1-year Biopsy Research Articles

1779 REPEAT PROSTATE BIOPSIES IN MEN WITH LOW RISK PROSTATE CANCER IN A PROSPECTIVE ACTIVE SURVEILLANCE PROGRAM: FINDINGS AND CONSEQUENCES

You have accessJournal of UrologyProstate Cancer: Localized1 Apr 20111779 REPEAT PROSTATE BIOPSIES IN MEN WITH LOW RISK PROSTATE CANCER IN A PROSPECTIVE ACTIVE SURVEILLANCE PROGRAM: FINDINGS AND CONSEQUENCES Meelan Bul, Roderick van den Bergh, Xiaoye Zhu, Pim van Leeuwen, Monique Roobol, Fritz Schröder, and Chris Bangma Meelan BulMeelan Bul Rotterdam, Netherlands More articles by this author , Roderick van den BerghRoderick van den Bergh Rotterdam, Netherlands More articles by this author , Xiaoye ZhuXiaoye Zhu Rotterdam, Netherlands More articles by this author , Pim van LeeuwenPim van Leeuwen Rotterdam, Netherlands More articles by this author , Monique RoobolMonique Roobol Rotterdam, Netherlands More articles by this author , Fritz SchröderFritz Schröder Rotterdam, Netherlands More articles by this author , and Chris BangmaChris Bangma Rotterdam, Netherlands More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2129AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Active surveillance (AS) protocols for low-risk prostate cancer (PC) generally include repeat prostate biopsies at predefined time points during follow-up. We studied the outcome of 1-year repeat biopsies and the predicting factors for possible risk reclassification in order to contribute to improve the inclusion strategy. METHODS We analyzed men with low-risk PC (clinical stage <=T2, PSA <=10 ng/ml, PSA density <0.2 ng/ml/ml, 1 or 2 positive biopsy cores and Gleason score <=6) included in a prospective AS protocol (PRIAS study) from December 2006 to October 2010. PSA was measured 3-monthly and the first, volume–dependent (prostate volume <40cc: 8 biopsy-cores, 40–60cc: 10, and >60cc: 12) repeat biopsy was scheduled 1 year after diagnosis. Risk reclassification towards high risk on repeat biopsy was defined as a Gleason score >7 or >3 positive biopsy cores. We assessed the relation of the baseline patient characteristics and PSA doubling time (PSA-DT) with reclassification towards high risk on repeat biopsy. RESULTS A total of 1482 patients were included. In 757 patients a first repeat biopsy was taken after a median follow-up of 1.03 yrs. Repeat biopsy showed favourable results (no or low-risk PC) in 594 patients (78.5%) and risk reclassification in 163 patients (21.5%). Multivariate logistic regression (table) showed the following baseline characteristics to have a significant relation to risk reclassification: number of initial positive cores (2 vs 1) (OR=1.8; p=0.002) and PSA density (OR=2.5; p=0.002). Age, clinical stage, total number of biopsy cores and PSA did not show significant results. Adding PSA-DT at the time of repeat biopsy as a predictor for high risk reclassification showed an increased risk for patients with PSA-DT <3 years (OR=1.8; p= 0.011). Table. Association of patient characteristics with risk reclassification on repeat biopsy. Baseline characteristics Baseline characteristics and PSA-DT OR (95% CI) P-value OR (95% CI) P-value Age at diagnosis 1.0 0.44 1.0 0.51 PSA 0.9 0.08 0.9 0.11 PSA-Dξ 2.1(1.3-3.4) 0.003⁎ 2.1(1.3-3.5) 0.003⁎ Clinical stage 1.1 0.79 1.1 0.66 Total biopsy cores 1.0 0.91 1.0 0.96 Positive cores 1.8(1.3-2.7) 0.001⁎ 1.8(1.2-2.6) 0.002⁎ PSA-DT <3 yr - - 1.7(1.1-2.5) 0.019⁎ PSA-DT 3-10 yr - - 1.4 0.12 ξ OR for PSA-D is reported per 0.10 units increase; ⁎ significant result (P <0.05) CONCLUSIONS The number of positive biopsy cores and PSA density at diagnosis are associated with risk reclassification towards high risk on repeat biopsy in our AS cohort. These characteristics potentially might be used as an indication for early re-staging biopsy. The relation between PSA-DT and repeat biopsy findings supports our protocol in which men with higher PSA-DT undergo more intensive biopsy schemes. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e714 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Meelan Bul Rotterdam, Netherlands More articles by this author Roderick van den Bergh Rotterdam, Netherlands More articles by this author Xiaoye Zhu Rotterdam, Netherlands More articles by this author Pim van Leeuwen Rotterdam, Netherlands More articles by this author Monique Roobol Rotterdam, Netherlands More articles by this author Fritz Schröder Rotterdam, Netherlands More articles by this author Chris Bangma Rotterdam, Netherlands More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Rapamycin Prevents Interstitial Fibrosis in Renal Allografts through Decreasing Angiogenesis and Inflammation

