History of proliferative glomerulonephritis predicts end stage kidney disease in pure membranous lupus nephritis.

OBJECTIVES: Pure membranous (class V) LN is considered a less aggressive phenotype, but tissue fibrosis and chronic kidney disease may still develop. This study aimed to elucidate the prognostic value of a history of class switch in pure membranous LN. METHODS: We included LN patients with at least two clinically indicated kidney biopsies. New onset of end stage kidney disease (ESKD) was defined as estimated glomerular filtration rate <15 ml/min/1.73 m2, initiation of dialysis or kidney transplantation. RESULTS: Among 220 patients (542 biopsies), 199 (90%) were female, and 118 (54%) were African American, 59 (27%) Caucasian, with median age of 28 years at the first kidney biopsy. Patients with pure class V in a first biopsy converted to proliferative LN in 41% of cases. Pure class V in a repeat biopsy was preceded by proliferative LN in 52%. Trajectory analysis of up to four repeat biopsies revealed that ISN class switch may happen at any time, even after multiple biopsies with the same class. New onset ESKD was observed within 2 years in 5/56 (9%) patients with pure class V in a repeat biopsy. All five patients had proliferative LN in the first biopsy (log rank P = 0.024). CONCLUSIONS: The conversion from proliferative to membranous (and vice-versa) is frequent in SLE. It can occur at any time in the course of disease, limiting the prognostic value of the first biopsy. Evidence of prior proliferative LN is key as it is associated with higher risk of ESKD in non-proliferative LN.

Negative first follow-up prostate biopsy on active surveillance is associated with decreased risk of upgrading, suspicion of progression and converting to active treatment.

OBJECTIVE: To determine the risk of disease progression and conversion to active treatment following a negative biopsy while on active surveillance (AS) for prostate cancer (PCa). PATIENTS AND METHODS: Men on an AS programme at a single tertiary hospital (London, UK) between 2003 and 2018 with confirmed low-intermediate-risk PCa, Gleason Grade Group <3, clinical stage 30% positive cores, magnetic resonance imaging (MRI) Likert score >3/T3 or PSA level of >20 ng/mL. Conversion to treatment included radical or hormonal treatment. RESULTS: Among the 460 eligible patients, 23% had negative follow-up biopsy findings. The median follow-up was 62 months, with one to two repeat biopsies and two MRIs per patient during that period. Negative biopsy findings at first repeat biopsy were associated with decreased risk of converting to active treatment (hazard ration [HR] 0.18, 95% confidence interval [CI] 0.09-0.37; P < 0.001), suspicion of disease progression (HR 0.56, 95% CI: 0.34-0.94; P = 0.029), and upgrading (HR 0.48, 95% CI 0.23-0.99; P = 0.047). Data are limited by fewer men with multiple follow-up biopsies. CONCLUSION: A negative biopsy finding at the first scheduled follow-up biopsy among men on AS for PCa was strongly associated with decreased risk of subsequent upgrading, clinical or radiological suspicion of disease progression, and conversion to active treatment. A less intense surveillance protocol should be considered for this cohort of patients.

Correlation between the clinical remission and histological remission in repeat biopsy findings of quiescent proliferative lupus nephritis.

BACKGROUND: The optimal duration of maintenance therapy is controversial in proliferative lupus nephritis (LN). Discordance between clinical parameters of renal remission and histological findings has made repeat biopsy a compulsory tool to confirm the histological remission (HR), but the timing is debatable. Aim of this study was to find the correlation of sustained complete clinical remission (CR) in sever lupus nephritis with histological findings on repeat kidney biopsy and appropriate duration of treatment in maintenance phase after achieving complete clinical remission. METHODS: Repeated kidney biopsy (biopsy 2) was performed on patients of biopsy proven (biopsy 1) proliferative LN who had been in CR for at least 2-years. The clinical and histologic findings of these groups (biopsy 1 and biopsy 2) were compared. Total 29 patients were included for the final analysis. Group 2 was further divided as per the duration of sustained CR (>48 months & <48 months). Regression analysis were used to find predictors of the HR. RESULTS: Average time taken to achieve CR was 9(range 2-24) months. Average duration of follow up and maintenance therapy was 68 ± 17.8 and 62.5 ± 14.2 months respectively. In the repeat kidney biopsy, HR was observed in 93.1% patients. Immunofluorescence study (IF) was normal in 72% of the patients. Normal light microscopy (LM) findings were observed in 58% patients. Transformation from proliferative to nonproliferative LN was noted in 82% cases. Other than the duration of CR on maintenance therapy and blood pressure, rest of the variables failed to predict HR. In sustained remission for more than 48-months group, 100% patients achieved HR whereas only 84% in 24-48-months group. CONCLUSION: Sustained CR on maintenance immunosuppressive therapy for more than 48-months duration predicts HR in repeat kidney biopsy findings in quiescent proliferative LN. Hence the minimum duration of maintenance therapy in proliferative LN should be at least for another 48 months after achieving CR.

