Glomerular planted antigens (histones, DNA, and C1q) are potential targets of autoimmunity in lupus nephritis (LN). However, the characterization of these antigens in human glomeruli in vivo remains ...inconsistent. We eluted glomerular autoantibodies recognizing planted antigens from laser-microdissected renal biopsy samples of 20 patients with LN. Prevalent antibody isotypes were defined, levels were determined, and glomerular colocalization was investigated. Renal and circulating antibodies were matched, and serum levels were compared in 104 patients with LN, 84 patients with SLE without LN, and 50 patients with rheumatoid arthritis (RA). Autoantibodies against podocyte antigens (anti-α-enolase/antiannexin AI) were also investigated. IgG2 autoantibodies against DNA, histones (H2A, H3, and H4), and C1q were detected in 50%, 55%, and 70% of biopsy samples, respectively. Anti-DNA IgG3 was the unique non-IgG2 anti-DNA deposit, and anti-C1q IgG4 was mainly detected in subepithelial membranous deposits. Anti-H3, anti-DNA, and anti-C1q IgG2 autoantibodies were also prevalent in LN serum, which also contained IgG3 against the antigen panel and anti-C1q IgG4. Serum and glomerular levels of autoantibodies were not strictly associated. High serum levels of all autoantibodies detected, including anti-α-enolase and antiannexin AI, identified LN versus SLE and RA. Anti-H3 and anti-α-enolase IgG2 levels had the most remarkable increase in LN serum and represented a discriminating feature of LN in principal component analysis. The highest levels of these two autoantibodies were also associated with proteinuria>3.5 g/24 hours and creatinine>1.2 mg/dl. Our findings suggest that timely autoantibody characterization might allow outcome prediction and targeted therapies for patients with nephritis.
The role of positive surgical margins (PSMs) on the recurrence of renal cell carcinoma (RCC) after partial nephrectomy (PN) is debated, and available evidence lacks long-term data. The aim of this ...study was to evaluate the predictive role of PSMs on progression-free survival (PFS) in a large cohort followed for at least 5 years.
This study was a retrospective analysis of a prospectively compiled single-institution database collecting complete information on more than 2700 patients who had undergone surgery for renal tumor. The data of all the patients submitted to PN for RCC and with least 5 years follow-up were extracted. Surgical specimens were examined at the time of surgery only by 2 expert uro-pathologists. A PSM was defined as the presence of cancer cells at the inked surface of the specimen. The role of PSMs on survival was estimated by Cox regression models adjusted for influent covariates.
A total of 459 patients fulfilled the inclusion criteria and were evaluated. PSMs were observed in 27 (5.9%) cases. No differences in preoperative and pathologic data were found comparing patients with and without PSMs. At a median follow-up of 96 months (interquartile range, 74-131 months), a clinically evident relapse of RCC was diagnosed in 36 (7.8%) patients at a median interval of 36 months from PN. Among these, 6 had a PSM for an incidence of relapse of 22.2% in the PSM group, whereas 30 had negative margins, for an incidence of 6.9% (P = .013). The sites of relapse were distant organs in 18 cases, and the kidney underwent PN in 21. The patients with PSMs showed a borderline significantly higher incidence of distant metastasis (11.1% vs. 3.5%; P = .071) and a significantly higher incidence of renal relapses (14.8% vs. 3.9%; P = .029). Multivariable Cox models confirmed that the presence of PSMs was an independent predictor of PFS (odds ratio, 3.127; P = .013).
PSMs are an independent predictor of PFS in patients who underwent PN for RCC, owing to a higher incidence of distant and local relapses. Surveillance in presence of PSMs should be intensified and extended for a long time.
The presence of positive surgical margins (PSMs) after partial nephrectomy has been associated with an increased risk of disease recurrence, but conclusive evidence is lacking. The aim of this study is to examine the prognostic role of PSMs in a large retrospective cohort with long-term follow-up. PSMs were associated with disease recurrence, both local and distant, and decreased progression-free survival. Patients with PSMs should undergo a more intense follow-up.
Clear cell renal cell carcinoma (ccRCC) shows variable chromosomal abnormalities. The aim of this study was to assess the prognostic role of ccRCC chromosomal abnormalities in a single-center cohort ...with an extended follow-up.
A systematic cytogenetic analysis was performed in 283 consecutive surgically-treated patients for renal masses between 1997 and 2002. Kaplan-Meier and multivariable Cox regression (MCR) models were used to calculate cancer specific survival (CSS).
Among 174 ccRCC patients, the most common abnormality was deletion in chromosome 3 (54.6%). At a median follow-up of 119 months, 38 patients (21.8%) died from RCC. At MCR models, worse CSS was independently predicted by deletions in chromosomes 2, 19, 20 or 22 and insertions in chromosome 18.
Specific ccRCC chromosomal abnormalities are independently associated with worse CSS. Cytogenetic evaluation may direct further genetic analysis for personalized prognostic stratification.