Rapamycin (RPM) has antiangiogenic and antiproliferative effects on cells. The aim of this study was to evaluate the mechanism of RPM as a novel antifibrotic agent by assessing its effect on interstitial fibrosis (IF). Among 60 renal transplant recipients, group 1 patients ( n = 20) were treated with RPM and group 2 ( n = 40), with cyclosporine. The proportions of infiltrating macrophages and lymphocytes in the interstitium were evaluated in 1-year biopsies. The microvessels were highlightened with CD34. After an initial biopsy, the development of diffuse IF over 18 months was evaluated by follow-up biopsies. The mean microvessel density (MVD) was significantly lower among group 1 (69.3 ± 16) versus group 2 (96.5 ± 30; P < .001). The proportions of macrophages and lymphocytes were lower in group 1 compared to group 2 biopsies ( P < .001 for both). Fourteen (35%) group 2 and only 2 (10%) group 1 cases developed IF over 18 months ( P < .05). The mean MVD in the initial biopsy was 75.6 ± 18 in cases that did not versus 120 ± 28 among those who did develop IF ( P < .001). The amount of interstitial inflammation was greater among patients who did compared with cases who did not develop IF ( P < .01). The overall 1-, 3-, and 5-year graft survival rates for group 1 were 95%, 95%, and 89% versus 95%, 65%, and 45% for group 2 patients, respectively ( P < .001). RPM-treated patients showed a lower incidence of diffuse IF, which can be explained by antiproliferative and antiangiogenic effects of RPM. In conclusion, RPM therapy displayed an independently positive impact on long-term graft survival.

Adaptive seamless design for an efficacy trial of replication-competent adenovirus-mediated suicide gene therapy and radiation in newly-diagnosed prostate cancer (ReCAP Trial)

Purpose Cumulative evidence has suggested investigation of the efficacy of Replication-Competent Adenovirus-mediated Suicide Gene Therapy in newly-diagnosed Prostate Cancer (ReCAP). There is a challenge in designing an efficacy trial for newly-diagnosed prostate cancer given its long natural history. The regulatory agency recommended a Phase II trial for safety before conducting the efficacy trial. Experimental design The ReCAP trial is an adaptive seamless, multi-site open-label, randomized Phase II/III trial. Two hundred eighty men will be randomized to receive either replication-competent adenovirus-mediated suicide gene therapy followed by radiation (Arm 1) or radiation alone (Arm 2). Phase II trial component will include the first 21 patients in Arm 1 with complete toxicity through day 90 for safety evaluation. The primary efficacy endpoint is the time free from biochemical and/or clinical failure (FFF). The secondary efficacy endpoints are 2-year prostate biopsies and overall survival. Unequal spaced interim looks are proposed with the adaptive sample-size re-estimation. Results This trial has been approved by the FDA for the study therapy investigation and is currently recruiting patients. Conclusions Challenges remain in designing newly-diagnosed prostate cancer trials. Adaptive seamless design is time-saving and a cost-effective design in the development of novel medical therapies, but requires a specified statistical plan in the decision process involved.

Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C Virus 1 year after liver transplantation

Clinical outcomes of recurrent hepatitis C virus after liver transplantation are difficult to predict. We evaluated collagen proportionate area (CPA), a quantitative histological index, at 1 year with respect to the first episode of clinical decompensation. Patients with biopsies at 1 year after liver transplantation were evaluated by Ishak stage/grade, and biopsy samples stained with Sirius red for digital image analysis were evaluated for CPA. Cox regression was used to evaluate variables associated with first appearance of clinical decompensation. Receiver operating characteristic (ROC) curves were also used. A total of 135 patients with median follow-up of 76 months were evaluated. At 1 year, median CPA was 4.6% (0.2%-36%) and Ishak stage was 0-2 in 101 patients, 3-4 in 23 patients, and 5-6 in 11 patients. Decompensation occurred in 26 (19.3%) at a median of 61 months (15-138). Univariately, CPA, tacrolimus monotherapy, and Ishak stage/grade at 1 year were associated with decompensation; upon multivariate analysis, only CPA was associated with decompensation (P = 0.010; Exp(B) = 1.169; 95%CI, 1.037-1.317). Area under the ROC curve was 0.97 (95%CI, 0.94-0.99). A cutoff value of 6% of CPA had 82% sensitivity and 95% specificity for decompensation. In the 89 patients with hepatic venous pressure gradient (HVPG) measurement, similar results were obtained. When both cutoffs of CPA > 6% and HVPG ≥ 6 mm Hg were used, all patients decompensated. Thus, CPA at 1-year biopsy after liver transplantation was highly predictive of clinical outcome in patients infected with hepatitis C virus who underwent transplantation, better than Ishak stage or HVPG.