Per-protocol repeat kidney biopsy portends relapse and long-term outcome in incident cases of proliferative lupus nephritis.

OBJECTIVES: In patients with LN, clinical and histological responses to treatment have been shown to be discordant. We investigated whether per-protocol repeat kidney biopsies are predictive of LN relapses and long-term renal function impairment. METHODS: Forty-two patients with incident biopsy-proven active proliferative (class III/IV±V) LN from the database of the UCLouvain were included in this retrospective study. Per-protocol repeat biopsies were performed after a median [interquartile range (IQR)] time of 24.3 (21.3-26.2) months. The National Institutes of Health activity index (AI) and chronicity index (CI) scores were assessed in all biopsies. RESULTS: Despite a moderate correlation between urinary protein/creatinine ratios (UPCR) and AI scores at repeat biopsy (r = 0.48; P = 0.001), 10 patients (23.8%) with UPCR < 1.0 g/g still had a high degree of histological activity (AI > 3). High AI scores (continuous) in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (n = 11) following the repeat biopsy [hazard ratio (HR) = 1.2, 95% CI: 1.1, 1.3; P = 0.007], independently of proteinuria levels. High CI scores (continuous) in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR = 1.8, 95% CI: 1.1, 2.9; P = 0.016) through a median (IQR) follow-up time of 131.5 (73.8-178.2) months, being also the case for acute tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy in repeat but not baseline biopsies. CONCLUSION: Our results highlight the usefulness of per-protocol repeat biopsies, herein performed after a median time of 24 months from baseline, as an integral part of the treatment evaluation, also in patients showing adequate clinical response.

Repeat renal biopsy improves the Oxford classification-based prediction of immunoglobulin A nephropathy outcome.

BACKGROUND: The prognosis of IgA nephropathy (IgAN) is very heterogeneous. Predicting the nature and the rate of the disease progression is crucial for refining patient treatment. The aim of this study was to evaluate the prognostic impact of an Oxford classification-based repeat kidney tissue evaluation to predict end-stage renal disease (ESRD). METHODS: Patients with biopsy-proven primary IgAN who underwent two renal biopsies at our centre were analyzed retrospectively. Renal biopsies were scored by two pathologists blinded to the clinical data and according to the updated Oxford classification. Cox models were generated to evaluate the prognostic impact considering the Oxford classification elementary lesions from the first (Model 1) or the second (Model 2) biopsy, adjusted on clinical data at time of reevaluation. The prognostic impacts of the dynamic evolution of each elementary lesion between biopsies were also assessed through univariate and multivariate evaluation. RESULTS: A total of 168 adult patients were included, with a median follow-up duration of 18 (range 11-24) years. The second biopsy was performed either systematically (n = 112) of for-cause (n = 56), after a median time of 5.4 years. The prognostic performances of Model 2 (second biopsy) were significantly better than Model 1 (first biopsy, analysis of deviance P < 0.0001). The dynamic changes of C and T lesions were significantly associated with the progression toward ESRD after adjustment on variables from Model 2. CONCLUSION: Both static and dynamic Oxford-based histological evaluation offered by a repeat biopsy improves the prediction of ESRD in patients with IgAN.

Additive Value of Transrectal Systematic Ventral Biopsies in Combination with Magnet Resonance Imaging/Ultrasound Fusion-Guided Biopsy in Patients with 3 or More Negative Prostate Biopsies.

