Performance of a Region of Interest-based Algorithm in Diagnosing International Society of Urological Pathology Grade Group ≥2 Prostate Cancer on the MRI-FIRST Database-CAD-FIRST Study.

BACKGROUND AND OBJECTIVE: Prostate multiparametric magnetic resonance imaging (MRI) shows high sensitivity for International Society of Urological Pathology grade group (GG) ≥2 cancers. Many artificial intelligence algorithms have shown promising results in diagnosing clinically significant prostate cancer on MRI. To assess a region-of-interest-based machine-learning algorithm aimed at characterising GG ≥2 prostate cancer on multiparametric MRI. METHODS: The lesions targeted at biopsy in the MRI-FIRST dataset were retrospectively delineated and assessed using a previously developed algorithm. The Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2) score assigned prospectively before biopsy and the algorithm score calculated retrospectively in the regions of interest were compared for diagnosing GG ≥2 cancer, using the areas under the curve (AUCs), and sensitivities and specificities calculated with predefined thresholds (PIRADSv2 scores ≥3 and ≥4; algorithm scores yielding 90% sensitivity in the training database). Ten predefined biopsy strategies were assessed retrospectively. KEY FINDINGS AND LIMITATIONS: After excluding 19 patients, we analysed 232 patients imaged on 16 different scanners; 85 had GG ≥2 cancer at biopsy. At patient level, AUCs of the algorithm and PI-RADSv2 were 77% (95% confidence interval [CI]: 70-82) and 80% (CI: 74-85; p = 0.36), respectively. The algorithm's sensitivity and specificity were 86% (CI: 76-93) and 65% (CI: 54-73), respectively. PI-RADSv2 sensitivities and specificities were 95% (CI: 89-100) and 38% (CI: 26-47), and 89% (CI: 79-96) and 47% (CI: 35-57) for thresholds of ≥3 and ≥4, respectively. Using the PI-RADSv2 score to trigger a biopsy would have avoided 26-34% of biopsies while missing 5-11% of GG ≥2 cancers. Combining prostate-specific antigen density, the PI-RADSv2 and algorithm's scores would have avoided 44-47% of biopsies while missing 6-9% of GG ≥2 cancers. Limitations include the retrospective nature of the study and a lack of PI-RADS version 2.1 assessment. CONCLUSIONS AND CLINICAL IMPLICATIONS: The algorithm provided robust results in the multicentre multiscanner MRI-FIRST database and could help select patients for biopsy. PATIENT SUMMARY: An artificial intelligence-based algorithm aimed at diagnosing aggressive cancers on prostate magnetic resonance imaging showed results similar to expert human assessment in a prospectively acquired multicentre test database.

Prognostic value of programmed death ligand-1 and programmed death-1 expression in patients with upper tract urothelial carcinoma.

OBJECTIVE: To evaluate the prognostic value of programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) expression in patients with upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: A retrospective multicentre study was conducted in 283 patients with UTUC treated with radical nephroureterectomy (RNU) between 2000 and 2015 at 10 French hospitals. Immunohistochemistry analyses were performed using 2 mm-core tissue microarrays with NAT105® and 28.8® antibodies at a 5% cut-off for positivity on tumour cells and tumour-infiltrating lymphocytes to evaluate PD-L1 and PD-1 expression, respectively. Multivariable Cox regression models were used to determine the independent predictors of recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). RESULTS: Overall, 63 (22.3%) and 220 (77.7%) patients with UTUC had PD-L1-positive and -negative disease, respectively, while 91 (32.2%) and 192 (67.8%) had PD-1-positive and -negative disease, respectively. Patients who expressed PD-L1 or PD-1 were more likely to have pathological tumour stage ≥pT2 (68.3% vs 49.5%, P = 0.009; and 69.2% vs 46.4%, P < 0.001, respectively) and high-grade (90.5% vs 70.0%, P = 0.001; and 91.2% vs 66.7%, P < 0.001, respectively) disease with lymphovascular invasion (52.4% vs 17.3%, P < 0.001; and 39.6% vs 18.2%, P < 0.001, respectively) as compared to those who did not. In multivariable Cox regression analysis adjusting for each other, PD-L1 and PD-1 expression were significantly associated with decreased RFS (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.09-3.08, P = 0.023; and HR 1.59, 95% CI 1.01-2.54, P = 0.049; respectively), CSS (HR 2.73, 95% CI 1.48-5.04, P = 0.001; and HR 1.96, 95% CI 1.12-3.45, P = 0.019; respectively) and OS (HR 2.08, 95% CI 1.23-3.53, P = 0.006; and HR 1.71, 95% CI 1.05-2.78, P = 0.031; respectively). In addition, multivariable Cox regression analyses evaluating the four-tier combination of PD-L1 and PD-1 expression showed that only PD-L1/PD-1-positive patients (n = 38 [13.4%]) had significantly decreased RFS (HR 3.07, 95% CI 1.70-5.52; P < 0.001), CSS (HR 5.23, 95% CI 2.62-10.43; P < 0.001) and OS (HR 3.82, 95% CI 2.13-6.85; P < 0.001) as compared to those with PD-L1/PD-1-negative disease (n = 167 [59.0%]). CONCLUSIONS: We observed that PD-L1 and PD-1 expression were both associated with adverse pathological features that translated into an independent and cumulative adverse prognostic value in UTUC patients treated with RNU.