Mean Glomerular Volume After Renal Transplantation in Patients Receiving Sirolimus and Cyclosporine A Compared With Elimination of Cyclosporine A at 3 Months

Glomerular enlargement after renal transplantation is associated with kidney allograft preservation. Increased glomerular size in donor biopsies is associated with donor age and with increased serum creatinine during follow-up, suggesting that older donors with larger glomeruli have exhausted their capacity for further glomerular adaptation (1). Allografts from younger donors with smaller glomeruli experience further increase of glomerular size after transplantation (2), which is associated with an improvement of renal function. The use of anticalcineurinic agents is associated with vasoconstriction and decreased glomerular filtration rate (GFR) (3). Sirolimus (SRL) has allowed withdrawing cyclosporine A (CsA) early after transplantation as it has been observed in the Rapamune Maintenance Regimen (RMR) study in which a steady improvement of GFR was observed in patients in the CsA withdrawal arm in comparison with the CsA maintenance group (4). We hypothesized that amelioration of GFR in patients after CsA withdrawal is related to glomerular size increase after transplantation. Sixty-four patients from a substudy (5) of the RMR trial conducted in Spain and Portugal with a donor and 1-year paired biopsies were reviewed. Details of the RMR study design and clinical results were published elsewhere (4–6). Of the 64 patients reviewed for this study, only 15 contained at least 10 glomerular sections in both biopsies (6 randomized to CsA elimination at 3 months and 9 maintained with CsA and SRL during the first year). Banff acute and chronic scores were blindly evaluated by a central pathologist. Vg was estimated according to the Weibel and Gomez formula using the mean glomerular area evaluated with an optical pen. Absolute differences between chronic Banff scores and mean glomerular volume (Vg) in both biopsies were calculated. Unpaired comparisons between means were done by Mann-Whitney U test and paired comparisons by Wilcoxon t test. The Vg in the donor and 1-year protocol biopsies in both groups is shown in Figure 1. In the CsA withdrawal group, a significant glomerular enlargement was observed (2.15±0.73× 106 μ3 in the donor and 2.66±0.78×106 μ3 in the 1-year biopsy, P=0.009) whereas in patients maintaining CsA, Vg decreased (2.87±0.81×106 μ3 in the donor and 2.27±0.70×106 μ3 in the 1-year biopsy, P=0.026). The Vg difference between the 1-year and the donor biopsy was significantly different between treatment arms (+0.51±0.31 vs. −0.60± 0.66×106 μ3, P=0.002).FIGURE 1.: Mean glomerular volume in donor and 1-year biopsies from patients randomized to cyclosporine A (CsA) maintenance or elimination at 3 months. Thin lines represent evolution of individual kidneys, and thick lines represent the mean for each group. SRL, sirolimus; P, prednisone.There was a positive correlation between Vg in the donor and 1-year biopsies (R=0.53; P=0.042), and this relationship was closer in patients eliminating CsA at 3 months (R=0.92, P=0.009) than in those maintaining CsA during the first year (R=0.65, P=0.059). The capsular tuft volume fraction was not different between both groups in the donor biopsy (0.58±0.13 vs. 0.61±0.07), whereas in the 1-year biopsy, it was lower in the CsA maintaining group (0.55±0.11 vs. 0.66± 0.34; P=0.045). Glomerular enlargement was associated with a lower progression of chronic lesions (Banff chronic score −0.7±1.0 vs. 2.5±1.7, P<0.01), whereas acute lesions at 1 year were not different between groups. Our data suggest that CsA prevents glomerular adaptation after transplantation and may contribute to explain why estimated GFR was superior in the CsA withdrawal group at 1 and 3 years of follow-up (4). In our study, it is important to remark that in patients receiving CsA and SRL during the first year, glomerular size significantly decreased, which may be the result of a synergistic effect of CsA and SRL impairing glomerular adaptation after renal transplantation by two different mechanisms: renal ischemia and inhibition of glomerular hypertrophy. This hypothesis is further sustained by the observation that 1-year capsule tuft volume fraction was lower in CsA- and SRL-treated patients. The higher degree of chronic tubulointerstitial damage observed in patients treated with CsA and SRL may constitute a third mechanism contributing to the impeded glomerular adaptation in patients receiving CsA and SRL. We have previously shown that interstitial inflammation and interstitial fibrosis are two major predictors of glomerular adaptation after transplantation (7). Thus, worse preservation of interstitial structure in CsA maintenance group may also account for the lack of glomerular adaptation because of peritubular capillary damage associated with interstitial fibrosis and inflammation. In summary, despite the number of cases included is low and consequently, these results should be interpreted with caution, we show that in stable grafts, the combination of CsA and SRL prevents glomerular enlargement after transplantation when compared with CsA withdrawal and SRL continuation. Joana Sellarés1 Francesc Moreso2 Juan Carlos Ruiz3 Daniel Seron2 1 Nephrology Department Hospital Universitari Bellvitge L'Hospitalet, Barcelona, Spain 2 Nephrology Department Hospital Vall d'Hebron Universitat Autonoma Barcelona Barcelona, Spain 3 Nephrology Department Hospital Universitario Marqués de Valdecilla Santander, Spain