INTRODUCTION: Patients with consistent suspicion for prostate cancer (PCa) and multiple negative prebiopsies prior to multiparametric magnetic resonance imaging (mpMRI) are still frequently evaluated for an image-guided biopsy and are reported with heterogeneous detection rates. The inclusion of a systematic biopsy (SB) is also still recommended with predominant sampling within the posterior/peripheral zone of the prostate. The aim of this study was (I) to evaluate PCa detection rates using a modified 10 core SB template including anterior biopsies in combination with mpMRI/ultrasound fusion-guided targeted biopsy (TB) in patients with 3 or more negative prebiopsies and (II) to compare mpMRI index lesion localization with histologically confirmed locali-zation from associated prostatectomy samples. METHODS: Overall 1,337 consecutive patients underwent sensor-based registration TB of the prostate and a subsequent 10-core SB between January 2012 and December 2015 at our institution. For this study, 101 patients with ≥3 negative prebiopsies and prostate imaging - reporting data system lesions ≥3 were pooled prospectively and underwent TB and a modified SB including 2 ventral (anterior) biopsies. Detection rates were estimated for the modified SB, TB, and its combination. A subgroup analysis of 35 patients undergoing prostatectomy was performed by a head-to-head comparison of mpMRI index lesion and histologically confirmed PCa index lesion localization. RESULTS: The overall detection rate for PCa was 54.5%. The combination of TB and SB detected 14 (25.4%) more cases missed by TB alone (p < 0.001) and 7 (12.7%) more cases missed by SB alone (p = 0.016), respectively. A postoperative Gleason upgrade was seen in 12/35 (34.3%) cases within the TB group and in 14/35 (40.0%) in the SB group, respectively. The subgroup analysis showed a predominant location of PCa index lesions anteriorly at the level of the midgland. The MRI detection rate of the anteriorly located index lesions was 70.4% (15/21 cases) with a clinically significant Gleason score (≥3 + 4 = 7a [International Society of Urological Pathology grade 2]) in 80.9%. Interestingly a modified SB template detected 90.5% (19/21) of the anteriorly located index lesions. CONCLUSION: Our data suggest that in patients with multiple prebiopsies PCa seems to be predominantly located anteriorly. We suggest the general integration of anterior biopsies despite TB in repeat biopsy patients.

Low-risk prostate cancer selected for active surveillance with negative MRI at entry: can repeat biopsies at 1 year be avoided? A pilot study.

PURPOSE: In patients considered for active surveillance (AS), the use of MRI and targeted biopsies (TB) at entry challenges the approach of routine "per protocol" repeat systematic biopsies (SB) at 1 year. This pilot study aimed to assess whether an approach of performing repeat biopsies only if PSA kinetics are abnormal would be safe and sufficient to detect progression. METHODS: Prospective single-centre study of 149 patients on AS with low-risk PCa, a negative MRI at entry, followed for a minimum of 12 months between 01/2007 and 12/2015. Group 1 (n = 78) patients had per-protocol 12-month repeat SB; group 2 (n = 71) patients did not. Surveillance tests for tumour progression were for both groups: for cause SB and MRI-TB biopsies if PSA velocity (PSA-V) > 0.75 ng/ml/year, or PSA doubling time (PSADT) < 3 years. The main objectives are to compare the 2-year rates of tumour progression and AS discontinuation between groups. The secondary objectives are to estimate the diagnostic power of PSA-V and PSA-DT, to predict the risk of tumour progression. RESULTS: Overall, 21 out of 149 patients (14.1%) showed tumour progression, 17.1% for group 1 and 12.3% for group 2, and 31 (21.2%) discontinued AS at 2 years. There was no difference between the 2 groups (p = 0.56). The area under the PSA-V and PSADT curves to predict tumour progression was 0.92 and 0.83, respectively. CONCLUSIONS: We did not find any significant difference for progression and AS discontinuation rate between the 2 groups. The PSA kinetic seems accurate as a marker of tumour progression. These results support the conduct of a multi-centre prospective trial to confirm these findings.

Does the introduction of prostate multiparametric magnetic resonance imaging into the active surveillance protocol for localized prostate cancer improve patient re-classification?

