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Background: Cancer progression and metastasis occur such that cells with acquired mutations enhancing growth and survival (or inhibiting cell death) increase in number, a concept that has been recognized as analogous to Darwinian evolution of species since Peter C. Nowell's description in 1976. Selective forces include those intrinsic to the host (including metastatic site) as well as those resulting from anti-cancer therapies. By examining the mutational status of multiple tumor sites within an individual patient some insight may be gained into those genetic variants that enhance site-specific metastasis. By comparing these data across multiple individuals, recurrent patterns may identify alterations that are fundamental to successful site-specific metastasis., Methods: We sequenced the mitochondrial genome in 10 prostate cancer patients with bone metastases enrolled in a rapid autopsy program. Patients had late stage disease and received androgen ablation and frequently other systemic therapies. For each of 9 patients, 4 separate tissues were sequenced: the primary prostate cancer, a soft tissue metastasis, a bone metastasis and an uninvolved normal tissue that served as the non-cancerous control. An additional (10th) patient had no primary prostate available for sequencing but had both metastatic sites (and control DNA) sequenced. We then examined the number and location of somatically acquired mitochondrial DNA (mtDNA) mutations in the primary tumor and two metastatic sites in each individual patient. Finally, we compared patients with each other to determine any common patterns of somatic mutation., Results: Somatic mutations were significantly more numerous in the bone compared to either the primary tumor or soft tissue metastases. A missense mutation at nucleotide position (n.p.) 10398 (A10398G; Thr114Ala) in the respiratory complex I gene ND3 was the most common (7 of 10 patients) and was detected only in the bone. Other notable somatic mutations that occurred in more than one patient include a tRNA Arg mutation at n.p. 10436 and a tRNA Thr mutation at n.p. 15928. The tRNA Arg mutation was restricted to bone metastases and occurred in three of 10 patients (30%). Somatic mutation at 15928 was not restricted to the bone and also occurred in three patients., Conclusions: Mitochondrial genomic variation was greater in metastatic sites than in the primary tumor and bone metastases had statistically significantly greater numbers of somatic mutations than either the primary or the soft tissue metastases. The genome was not mutated randomly. At least one mutational "hot-spot" was identified at the individual base level (nucleotide position 10398 in bone metastases) indicating a pervasive selective pressure for bone metastatic cells that had acquired the 10398 mtDNA mutation. Two additional recurrent mutations (tRNA Arg and tRNA Thr) support the concept of bone site-specific "survival of the fittest" as revealed by variation in the mitochondrial genome and selective pressure exerted by the metastatic site., (Published by Elsevier Inc.)

Objective: To investigate the clinicopathologic and immunohistochemical features associated with invasive low-grade papillary urothelial carcinoma (LGPUC), an uncommon entity not previously described in published studies., Methods: A multicenter effort originally identified 36 cases diagnosed as invasive LGPUC by urologic pathology subspecialists; after re-review, 23 cases were included., Results: The average patient age was 69 years (range 46-82); 20 patients were men and 3 were women. Stage pT1 disease was present in 19 (83%) of 23 and pT2 disease in 4 patients. Of the 23 cases, 13 (57%) showed a single focus of invasion and 10 multiple foci. The invasive front showed rounded, variably sized nests in 17 cases (74%) and irregular nests with retraction artifact in 6. Additional findings in the noninvasive component included inverted growth in 23, apoptotic debris in 5, focal brisk mitotic activity in 4, dispersed chromatin in individual cells in 4, and a single atypical cell in 2. Immunohistochemical stains showed focal p53 nuclear stain in 23, patchy full-thickness cytokeratin 20 stain in 20, full-thickness CD44 expression in 17, and retention of E-cadherin in 23 cases. Clinical follow-up was available for all patients. The subsequent diagnosis included papilloma in 1 patient (4%), LGPUC in 5 (22%), and high-grade papillary urothelial carcinoma in 8 (35%) of the 23 patients, with 5 demonstrating invasion. Of the latter patients, 2 developed metastatic disease., Conclusion: Given the risk of progressive disease in these patients, especially the limited stage pT1 disease in most patients, additional studies investigating the molecular properties and outcomes associated with this uncommon lesion are warranted., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Preoperative C-reactive protein (CRP) predicts metastasis and mortality in localized renal cell carcinoma (RCC). However, the predictive potential of after resection of localized RCC remains unclear. Therefore, we assessed the absolute ability of postoperative CRP to predict metastases and mortality