherapy and RP (matched for age, PSA, clinical stage, and biopsy Gleason score).

Results and limitations

Complete follow-up was available in 70 patients (median follow-up: 3.7 yr; range: 1–8.5 yr). No patient died or developed metastases. Precryotherapy mean PSA was 5.9 ng/ml and Gleason score was 6 (n = 30) or 7 (n = 43). Postcryotherapy mean PSA was 1.6 ng/ml (70% reduction compared to precryotherapy; p < 0.001). Of 48 patients undergoing postcryotherapy biopsy, 36 (75%) had negative biopsies; positive biopsy for cancer (n = 12) occurred in the untreated contralateral (n = 11) or treated ipsilateral lobe (n = 1). Complete continence (no pads) and potency sufficient for intercourse were documented in 100% and 86% of patients, respectively. Matched-pair comparison of focal cryotherapy and RP revealed similar oncologic outcome, defined as needing salvage treatment.

Conclusions

Primary focal cryoablation for low-intermediate risk unilateral cancer affords encouraging oncologic and functional outcomes over a median 3.7-yr follow-up. Close surveillance with follow-up whole-gland biopsies is mandatory.     

Prevention of hypertension attenuates albuminuria and renal expression of fibronectin in diabetic spontaneously hypertensive rats

BACKGROUND/AIM: The aim of this study was to evaluate the effect of preventing hypertension on renal disease in a model of genetic hypertension and diabetes. METHODS:Four-week-old spontaneously hypertensive rats (SHR) with streptozotocin-induced diabetes were randomized for no treatment, or for treatment with captopril, losartan or triple therapy (hydrochlorothiazide, reserpine and hydralazine) for 16 weeks. RESULTS: Increase in systolic blood pressure was equally prevented by captopril (128 +/- 3 mm Hg), losartan (128 +/- 2) and triple therapy (129 +/- 2, p < 0.0001). Albuminuria was similarly reduced by captopril (499 (404-659)), losartan (622 (470-976)) and triple therapy (479 (362-600) microg/24 h (p < 0.0001)). Renal fibronectin expression increased in diabetic SHR (125 +/- 13 densitometric unit) as compared to the controls (51 +/- 9, p < 0.0001), and decreased (p < 0.0001 vs. diabetic SHR) with captopril (32 +/- 8), losartan (27 +/- 4) and triple therapy (35 +/- 6). CONCLUSION: The prevention of hypertension in diabetic SHR by captopril, losartan or triple therapy was equally efficacious in impeding increase of albuminuria and the expression of renal fibronectin. Under these conditions, tight blood pressure control was the main determinant in attenuating nephropathy.     

Sources of hepatic glucose production by 2H2O ingestion and Bayesian analysis of 2H glucuronide enrichment

The contribution of gluconeogenesis to hepatic glucose production (GP) was quantified after ²H₂O ingestion by Bayesian analysis of the position 2 and 5 ²H‐NMR signals (H2 and H5) of monoacetone glucose (MAG) derived from urinary acetaminophen glucuronide. Six controls and 10 kidney transplant (KTx) patients with cyclosporine A (CsA) immunosuppressant therapy were studied. Seven KTx patients were lean and euglycemic (BMI = 24.3 ± 1.0 kg/m²; fasting glucose = 4.7 ± 0.1 mM) while three were obese and hyperglycemic (BMI = 30.5 ± 0.7 kg/m²; fasting glucose = 7.1 ± 0.5 mM). For the 16 spectra analyzed, the mean coefficient of variation for the gluconeogenesis contribution was 10% ± 5%. This uncertainty was associated with a mean signal‐to‐noise ratio (SNR) of 79:1 and 45:1 for the MAG H2 and H5 signals, respectively. For control subjects, gluconeogenesis contributed 54% ± 7% of GP as determined by the mean and standard deviation (SD) of individual Bayesian analyses. For the lean/normoglycemic KTx subjects, the gluconeogenic contribution to GP was 62% ± 7% (P = 0.06 vs. controls), while hyperglycemic/obese KTx patients had a gluconeogenic contribution of 68% ± 3% (P < 0.005 vs. controls). These data suggest that in KTx patients, an increased gluconeogenic contribution to GP is strongly associated with obesity and hyperglycemia. Magn Reson Med 60:517–523, 2008. © 2008 Wiley‐Liss, Inc.     

Comparison of computed tomographic angiography with digital subtraction angiography in the diagnosis of cerebral aneurysms: a meta-analysis

OBJECTIVE: To compare a novel diagnostic radiological technique, computed tomographic angiography (CTA), with the standard method, namely digital subtraction angiography (DSA), in the diagnosis of cerebral aneurysms. METHODS: A comprehensive search of the world literature on CTA was performed. Articles that reported on prospective comparisons of CTA and DSA in the evaluation of patients suspected of harboring cerebral aneurysms were selected for data extraction. Suitable statistical methods were applied to the extracted data for meta-analysis. RESULTS: Twenty-one references met the criteria for use in the meta-analysis. Unweighted calculations based on data for 1251 patients resulted in a sensitivity of 0.933 (93.3%; range, 75.4-100%) and a specificity of 0.878 (87.8%; range, 0-100%). When the studies were weighted for the number of patients in each study, the sensitivity decreased slightly, to 0.927 (92.7%), and the specificity decreased more substantially, to 0.772 (77.2%). CONCLUSION: On the basis of this meta-analysis, DSA remains the standard method. However, many who use CTA have reported it to be as good as or better than DSA in the diagnosis and treatment of cerebral aneurysms, as well as being of less risk and discomfort to their patients and easier and less expensive to perform.     