OBJECTIVES: To determine whether replacement of protocol-driven repeat prostate biopsy (PB) with multiparametric magnetic resonance imaging (mpMRI) ± repeat targeted prostate biopsy (TB) when evaluating men on active surveillance (AS) for low-volume, low- to intermediate-risk prostate cancer (PCa) altered the likelihood of or time to treatment, or reduced the number of repeat biopsies required to trigger treatment. PATIENTS AND METHODS: A total of 445 patients underwent AS in the period 2010-2016 at our institution, with a median (interquartile range [IQR]) follow-up of 2.4 (1.2-3.7) years. Up to 2014, patients followed a 'pre-2014' AS protocol, which incorporated PB, and subsequently, according to the 2014 National Institute for Health and Care Excellence (NICE) guidelines, patients followed a '2014-present' AS protocol that included mpMRI. We identified four groups of patients within the cohort: 'no mpMRI and no PB'; 'PB alone'; 'mpMRI ± TB'; and 'PB and mpMRI ± TB'. Kaplan-Meier plots and log-rank tests were used to compare groups. RESULTS: Of 445 patients, 132 (30%) discontinued AS and underwent treatment intervention, with a median (IQR) time to treatment of 1.55 (0.71-2.4) years. The commonest trigger for treatment was PCa upgrading after mpMRI and TB (43/132 patients, 29%). No significant difference was observed in the time at which patients receiving a PB alone or receiving mpMRI ± TB discontinued AS to undergo treatment (median 1.9 vs 1.33 years; P = 0.747). Considering only those patients who underwent repeat biopsy, a greater proportion of patients receiving TB after mpMRI discontinued AS compared with those receiving PB alone (29/66 [44%] vs 32/87 [37%]; P = 0.003). On average, a single set of repeat biopsies was needed to trigger treatment regardless of whether this was a PB or TB. CONCLUSIONS: Replacing a systematic PB with mpMRI ±TB as part of an AS protocol increased the likelihood of re-classifying patients on AS and identifying men with clinically significant disease requiring treatment. mpMRI ±TB as part of AS thereby represents a significant advance in the oncological safety of the AS protocol.

Burned-out Prostate Cancer ? Primary Metastatic Cancer Not Detected on Repeat Biopsy.

Metastatic prostate cancer (PCa) cases that cannot be detected on repeat prostate biopsy are extremely rare. Our patient was a 51-year-old Japanese man diagnosed as metastatic PCa by histopathological examination of lesions obtained bone biopsy and lymph node dissection. The primary tumor was not detected after repeated prostate biopsy. Metastatic PCa was diagnosed based on immunohistochemical staining: PSA, AR, P504S, and NKX3.1 of bone and lymph node with metastasis. We speculate that the primary PCa was "burned-out," demonstrating remote metastases with no apparent primary tumor in the prostate. Burned-out PCa may be difficult to diagnose and treat due to its rarity.

[Development of a Chinese nomogram based on muti-parametric magnetic resonance for predicting the probability of prostate cancer in patients after initial negative biopsy].

Objective: To develop a predictive nomogram based on multi-parametric magnetic resonance imaging (mpMRI) information to identify men more likely to have a cancer diagnosed on repeat prostate biopsy. Methods: The clinical data of 237 patients who received repeat prostate biopsy after initial negative biopsy from Department of Urology of Peking University First Hospital between January 2001 and August 2016 was reviewed. Patient age, body mass index (BMI), serum total prostate-specific antigen (PSA), percent free PSA (f/t), prostate volume (PV), PSA density (PSAD), PSA velocity (PSAV), digital rectal examination (DRE), transrectal ultrasound (TRUS)and mpMRI results were included in the univariate and multivariate analysis. A nomogram was developed using selected variables and the area under the receiver operating characteristic (ROC) curve was calculated as a measure of discrimination. Results: A total of 76 patients (32.07%) had prostate cancer (PCa) detected on repeat biopsy. Based on univariate and multivariate logistic regression analysis, the patient age, PSA, PV, DRE and mpMRI results were independent predictors for the diagnosis of PCa on repeat biopsy. The current nomogram performed well (AUC=0.910) and showed excellent calibration. Conclusions: Multi-parametric magnetic resonance imaging combined with age, PSA, PV and DRE can predict the probability of PCa in patients with initial negative biopsy. The nomogram might help in decision-making for men with prior benign histology before the performance of repeat biopsy.

[Developing a Chinese PI-RADS v2-based nomogram for predicting clinically significant prostate cancer in patients with a prior negative biopsy].