as a continuous variable., Methods: Patients with clinically localized (T1-T3N0M0) clear-cell RCC were followed for 1 year postoperatively. Metastases were identified radiologically and mortality by death certificate. Univariate and multivariate binary logistic regression analyses examined 1 year relapse-free survival (RFS) and overall survival (OS) across patient and disease characteristics., Results: Of the 110 patients in this study, 16.4% developed metastases and 6.4% died. Mean (SD) postoperative CRP for patients who did and did not develop metastases were 69.06 (73.55) mg/L and 5.27 (7.80), respectively. Mean (SD) postoperative CRP for patients who did and did not die were 89.31 (69.51) mg/L and 10.88 (30.32), respectively. In multivariate analysis, T-stage (OR: 12.452, 95% CI: 2.889-53.660) and postoperative CRP ((B: .080, SE: .025; P < .001) were significant predictors of RFS. T-Stage (OR: 11.715; 95% CI: 1.102-124.519) and postoperative CRP (B: .017; SE: .007; P < .001) were also significant predictors of OS. After adjusting for postoperative CRP, preoperative CRP was not predictive of these outcomes., Conclusions: Postoperative, not preoperative, CRP is the better predictor of metastasis and mortality following nephrectomy for localized RCC. Clinicians should consider absolute postoperative CRP to identify high-risk patients for closer surveillance or additional therapy. Predictive algorithms should consider incorporating postoperative CRP as a continuous variable to maximize predictive ability., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objectives: To develop a serum-based assay to detect neutralizing antibodies to the xenotropic murine leukemia virus-related virus (XMRV) retrovirus and to use this assay with polymerase chain reaction and fluorescence in situ hybridization to identify patients with prostate cancer previously exposed to XMRV infection and those who carry XMRV viral sequences in their prostate., Methods: Patients who had undergone radical prostatectomy were enrolled, and biologic specimens were obtained at surgery. The patients were genotyped for the R462Q RNASEL variant using a TaqMan genotyping assay on DNA from the peripheral blood. A serum assay that detects XMRV neutralizing antibodies was developed and used to determine which patients had serologic evidence of previous infection with XMRV virus. Some of these patients were also tested for the presence of XMRV nucleotide sequences in their prostate using polymerase chain reaction and fluorescence in situ hybridization analysis., Results: At a serum dilution of 1:150, our assay detected 11 (27.5%) of 40 patients with XMRV neutralizing antibodies, including 8 (40%) of 20 with the RNASEL genotype QQ and 3 (15%) of 20 with either the RQ or RR genotype. These results were in complete concordance with 2 other assays (polymerase chain reaction and fluorescence in situ hybridization), which were designed to detect XMRV infection., Conclusions: XMRV infects some patients with prostate cancer. Neutralizing antibodies against XMRV correlated with 2 independent methods of detecting the virus in the prostate. The antibody response suggests that with clinical serologic assay development, it might be possible to screen patients for XMRV infection. The cases presented in the present report provided biologic samples that can be used for the development of a clinically relevant assay., (Published by Elsevier Inc.)

Objectives: One would expect cases with small foci of cancer at radical prostatectomy to be associated with correspondingly favorable (Gleason score < or = 6, < 3 positive cores, no core with greater than 50% cancer) biopsy and preoperative clinical findings., Methods: Radical prostatectomies from The Johns Hopkins Hospital (July 2004 to July 2006) with only 1 to 3 slides involved by 3+3=6 adenocarcinoma of the prostate with no focus of cancer measuring greater than 2 mm in dimension were identified., Results: One hundred fifty-one radical prostatectomy specimens were obtained with cancer involving 1 slide in 69 cases (45.7%), 2 slides in 61 cases (40.4%), and 3 slides in 21 cases (13.9%). Predominantly transition zone cancer was present in 1 patient (0.66%). Mean patient age was 57.1 years (41 to 73 years). Twenty-two patients (14.6%) had a suspicious digital rectal examination. Mean serum prostate-specific antigen (PSA) and percentage free PSA were 5.2 ng/dL (0.3 to 16.7 ng/dL) and 15.5% (8% to 36%), respectively. Of 146, 127 (87%) men with available information had PSA density of less than 0.15. Mean number of cores obtained was 12 (4 to 27 cores) and all were Gleason 3+3=6 cancers on biopsy. One hundred fourteen cases (75.5%) had 1 core positive, 28 cases (18.5%) 2 cores, and 9 cases (6%) had 3 or more cores positive. One hundred forty-eight cases (98%) had cancer involving 50% or less of 1 core; 2 of these cases with greater than 50% cancer were discontinuous foci., Conclusions: Although, typically, biopsy and clinical preoperative findings associated with very limited cancer at radical prostatectomy are correspondingly favorable, exceptions occur in terms of biopsy cancer extent, serum PSA measurements, and digital rectal examination findings.