A molecular view of liver regeneration

The purpose of this review was to carry out an analysis of the liver regenerative process focusing on the molecular interactions involved in this process. The authors undertook a review of scientific publications with a focus on the liver regeneration. The cellular processes involved in liver regeneration require multiple systematic actions related to cytokines and growth factors. These interactions result in the initiation of mitogenic potential of the hepatocytes. The action of these modulators in the regenerative process require a processing in the extra-cellular matrix. Serines and metal proteins are responsible for the bio availability of cytokines and growth factors so that they can interact as receptors in the cellular membrane generating signaling events for the beginning and end of the liver regenerative process. The exact mechanism of interaction between cells, cytokines and growth factors is not well established yet. A series of ordered events that result in the hepatic tissue regeneration has been described. The better understanding of these interactions should provide a new approach of the treatment for liver diseases, aiming at inducing the regenerative process.     

COL1A1 Sp1-binding site polymorphism as a risk factor for genital prolapse

The objective of this study was to verify the possible association between the Sp1-binding site polymorphism and genital prolapse. A case–control study was conducted in 107 patients with stages III and IV genital prolapse. The control group included 209 women with stages 0 and I. The polymorphism of type I collagen Sp1-binding site was identified by amplification of the first intron of the COL1A1 gene. We did not find differences in the prevalence of the GT and TT genotypes between the groups (p = 0.34), even when we grouped patients with at least one polymorphic allele (GT and TT) and compared them with patients without the polymorphic allele (GG; p = 0.17) The presence of at least one vaginal delivery, family history for prolapse, and macrosomatic fetus were independent risk factors for prolapse. In conclusion, the COL1A1 Sp1-binding site was not significantly associated with genital prolapse among our study subjects.     

Incidence and management of pancreatic leakage after pancreatoduodenectomy

BACKGROUND: Optimal management of severe pancreatic leakage after pancreatoduodenectomy can reduce morbidity and mortality. Completion pancreatectomy may be adequate but leads to endocrine insufficiency. This study evaluated an alternative management strategy for pancreatic leakage. METHODS: Outcome after disconnection of the jejunal limb, resection of the pancreatic body and preservation of a small pancreatic remnant, performed between 1997 and 2002, was compared with that after completion pancreatectomy performed between 1992 and 1996. RESULTS: Pancreatoduodenectomy was performed in 459 consecutive patients. Pancreatic leakage occurred in 41 patients (8.9 per cent); its incidence did not change over the study period. Non-surgical drainage procedures were performed in 14 patients, of whom one died, and surgical drainage in eight patients, of whom two died. Completion pancreatectomy was performed in nine patients with no deaths. A pancreatic remnant was preserved in ten patients, of whom three died. A remnant tail had to be resected in two patients and three patients still developed endocrine insufficiency ('brittle' diabetes). CONCLUSION: The incidence of pancreatic leakage did not change over the study interval. Preservation of a small pancreatic tail was associated with higher morbidity and mortality rates than those of completion pancreatectomy.     

Higher initial tacrolimus blood levels and concentration-dose ratios in kidney transplant recipients who develop diabetes mellitus

Posttransplantation diabetes mellitus (PTDM) is a common complication of kidney transplantation, associated with poorer graft and patient outcomes. Tacrolimus is a strong immunosuppressive drug associated with low acute rejection rates, but a higher risk for PTDM. High trough levels of tacrolimus during the first month after transplantation have been found to be a significant risk factor for the development of PTDM. The aim of this single-center study was to identify the risk factors for the development of PTDM among kidney transplant recipients under tacrolimus therapy. We examined 73 cadaveric kidney transplant recipients receiving tacrolimus between 1994 and 2003. Age, donor and recipient gender, dialysis method, body mass index (BMI), first year weight gain, mismatches, incidence of acute rejection and delayed graft function, hepatitis C serology, first year cumulative steroid dose, first tacrolimus blood level, first tacrolimus blood level <15 ng/mL, and corresponding tacrolimus daily doses and concentration/dose ratios (CDR) were also collected. PTDM was defined as at least 2 fasting blood glucose values > or =126 mg/dL, according to the World Health Organization criteria. Incidence of first year PTDM was 27.4%. Patients with PTDM showed significantly higher age, BMI, first tacrolimus blood level, first tacrolimus CDR, and CDR with tacrolimus blood level <15 ng/mL as well as less 1-year weight gain. After logistic regression, age (relative risk [RR] 1.060, confidence interval [CI] 95%, 1.001-1.122; P = .043) and first tacrolimus blood level (RR 1.154; CI 95%, 1.038-1.283; P = .008) remain significant risk factors for developing PTDM. Older age and initial tacrolimus blood levels were the main risk factors for PTDM among our group of patients. Kidney transplant recipients who develop PTDM maintain a high CDR of tacrolimus.