Objective: To develop a nomogram based on prostate imaging reporting and data system version 2 (PI-RADS v2) to predict clinically significant prostate cancer in patients with a prior negative prostate biopsy. Methods: The clinical and pathological data of 231 patients who underwent repeat prostate biopsy and multiparametric MRI (mpMRI) were reviewed. Based on PI-RADS v2, the mpMRI results were assigned as PI-RADS grade from 0 to 2. A Logistic regression nomogram for predicting the probabilities of clinically significant prostate cancer were constructed. The performances of the nomogram were assessed using area under the receiver operating characteristic (ROC) curve, calibrations and decision curve analysis. Results: Of the total 231 repeat prostate biopsy patients, clinically significant prostate cancer was detected in 59 cases(25.5%). In multivariate Logistic regression analysis, age, prostate specific antigen (PSA), prostate volume (PV), digital rectal examination (DRE) and mpMRI results were significant independent predictors of the diagnosis of clinically significant prostate cancer (P<0.05). The nomogram with super predictive accuracy were constructed (AUC=0.927, P<0.001), and exhibited excellent calibration. Decision curve analysis also demonstrated a high net benefit across a wide range of threshold probabilities . Conclusions: PI-RADS v2 combined with age, PSA, PV and DRE can predict the probability of clinically significant prostate cancer in patients with negative initial biopsies. The nomogram generated may help the decision-making process in patients with prior benign histology before the performance of repeat biopsy.

JOURNAL CLUB: Utility of Repeat Core Needle Biopsy of Musculoskeletal Lesions With Initially Nondiagnostic Findings.

OBJECTIVE: The purpose of the present study is to assess the utility of repeat image-guided core needle biopsy (CNB) of musculoskeletal lesions in the setting of initially nondiagnostic CNB findings. MATERIALS AND METHODS: A retrospective review was conducted of 1302 consecutive CNBs performed on bone or soft-tissue lesions at a single institution. Pediatric cases and spine lesions were not included. All cases for which a repeat biopsy of the same lesion was performed because biopsy results were nondiagnostic were included in the study. Tumor characteristics, such as lesion size and type (i.e., bone vs soft tissue), were correlated with the diagnostic yield on repeat biopsy. Technical factors, including the modality used, the number of passes performed, the gauge of the biopsy device, the time between biopsies, the radiologist performing the procedure, and the portion of the lesion biopsied, were also correlated. RESULTS: Twenty-six of the 1302 CNBs (2.0%) performed had been referred for repeat biopsy. A diagnosis was obtained for 10 of these 26 cases (38.5%) after repeat CNB. For five of the cases (19.2%), repeat CNB yielded a diagnosis of malignancy. Overall, 11 cases ultimately had histologic findings indicating malignancy, and five of these cases (45.4%) had diagnostic findings after rebiopsy. Of the 14 cases that were found to be benign, five (35.7%) had diagnostic findings after rebiopsy. One case was lost to follow-up. A statistically significant difference in the diagnostic yield was found in association with an increase in the number of passes (p = 0.047) and an increase in time (p = 0.020) between biopsies. CONCLUSION: Repeat CNB of musculoskeletal lesions with initially nondiagnostic biopsy findings can be useful. Increasing the number of passes on the second biopsy attempt is recommended.

Assessment of free-hand transperineal targeted prostate biopsy using multiparametric magnetic resonance imaging-transrectal ultrasound fusion in Chinese men with prior negative biopsy and elevated prostate-specific antigen.