Radiofrequency Ablation of Renal Tumors: Our Experience

PurposeTo report our results of nephron-sparing radiofrequency ablation (RFA) of renal tumors.Materials and MethodsSince August 2004, 49 patients with renal tumors were treated with either percutaneous or laparoscopic RFA. All patients underwent preoperative imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and were suspected to have renal cell carcinoma. The follow-up for each patient included a physical examination, chest radiography, liver function tests, and a contrast-enhanced CT or MRI. To confirm the pathologic criteria of complete ablation, 30 patients underwent 6-month or 1-year follow-up biopsy. Recurrence was defined as growth of the tumor or any new enhancing portions at 3 months after confirmed nonenhancement of the initial RFA lesion.ResultsTechnical success was achieved in 46/49 cases (94%). The mean tumor size was 2.4 cm and the mean follow-up period was 31.7 months (range, 6-68 months). Of 49 patients, repeated RFA was necessary in 7 patients (14%). Three patients were found to have recurrence at various follow-up intervals. Twenty-three patients (47%) experienced complications, and all but one necessitated intervention. No distant metastasis was found in any cases, and all patients are alive and are being serially followed up.ConclusionsPercutaneous or laparoscopic RFA is considered to be a useful treatment for selected patients with small renal masses and for nephron-sparing. With a mean follow-up of 31.7 months, our intermediate data suggest excellent therapeutic outcome with RFA with effective local tumor control and preservation of renal function. The ultimate role of this modality will continue to evolve and warrants further studies.

Low-density array PCR analysis of reperfusion biopsies: an adjunct to histological analysis

Histologic evaluation of baseline kidney biopsies is an inconsistent tool to predict graft outcomes, which might be assisted by gene expression analysis. We evaluated 49 consecutive kidney graft biopsies obtained post-reperfusion in 18 deceased donors (DD) and 31 living donors (LD) at our center. Biopsies were evaluated and scored using Banff criteria. Low-density real-time polymerase chain reaction arrays were used to measure intragraft expression of 95 genes associated with programmed cell death, fibrosis, innate and adaptive immunity and oxidative stress signaling. A pool of 25 normal kidney biopsies was used as control. We applied a stepwise forward selection procedure to build a multiple regression model predicting estimated glomerular filtration rate (eGFR) at 1 year after transplant using baseline clinical characteristics and gene expression levels. DD grafts displayed a pattern of gene expression remarkably different from LD, including an increased expression of complement protein C3, and chemokines, CXCL1 and CXCL2, consistent with the proinflammatory setting of ischaemia-reperfusion injury. There was no association between any of the reperfusion biopsy histological features and either renal function at 1 year post-transplant or risk of acute rejection. Conversely, older donor age (R(2) = 0.17, P < 0.001) and higher integrin β2 gene expression levels (incremental R(2) versus Donor Age-only model = 0.23, P < 0.001) jointly predicted lower eGFR at 1 year after transplant (multiple regression R(2) = 0.40). Patients with higher ITGβ2 expression levels in baseline biopsies showed lower eGFR, higher levels of proteinuria and more transplant glomerulopathy on the 1-year per-protocol biopsies. ITGβ2 gene expression in reperfusion biopsies may represent a prognostic marker for kidney transplant recipients, potentially helpful in shaping patients' treatment. Further studies are needed to confirm our findings.

The predictive value of HGPIN and ASAP for the subsequent diagnosis of prostate cancer in the Reduction by Dutasteride of Cancer Events (REDUCE) study.