Objective To find out which factors could predict the diagnosis of insignificant prostate cancer (ins-PCa) according to a recently updated definition (overall tumor volume up to 2.5 cm3 ; final ...Gleason score ≤6; organ-confined disease) on a prostatic biopsy specimen. Methods This was a retrospective analysis of 210 patients undergoing radical prostatectomy for a cT1c prostate neoplasm with a biopsy specimen Gleason score of ≤6. A logistic regression model was used to assess the differences in the distribution of some possibly predictive factors between the ins-PCa patients, according to the updated definition, and the remaining patients. Results By applying an updated definition of ins-PCa, the prevalence of this condition increased from 13.3% to 49.5% (104 of 210 patients). The univariate analysis showed a statistically different distribution of the following factors: prostate-specific antigen density, prostate volume, number of cancer-involved cores, and maximum percentage of core involvement by cancer. At the multivariable analysis, the maximum percentage of involvement of the core retained its relevance (27.0% in ins-PCa patients and 43.8% in the remaining patients; hazard ratio, 0.972; P = .046), and a 20% cutoff was detected. Conclusion In a cohort of patients with PCa cT1c and a biopsy specimen Gleason score of ≤6, the ins-PCa rate, according to the updated definition, is close to 50%, and the percentage of cancer involvement of the core is the single factor that best predicts this diagnosis.
Introduction
The widespread screening for PSA has contributed to the increased incidence of prostate cancer (PCa), mostly identifying disease at earlier stages. Many of these patients will probably ...not require treatment because of the indolent course of the disease. The European Randomized Study of Screening for Prostate Cancer (ERSPC) has showed that 1410 men needed to be screened and 48 prostatectomies performed to prevent death. The aim of this study was to evaluate predictive factors of insignificant PCa in our experience.
Materials and Methods
We analyzed various preoperative clinical and biopsy findings of 225 consecutive patients who underwent prostatectomy from October 2007 to June 2010. The indication for biopsy was placed in presence of an abnormal rectal examination and/or suspected transrectal ultrasound and/or PSA >4 ng/ml. We consider insignificant a tumor with a volume ≤5% of the entire gland with a Gleason score ≤ 6, with no grades 4 or 5 and organ confined.
Results
The prevalence of potentially insignificant PCa in our experience was 12%. The preoperative findings of patients with insignificant PCa were significantly more favorable than the remaining cases with PCa not insignificant. Multivariate analysis did not reveal any independent predictors.
Conclusions
In our experience, in a population not screened for PCa, we have not identified any factors that can predict with certainty the insignificant nature of a tumor and, therefore, useful to start a patient on an active surveillance program.
Renal cell carcinoma with prominent smooth muscle stroma is a rare neoplasm composed of an admixture of epithelial cell with clear cytoplasm arranged in small nest and tubular structures and a stroma ...composed of smooth muscle. In the epithelial component, loss of chromosome 3p detected by fluorescence in situ hybridization (FISH) has been reported and on this basis these neoplasms have been viewed as variants of clear cell renal cell carcinoma. To test the validity of this classification, we have evaluated the chromosome 3 and VHL status of three of these tumors using FISH, array comparative genomic hybridization, gene sequencing, and methylation-specific multiplex ligation-dependent probe amplification analysis. None of the tumors showed deletion of chromosome 3p, VHL mutation, a significant VHL methylation, or changes in VHL copy number and all three tumors demonstrated a flat profile in the comparative genomic hybridization analysis. We conclude that renal cell carcinoma with smooth muscle stroma should be considered as an entity distinct from clear cell renal cell carcinoma.
The disease complex medullary cystic disease/familial juvenile hyperuricemic nephropathy (MCKD/FJHN) is characterized by alteration of urinary concentrating ability, frequent hyperuricemia, ...tubulo-interstitial fibrosis, cysts at the cortico-medullary junction and renal failure. MCKD/FJHN is caused by mutations of the gene encoding uromodulin, the most abundant protein in urine. Here, we describe new missense mutations in three families with MCKD/FJHN and demonstrate allelism with a glomerulocystic kidney disease (GCKD) variant, showing association of cyst dilatation and collapse of glomeruli with some clinical features similar to MCKD/FJHN as hyperuricemia and impairment of urine concentrating ability. Furthermore, we provide the first functional characterization of uromodulin mutations. The four newly identified mutants were characterized by immunofluorescence and FACS analysis on transfected cells. These experiments showed that all uromodulin mutations cause a delay in protein export to the plasma membrane due to a longer retention time in the endoplasmic reticulum. Immunohistochemistry on GCKD and MCKD/FJHN kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle's loop. Electron microscopy demonstrated accumulation of dense fibrillar material within the endoplasmic reticulum. Consistently, patient urines show a severe reduction of excreted uromodulin. The maturation impairment is consistent with the clinical findings and suggests a pathogenetic mechanism leading to these kidney diseases.
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