BACKGROUND: To evaluate the role of free-hand transperineal targeted prostate biopsy using multiparametric magnetic resonance imaging-transrectal ultrasound (mpMRI-TRUS) fusion in Chinese men with repeated biopsy. METHODS: A total of 101 consecutive patients suspicious of prostate cancer (PCa) at the mpMRI scan and with prior negative biopsy and elevated PSA values were prospectively recruited at two urological centers. Suspicious areas on mpMRI were defined and graded using PI-RADS score. Targeted biopsies (TB) were performed for each suspicious lesion and followed a 12-core systematic biopsy (SB). Results of biopsy pathology and whole-gland pathology at prostatectomy were analyzed and compared between TB and SB. The risk for biopsy positivity was assessed by univariate and multivariate logistic regression analysis. RESULTS: Fusion biopsy revealed PCa in 41 of 101 men (40.6%) and 25 (24.8%) were clinically significant. There was exact agreement between TB and SB in 74 (73.3%) men. TB diagnosed 36% more significant cancer than SB (22 vs 13 cases, P = 0.012). When TB were combined with SB, an additional 14 cases (34.1%) of mostly significant PCa (71.4%) were diagnosed (P = 0.036). TB had greater sensitivity and accuracy for significant cancer than SB in 26 men with whole-gland pathology after prostatectomy. PI-RADS score on mpMRI was the most powerful predictor of PCa and significant cancer. CONCLUSIONS: Free-hand transperineal TB guided with MRI-TRUS fusion imaging improves detection of clinical significant PCa in Chinese men with previously negative biopsy. PI-RADS score is a reliable predictor of PCa and significant cancer.

Prostate Biopsy in Active Surveillance Protocols: Immediate Re-biopsy and Timing of Subsequent Biopsies.

PURPOSE OF REVIEW: This manuscript reviews contemporary literature regarding prostate cancer active surveillance (AS) protocols as well as other tools that may guide the management of biopsy frequency and assess the possibility of progression in low-risk prostate cancer. RECENT FINDINGS: There is no consensus regarding the timing of surveillance biopsies; however, an immediate repeat biopsy within 12 months of diagnosis for patients considering AS confirms patients who have favorable risk disease yet also identifies patients who were undersampled initially. Studies regarding multiparametric MRI, nomograms, and biomarkers show promise in risk stratifying and counseling patients during AS. Further studies are needed to determine if these supplemental tests can decrease the frequency of surveillance biopsies. An immediate re-biopsy can help to reduce the risk of missing clinically significant disease. Other clinical tools, including mpMRI, exist that can be used as an adjunct to counsel patients and guide a personalized discussion regarding the frequency of surveillance biopsies.

Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies.

BACKGROUND: Prostate cancer (PCa) diagnosis is challenging because efforts for effective, timely treatment of men with significant cancer typically result in over-diagnosis and repeat biopsies. The presence or absence of epigenetic aberrations, more specifically DNA-methylation of GSTP1, RASSF1, and APC in histopathologically negative prostate core biopsies has resulted in an increased negative predictive value (NPV) of ∼90% and thus could lead to a reduction of unnecessary repeat biopsies. Here, it is investigated whether, in methylation-positive men, DNA-methylation intensities could help to identify those men harboring high-grade (Gleason score ≥7) PCa, resulting in an improved positive predictive value. METHODS: Two cohorts, consisting of men with histopathologically negative index biopsies, followed by a positive or negative repeat biopsy, were combined. EpiScore, a methylation intensity algorithm was developed in methylation-positive men, using area under the curve of the receiver operating characteristic as metric for performance. Next, a risk score was developed combining EpiScore with traditional clinical risk factors to further improve the identification of high-grade (Gleason Score ≥7) cancer. RESULTS: Compared to other risk factors, detection of DNA-methylation in histopathologically negative biopsies was the most significant and important predictor of high-grade cancer, resulting in a NPV of 96%. In methylation-positive men, EpiScore was significantly higher for those with high-grade cancer detected upon repeat biopsy, compared to those with either no or low-grade cancer. The risk score resulted in further improvement of patient risk stratification and was a significantly better predictor compared to currently used metrics as PSA and the prostate cancer prevention trial (PCPT) risk calculator (RC). A decision curve analysis indicated strong clinical utility for the risk score as decision-making tool for repeat biopsy. CONCLUSIONS: Low DNA-methylation levels in PCa-negative biopsies led to a NPV of 96% for high-grade cancer. The risk score, comprising DNA-methylation intensity and traditional clinical risk factors, improved the identification of men with high-grade cancer, with a maximum avoidance of unnecessary repeat biopsies. This risk score resulted in better patient risk stratification and significantly outperformed current risk prediction models such as PCPTRC and PSA. The risk score could help to identify patients with histopathologically negative biopsies harboring high-grade PCa. Prostate 76:1078-1087, 2016. © 2016 The Authors. The Prostate Published by Wiley Periodicals, Inc.

The evolution of morphological variants of focal segmental glomerulosclerosis: a repeat biopsy-based observation.