4561 Background: REDUCE was a 4-year, randomized placebo (pbo) controlled study of prostate cancer (PCa) risk reduction with once daily dutasteride 0.5 mg (dut). This analysis examines the effect of dut on initial detection of high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP) and the incidence of PCa on subsequent biopsy. Methods: Eligible men were aged 50–75 years, had a serum PSA 2.5–10.0 ng/ml, and a single, negative (no PCa, HGPIN or ASAP) biopsy of 6–12 cores in the 6 months prior to enrollment (4126 subjects randomized to pbo, 4105 dut). Ten-core prostate biopsies were taken at 2 and 4 years and examined for evidence of PCa. For subjects with 2-year biopsies and no PCa (2866 pbo, 2867 dut), the initial incidence of ASAP, HGPIN (without ASAP), and ASAP or HGPIN was compared between treatment groups using Fisher's exact test. PCa incidence in a subsequent biopsy was also compared between treatment groups with Fisher's exact test. Results: PCa incidence in subjects biopsied was 17.2% (pbo) and 13.4% (dut) in Years 1–2; and 11.8% (pbo) and 9.1% (dut) in Years 3–4. Dut was associated with a lower incidence of ASAP and/or HGPIN (p≤0.007; Table). For subjects with ASAP and/or HGPIN in initial study biopsy who had a subsequent biopsy (median time between biopsies 2 years), the incidence of PCa was higher vs. overall PCa incidence during Years 3–4. If a man was diagnosed with HGPIN or ASAP while taking dut, the likelihood of a future PCa diagnosis was similar to that of the pbo group. Conclusions: HGPIN and ASAP conferred a 2- and 3-fold increased risk of subsequent PCa, respectively compared to the overall rates for PCa in Years 3–4. Dut significantly reduced the incidence of HGPIN and/or ASAP with no significant differences vs. pbo observed in the risk of subsequent PCa. Incidence Pbo Dut p value ASAP 1st dx ASAP 206/2,866 (7.2%) 156/2,867 (5.4%) 0.007 Subsequent PCa 39/116 (33.6%) 29/95 (30.5%) 0.66 HGPIN and no ASAP 1st dx HGPIN 243/2,866 (8.5%) 143/2,867 (5.0%) <0.0001 Subsequent PCa 23/109 (21.1%) 12/63 (19.0%) 0.85 ASAP and/or HGPIN 1st dx ASAP/HGPIN 434/2,866 (15.1%) 288/2,867 (10.0%) <0.0001 Subsequent PCa 61/221 (27.6%) 40/153 (26.1%) 0.81 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Bostwick Laboratories, Ferring Pharmaceutical, GlaxoSmithKline Astellas Pharma, GlaxoSmithKline, Orion Pharma Bostwick Laboratories, GlaxoSmithKline Astellas Pharma, Ferring Pharmaceutical, GlaxoSmithKline, Orion Pharma GlaxoSmithKline GlaxoSmithKline

Short‐term outcomes of the prospective multicentre ‘Prostate Cancer Research International: Active Surveillance’ study

To evaluate the short-term outcomes of the prospective international Prostate Cancer Research International: Active Surveillance ('PRIAS') study (Dutch Trial Register NTR1718), as active surveillance (AS) for early prostate cancer might provide a partial solution to the current overtreatment dilemma in this disease. The first 500 (of >950) participants with asymptomatic T1c/T2 prostate cancer, with a prostate-specific antigen (PSA) level of < or =10.0 ng/mL, a PSA density of <0.2 ng/mL/mL, a Gleason score of < or =3 + 3 = 6, and one or two positive biopsy cores, were analysed. The follow-up protocol consisted of frequent PSA measurements, digital rectal examinations, and standard repeat biopsies (the first after 1 year). The primary outcome is survival free of active therapy; the secondary endpoints are reasons for stopping AS, findings in 1-year repeat biopsies, and outcomes after radical prostatectomy (RP). Patients were included between December 2006 and July 2008. The median (25-75th percentile) follow-up after diagnosis was 1.02 (0.6-1.5) years. The 2-year survival rate free from active therapy was 73%. Of the 82 men who changed to active therapy during the follow-up, 68 (83%) did so based on the protocol. Of the 261 repeat biopsies available for analysis, 90 (34%) showed no cancer, while 57 (22%) showed a Gleason score of >6 or more than two positive biopsy cores. There was a relatively unfavourable PSA doubling time of 0-10 years in 53% (102/194) and 62% (33/53) of men with favourable and unfavourable re-biopsy results, respectively. After RP, four of 24 (17%) men had T3 disease and 12 (50%) had a Gleason score of >6. AS seems feasible, but mortality outcomes are unknown. A strict follow-up protocol including standard 1-year repeat biopsies resulted in a quarter of men stopping AS after 2 years.

Impact of Subclinical Inflammation on the Development of Interstitial Fibrosis and Tubular Atrophy in Kidney Transplant Recipients

Our aim was to study the impact of subclinical inflammation on the development of interstitial fibrosis and tubular atrophy (IF/TA) on a 1-year protocol biopsy in patients on rapid steroid withdrawal (RSW). A total of 256 patients were classified based on protocol biopsy findings at months 1 or 4. Group 1 is 172 patients with no inflammation, group 2 is 50 patients with subclinical inflammation (SCI), group 3 is 19 patients with subclinical acute rejection (SAR) and group 4 is 15 patients with clinical acute rejection (CAR). On the 1-year biopsy, more patients in group 2 (SCI) (34%, p = 0.004) and group 3 (SAR) (53%, p = 0.0002), had an IF/TA score > 2 compared to group 1 (control) (15%). IF/TA was not increased in group 4 (CAR) (20%). The percent with IF/TA score > 2 and interstitial inflammation (Banff i score > 0) was higher in group 2 (16%, p = 0.004) and group 3 (37%, p < 0.0001) compared to group 1 (3%). In a multivariate analysis, patients in groups 2 or 3 had a higher risk of IF/TA score > 2 on the 1-year biopsy (OR 6.62, 95% CI 2.68-16.3). We conclude that SCI and SAR increase the risk of developing IF/TA in patient on RSW.