BACKGROUND: The Columbia classification employs a systematic, hierarchical approach to define five mutually exclusive variants. Studies have demonstrated differences in baseline clinical characteristics and outcomes among the Columbia classification variants. However, the evolution of the Columbia classification variants of primary focal segmental glomerulosclerosis (FSGS) is unclear. We assessed the evolution of morphological variants in FSGS based on repeat native renal biopsies. METHODS: Twenty-four patients (18 male, 6 female) with idiopathic FSGS who underwent more than one renal biopsy were enrolled in this study; three of these patients underwent three renal biopsies. The patients' clinicopathological features were reviewed. The subtypes of FSGS (2004 Columbia classification) included the collapsing, tip, cellular, perihilar and not otherwise specified (NOS) variants. The evolution of the Columbia classification variants of primary FSGS in each patient was evaluated. RESULTS: The interval between the first and second renal biopsy was 21.95 ± 24.33 months. No significant differences in laboratory data were noted between the first and second renal biopsy. At the first renal biopsy, 5 patients were classified with collapsing, 5 with tip, 6 with cellular, 2 with perihilar and 6 with NOS variants. At the second renal biopsy, 3 patients were classified with collapsing, 3 with tip lesion, 4 with cellular, 1 with perihilar and 13 with NOS variants. Subtype changes from the first to repeat biopsies occurred in 11 patients, 9 of which progressed from other variants to the NOS variant. CONCLUSION: Repeat renal biopsies are a useful tool for observing FSGS histological changes. The transformation from other subtypes to the NOS variant was the most common change; these alterations were accompanied by clinical progression.

Tubulointerstitial lesions in lupus nephritis: International multicentre study in a large cohort of patients with repeat biopsy.

BACKGROUND: The glomerulocentric International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification is the gold standard for the evaluation of lupus nephritis, while tubulointerstitial (TIN) parameters are often under-recognized in pathological reports. METHODS: Renal biopsies from 142 patients who underwent repeat biopsy (RB) were evaluated for the following histological parameters: (i) inflammatory interstitial infiltrates; (ii) interstitial fibrosis; (iii) tubulitis; and (iv) tubular atrophy. The inter-relationships between the four TIN variables were explored by multivariate analysis. A linear mixed model was used to investigate the potential impact of TIN variables on eGFR and proteinuria at the two biopsy occasions. RESULTS: The study showed that moderate-severe lesions were not so frequent at the reference biopsy, but more extensively represented upon RB. A strong association was found between the two inflammatory indices and between those related to chronic damage, while the relationship with the ISN/RPS classification was present at RB. If class IV-G was the most related with TIN (especially at RB), the existence of primary TIN in class II patients was also confirmed. Finally, our results support the hypothesis that tubulitis is an independent predictive factor for eGFR. CONCLUSIONS: We recommend that the standard histological evaluation of SLE nephritis also includes TIN features.

Urinary biomarkers for the detection of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia.

INTRODUCTION: High-grade prostatic intraepithelial neoplasia (HGPIN) is a recognized precursor stage of PCa. Men who present HGPIN in a first prostate biopsy face years of active surveillance including repeat biopsies. This study aimed to identify non-invasive prognostic biomarkers that differentiate early on between indolent HGPIN cases and those that will transform into actual PCa. METHODS: We measured the expression of 21 candidate mRNA biomarkers using quantitative PCR in urine sediment samples from a cohort of 90 patients with initial diagnosis of HGPIN and a posterior follow up of at least two years. Uni- and multivariate statistical analyses were applied to analyze the candidate biomarkers and multiplex models using combinations of these biomarkers. RESULTS: PSMA, PCA3, PSGR, GOLM, KLK3, CDH1, and SPINK1 behaved as predictors for PCa presence in repeat biopsies. Multiplex models outperformed (AUC = 0.81-0.86) the predictive power of single genes, including the FDA-approved PCA3 (AUC = 0.70). With a fixed sensitivity of 95%, the specificity of our multiplex models was of 41-58%, compared to the 30% of PCA3. The PPV of our models (30-38%) was also higher than the PPV of PCA3 (27%), suggesting that benign cases could be more accurately identified. Applying statistical models, we estimated that 33% to 47% of repeat biopsies could be prevented with a multiplex PCR model, representing an easy applicable and significant advantage over the current gold standard in urine sediment. DISCUSSION: Using multiplex RTqPCR-based models in urine sediment it is possible to improve the current diagnostic method of choice (PCA3) to differentiate between benign HGPIN and PCa cases.

Assessment of long-term outcomes associated with urinary prostate cancer antigen 3 and TMPRSS2:ERG gene fusion at repeat biopsy.

BACKGROUND: In men with clinically localized prostate cancer who have undergone at least 1 previous negative biopsy and have elevated serum prostate-specific antigen (PSA) levels, long-term health outcomes associated with the assessment of urinary prostate cancer antigen 3 (PCA3) and the transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) gene fusion (T2:ERG) have not been investigated previously in relation to the decision to recommend a repeat biopsy. METHODS: The authors performed a decision analysis using a decision tree for men with elevated PSA levels. The probability of cancer was estimated using the Prostate Cancer Prevention Trial Risk Calculator (version 2.0). The use of PSA alone was compared with the use of PCA3 and T2:ERG scores, with each evaluated independently, in combination with PSA to trigger a repeat biopsy. When PCA3 and T2:ERG score evaluations were used, predefined thresholds were established to determine whether the patient should undergo a repeat biopsy. Biopsy outcomes were defined as either positive (with a Gleason score of <7, 7, or >7) or negative. Probabilities and estimates of 10-year overall survival and 15-year cancer-specific survival were derived from previous studies and a literature review. Outcomes were defined as age-dependent and Gleason score-dependent 10-year overall and 15-year cancer-specific survival rates and the percentage of biopsies avoided. RESULTS: Incorporating the PCA3 score (biopsy threshold, 25; generated based on the urine PCA3 level normalized to the amount of PSA messenger RNA) or the T2:ERG score (biopsy threshold, 10; based on the urine T2:ERG level normalized to the amount of PSA messenger RNA) into the decision to recommend repeat biopsy would have avoided 55.4% or 64.7% of repeat biopsies for the base-case patient, respectively, and changes in the 10-year survival rate were only 0.93% or 1.41%, respectively. Multi-way sensitivity analyses suggested that these results were robust with respect to the model parameters. CONCLUSIONS: The use of PCA3 or T2:ERG testing for repeat biopsy decisions can substantially reduce the number of biopsies without significantly affecting 10-year survival.

The value of repeat biopsy in the management of lupus nephritis: an international multicentre study in a large cohort of patients.

BACKGROUND: The International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification represents the gold standard for the histological evaluation of Systemic Lupus Erythematosus (SLE) nephritis. A repeat biopsy (RB) might be an important tool to provide information on long-term renal outcomes and optimal therapy. Aims of this study were to evaluate the use of the ISN/RPS classification and the role of RB in routine clinical practice. METHODS: A total number of 142 patients with SLE nephritis and with adequate reference and RB samples were included in this multicentre retrospective study. A meticulous histological examination was centrally performed on first and RB and compared with clinical variables and follow-up data. RESULTS: Morphological features of the ISN/RPS classification: at first and RB, significant differences were observed between segmental classes (III, IV-S) and Class IV-G in mesangial proliferation, wire loops and tuft necrosis. Clinical features and ISN/RPS classification: the correlation between serum creatinine, proteinuria, blood pressure levels and histological classes at first and RB demonstrated more severe renal disease in Class IV-G, both at first and RB. Agreement between ISN/RPS classification at first and RB: 40.8% of patients changed the histological class. Fifty per cent of Class II (mild mesangial form) were reclassified as Class IV-G at RB, whereas 18.9% of Class IV-G were reclassified as Class II. The transition among segmental (III/IV-S) and mesangial forms (II/IV-G) was extremely rare. The comparison between the clinical parameters at the final follow-up and the ISN/RPS classification confirmed that the trend of serum creatinine and proteinuria between the different classes was better described at the RB (higher in Class IV-G) than on the first biopsy. CONCLUSIONS: The histopathological data suggest that morphological differences between segmental and global forms do exist, possibly due to different pathogenetic mechanisms. An RB strategy could provide additional information on long-term renal outcomes. A strategy of protocol biopsies could be useful in perspective future trials to better understand the therapeutic response and the natural history of this disease.