Interstitial Fibrosis Quantification in Renal Transplant Recipients Randomized to Continue Cyclosporine or Convert to Sirolimus

Conversion from cyclosporine (CsA) to sirolimus at week 12 after kidney transplantation is associated with a significant improvement in renal function. The aim of this analysis was to investigate the effect of this conversion on interstitial fibrosis (IF), a hallmark of chronic allograft injury, in patients taking part in the CONCEPT trial. This multicenter, prospective, trial included 193 renal recipients randomized at week 12 to switch from CsA to sirolimus or to continue CsA, with mycophenolate mofetil. Routine biopsy with automated, quantified assessment of IF by a program of color segmentation was performed at 1 year in 121 patients. At 1 year, renal function was significantly improved in the conversion group as assessed by estimated GFR (MDRD) and measured GFR. Biopsy results, however, showed no between-group difference in percentage of IF. Calculated GFR at 1 year was significantly associated with the percentage of IF (p = 0.004, R(2)= 0.07). By multivariate analysis diabetic patients had more fibrosis than non-diabetic patients. In conclusion, although kidney transplant patients converted from CsA to sirolimus showed significant improvement in renal function, we found no difference of IF on 1-year biopsies.

A Pilot Study Using Simvastatin in the Treatment of Nonalcoholic Steatohepatitis

This study was designed to assess the utility of statin therapy in patients with biopsy proven nonalcoholic steatohepatitis (NASH) and hyperlipidemia. Nonalcoholic fatty liver disease, as the hepatic manifestation of the metabolic syndrome, has become a growing public health concern. Nonalcoholic steatohepatitis (NASH) represents a subset of nonalcoholic fatty liver disease manifested by hepatic fatty infiltration and inflammation which may progress to cirrhosis and its subsequent complications, to include hepatocellular carcinoma. As the metabolic syndrome is thought to be central in the pathogenesis of NASH, it has been speculated that medications that improve metabolic profiles may be beneficial in treatment. In fact, recent studies have demonstrated potential benefit of 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), which are used in clinical practice to improve lipid panels. This double-blinded randomized placebo-controlled trial compared the HMG-CoA reductase inhibitor, simvastatin, with placebo in the treatment of NASH over a 12-month period using serum aminotransferases and repeat liver biopsy to assess for improvement. Sixteen patients with biopsy proven NASH were enrolled: 14 completed the study and 10 underwent 1-year repeat liver biopsy. Mean age: 53 years (+/-10.1), mean body mass index: 32.4 (+/-6.1) with 11 male and 5 female patients. Although a 26% reduction in low-density lipoprotein was seen in the simvastatin group compared with placebo, there was no statistically significant improvement in serum aminotransferases, hepatic steatosis, necroinflammatory activity or stage of fibrosis within or between groups. In this pilot trial, monotherapy with simvastatin does not seem to be an effective treatment for NASH.

Early and Limited Use of Tacrolimus to Avoid Rejection in an Alemtuzumab and Sirolimus Regimen for Kidney Transplantation: Clinical Results and Immune Monitoring

Alemtuzumab induction with 60 days of tacrolimus treatment and continuous sirolimus treatment prevented acute rejection in nine of 10 consecutive renal allograft recipients. All patients are alive with a functioning kidney graft at 27-39 months of follow-up. Extensive immune monitoring was performed in all patients. Alloantibody detection, cytokine kinetics assay (CKA), and trans vivo delayed-type hypersensitivity (DTH) assay were performed every 6 months showing correlation with clinical evolution. Despite alloantibody presence in five patients, eight patients remain without the need for specific treatment and only sirolimus monotherapy in decreasing dosage. Four patients take only 1 mg sirolimus daily with levels of 3-4 ng/mL. One patient showed clinical signs of rejection at month 9 post-transplant, with slow increase in serum creatinine and histological signs of mixed cellular (endarteritis) and humoral rejection (C4d positivity in peritubular capillaries and donor-specific antibody (DSA)). In summary, the addition of tacrolimus therapy for 2 months to a steroid-free, alemtuzumab induction and sirolimus maintenance protocol limited the previously shown acute rejection development. Nevertheless, alloantibody was present in serum and/or C4d present on 1-year biopsy in half the patients. The combination of CKA and DSA monitoring or the performance of transvivo DTH correlated with immune status of the patients.

An Eight-Year Experience of HDR Brachytherapy Boost for Localized Prostate Cancer: Biopsy and PSA Outcome

To evaluate the biochemical recurrence-free survival (bRFS), the 2-year biopsy outcome and the prostate-specific antigen (PSA) bounce in patients with localized prostate cancer treated with an inversely planned high-dose-rate (HDR) brachytherapy boost. Data were collected from 153 patients treated between 1999 and 2006 with external beam pelvic radiation followed by an HDR Ir-192 prostate boost. These patients were given a boost of 18 to 20 Gy using inverse-planning with simulated annealing (IPSA).We reviewed and analyzed all prostate-specific antigen levels and control biopsies. The median follow-up was 44 months (18-95 months). When categorized by risk of progression, 74.5% of patients presented an intermediate risk and 14.4% a high one. Prostate biopsies at 2 years posttreatment were negative in 86 of 94 patients (91.5%), whereas two biopsies were inconclusive. Biochemical control at 60 months was at 96% according to the American Society for Therapeutic Radiology and Oncology and the Phoenix consensus definitions. A PSA bounce (PSA values of 2 ng/mL or more above nadir) was observed in 15 patients of 123 (9.8%). The median time to bounce was 15.2 months (interquartile range, 11.0-17.7) and the median bounce duration 18.7 months (interquartile range, 12.1-29). The estimate of overall survival at 60 months was 97.1% (95% CI, 91.6-103%). Considering that inverse planned HDR brachytherapy prostate boosts led to an excellent biochemical response, with a 2-year negative biopsy rate, we recommend a conservative approach in face of a PSA bounce even though it was observed in 10% of patients.

Kidney Transplant Histology After One Year of Continuous Therapy With Sirolimus Compared With Tacrolimus

Analysis of 1-year surveillance biopsies was carried out for kidney transplant recipients participating in a randomized trial comparing tacrolimus- and sirolimus-based immunosuppression. The analysis was restricted to recipients remaining on assigned regimen throughout the first posttransplant year. Biopsies from 57 of 84 (68%) tacrolimus-randomized recipients were compared with 38 of 81 (47%) of sirolimus-randomized recipients, the discrepancy being explained by a higher rate of sirolimus discontinuation for non-graft-related complications. Included recipients from the two groups did not differ for baseline characteristics or 1-year iothalamate clearance. Histologic analysis indicated no differences between the groups for glomerular, arterial/arteriolar, or acute interstitial abnormalities. There were, however, significantly higher mean scores in the tacrolimus group for interstitial fibrosis and tubular atrophy with a trend toward higher estimated percent interstitial fibrosis. The results indicate that sirolimus may be associated with reduced early graft fibrosis compared with tacrolimus. This potential benefit is offset by lower success rate in maintaining the regimen and was not accompanied by superior glomerular filtration rate at 1 year.

Molecular Evidence of Injury and Inflammation in Normal and Fibrotic Renal Allografts One Year Posttransplant

Factors contributing to kidney transplant fibrosis remain incompletely understood, particularly in the absence of acute complications. Baseline and 1-year surveillance biopsies from 15 uncomplicated living donor kidney transplants were subjected to microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses to examine changes in gene expression patterns over time. Biopsy pairs were purposefully selected from allografts with no history of acute complications and were divided into those that were histologically normal (n=7) and those that had developed subclinical interstitial fibrosis (n=8) at 1 year. Compared with the paired baseline specimens, expression levels of 3578 probesets were found altered in all the 1-year biopsies studied. A large proportion of the up-regulated genes in this transplant-associated profile were functionally linked with inflammation, immunity, or response to injury. These included components of inflammation-related signaling pathways (integrin, interferon, and Toll-like receptor) as well as individual mediators of inflammatory and immune responses. An additional 2884 probesets demonstrated altered expression in fibrotic grafts only at 1 year. The gene products in this fibrosis-associated profile also were predominantly linked with inflammation and immune function, suggesting exaggerated inflammatory activity within the fibrotic grafts. qRT-PCR analyses confirmed the predicted expression patterns for selected transcripts from the microarray profiles. Transcriptional profiles of histologically normal living donor renal allografts indicate that there is ongoing injury response and inflammation at 1 year compared to the immediate posttransplant period. Subclinical development of interstitial fibrosis during the first posttransplant year is associated with additional up-regulation of inflammation-related genes.

Patterns of Local Failure Following Prostate Brachytherapy

We describe biopsy results in patients with prostate cancer treated with brachytherapy. A total of 1,562 men with localized prostate cancer were treated with permanent prostate brachytherapy, of whom 508 agreed to ultrasound guided biopsies 2 years after the completion of all therapy. Median followup was 6.7 years (range 2 to 14.6) and median prostate specific antigen was 7.4 ng/ml (range 0.3 to 300). Disease was categorized as Gleason score less than 7 in 74.8% of patients, stage T2a or less in 64.2%, low risk in 43.1%, intermediate risk in 24.2% and high risk in 32.7%. Of the 508 men 315 (62%) received (125)I, 110 (21.7%) received (103)Pd and 83 (16.3%) received (103)Pd and external beam radiotherapy. A total of 237 men (46.7%) received a short course of hormonal therapy (3 to 9 months). Subsequent biopsies were performed after 2 years if initial biopsy was positive or prostate specific antigen increased. Post-implantation dosimetry results were grouped into low, normal and high dose. Associations were tested by chi-square analysis. Survival functions were calculated with Kaplan-Meier analysis and Cox regression. A total of 643 biopsies were performed in 508 men between 2 and 11 years after implantation. Of the 508 men 39 (7.7%) had a final positive biopsy. Positive biopsy was associated with high prostate specific antigen (p=0.035), stage (p=0.003), risk (p=0.024), no hormonal therapy (p=0.002) and low dose (p<0.0001). On multivariate analysis only dose and hormonal therapy were significant (p<0.0001 and p=0.004, respectively). Of the patients 80% were free of PSA failure at 10 years if final biopsy was negative compared to 27.3% with a positive biopsy (p<0.0001). Death from prostate cancer was associated with a positive biopsy (OR 18.5, 95% CI 2.3-143, p<0.0001). Of the 52 men with a positive biopsy at year 2, 23 (44.2%) had negative results on subsequent biopsy, while 10 of the 456 (2.2%) with negative 2-year biopsies showed positive results. Positive biopsy occurred in the prostate only in 31 of 39 men (79.5%), in the prostate and seminal vesicles in 3 (7.7%), and in the seminal vesicles only in 5 (12.8%). Patients undergoing prostate brachytherapy must receive an adequate radiation dose to eradicate local disease. Hormonal therapy may benefit local control in patients with intermediate to high risk disease. Extraprostatic biopsies should be performed in patients with local failure who are considering salvage therapy to rule out seminal vesicle involvement.

The predictive value of 2-year posttreatment biopsy after prostate cancer radiotherapy for eventual biochemical outcome

To determine the value of a 2-year post-radiotherapy (RT) prostate biopsy for predicting eventual biochemical failure in patients who were treated for localized prostate cancer. This study comprised 164 patients who underwent a planned 2-year post-RT prostate biopsy. The independent prognostic value of the biopsy results for forecasting eventual biochemical outcome and overall survival was tested with other factors (the Gleason score, 1992 American Joint Committee on Cancer tumor stage, pretreatment prostate-specific antigen level, risk group, and RT dose) in a multivariate analysis. The current nadir + 2 (CN + 2) definition of biochemical failure was used. Patients with rising prostate-specific antigen (PSA) or suspicious digital rectal examination before the biopsy were excluded. The biopsy results were normal in 78 patients, scant atypical and malignant cells in 30, carcinoma with treatment effect in 43, and carcinoma without treatment effect in 13. Using the CN + 2 definition, we found a significant association between biopsy results and eventual biochemical failure. We also found that the biopsy status provides predictive information independent of the PSA status at the time of biopsy. A 2-year post-RT prostate biopsy may be useful for forecasting CN + 2 biochemical failure. Posttreatment prostate biopsy may be useful for identifying patients for aggressive salvage therapy.

Recurrence of light chain deposit disease after renal allograft transplantation: potential role of rituximab?

Light chain deposit disease (LCDD) is a monoclonal plasma cell disorder characterized by tissue deposition of nonamyloid immunoglobulin light chains, predominantly kappa chains, causing renal insufficiency. LCDD reoccurs almost invariably after renal grafting, leading to early graft loss, usually within a time span of months to years. We describe a female patient with LCDD who lost her first living donor graft after 1 year due to extensive recurrence of kappa chain deposition. Rituximab was administered on the seventh day after her second transplantation with a graft from a deceased donor, in order to prevent early recurrence of LCDD. The 2-year protocol biopsy - similarly to the completely normal 1-year protocol biopsy - revealed persistent absence of light chain deposition on light microscopy but immunohistochemical staining and electron microscopy showed very mild recurrence of light chain deposits. A second 4-week course of rituximab was repeated because of these electron microscopic findings. Subsequently, free kappa light chain concentration decreased from 693 to 74 mg/l and remained low 4 months after completion of therapy. Rituximab could be considered for delaying early LCDD recurrence in patients in whom treatment of the underlying bone marrow disorder failed or is contraindicated, but maintenance therapy is apparently necessary to consolidate this response.

Values and limitations of serum aminotransferases in clinical trials of nonalcoholic steatohepatitis

Choosing endpoints in nonalcoholic steatohepatitis (NASH) trials is challenging because of the lack of validated surrogates and the trade-off between accuracy and invasiveness. In this study, we assessed diagnostic accuracy of serum aminotransferase changes in predicting histological changes in NASH trials. We conducted a longitudinal cohort study by using 102 participants in ursodeoxycholic acid-NASH trial who had both baseline and 2-year liver biopsy and multiple measurements of serum aminotransferases. We calculated rates of alanine aminotransferase (ALT) [or aspartate aminotransferase (AST)] change as slopes of linear regression over 2 years (IU/l/month) and changes in each histological feature as differences in Brunt's scores of two biopsies in each individual. Rate of aminotransferase change correlated with changes in inflammation and fibrosis, but not steatosis and only with change in inflammation in multivariable analysis. In each histological feature, changes were inversely correlated with baseline histological grade. In predicting improvement of inflammation, areas under the receiver-operating characteristic curve of aminotransferase information alone were 0.72 for ALT and 0.73 for AST and were improved to 0.88 and 0.89, respectively, when baseline histology were taking account of. Serum aminotransferase changes could be useful as surrogates in screening therapies for NASH in clinical trials with appropriate consideration of baseline aminotransferase and histology.