Prognostic Impact of pT3 Subclassification in a Multicentre Cohort of Patients with Urothelial Carcinoma of the Renal Pelvicalyceal System Undergoing Radical Nephroureterectomy: A Propensity Score-weighted Analysis After Central Pathology Review.

BACKGROUND: The current pathological tumour-node-metastasis (pTNM) classification for upper tract urothelial carcinoma (UTUC) does not include any risk stratification of pT3 renal pelvicalyceal tumours. OBJECTIVE: To assess the prognostic impact of pT3 subclassification in a multicentre cohort of patients with UTUC of the renal pelvicalyceal system undergoing radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: Data from all consecutive patients treated with RNU for pT3 renal pelvicalyceal UTUC at 14 French centres from 1995 to 2013 were reviewed retrospectively. INTERVENTION: A central pathology review (CPR) was used to stratify pT3 patients into those with infiltration of the renal parenchyma on a microscopic level (pT3a) versus those with infiltration of the renal parenchyma visible on gross inspection of the resection specimen and/or invasion of peripelvic fat (pT3b). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Inverse probability weighting (IPW)-adjusted Cox regression analyses were used to compare recurrence-free survival (RFS) and cancer-specific survival (CSS) between pT3a and pT3b patients. RESULTS AND LIMITATIONS: Overall, 202 patients were included and further stratified into pT3a (n = 98; 48.5%) and pT3b (n = 104; 51.5%) subgroups. Median time to follow-up in the weighted population was 68 (interquartile range, 50-95) mo. In IPW-adjusted Cox regression analyses, pT3b versus pT3a substage was associated with a significant adverse effect on RFS (hazard ratio [HR] = 2.02; 95% confidence interval [CI] = [1.36-3.01]; p < 0.001) and CSS (HR = 1.84; 95% CI = [1.20-2.82]; p = 0.005). The study is limited by its retrospective design. CONCLUSIONS: Using IPW-adjusted analyses after the CPR, we observed that RNU patients with pT3b renal pelvicalyceal UTUC had adverse prognosis as compared with those with pT3a disease. As such, this subclassification could help refine the current pTNM system for UTUC. PATIENT SUMMARY: In this report, we looked at the prognostic interest of stratifying patients with pT3 renal pelvicalyceal upper tract urothelial carcinoma based on the extent of local invasion. We found that those with extensive infiltration (pT3b) had adverse prognosis as compared with those with limited infiltration (pT3a). This information could be provided on pathology reports to further guide clinical decision making.

Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study.

BACKGROUND: Whether multiparametric MRI improves the detection of clinically significant prostate cancer and avoids the need for systematic biopsy in biopsy-naive patients remains controversial. We aimed to investigate whether using this approach before biopsy would improve detection of clinically significant prostate cancer in biopsy-naive patients. METHODS: In this prospective, multicentre, paired diagnostic study, done at 16 centres in France, we enrolled patients aged 18-75 years with prostate-specific antigen concentrations of 20 ng/mL or less, and with stage T2c or lower prostate cancer. Eligible patients had been referred for prostate multiparametric MRI before a first set of prostate biopsies, with a planned interval of less than 3 months between MRI and biopsies. An operator masked to multiparametric MRI results did a systematic biopsy by obtaining 12 systematic cores and up to two cores targeting hypoechoic lesions. In the same patient, another operator targeted up to two lesions seen on MRI with a Likert score of 3 or higher (three cores per lesion) using targeted biopsy based on multiparametric MRI findings. Patients with negative multiparametric MRI (Likert score ≤2) had systematic biopsy only. The primary outcome was the detection of clinically significant prostate cancer of International Society of Urological Pathology grade group 2 or higher (csPCa-A), analysed in all patients who received both systematic and targeted biopsies and whose results from both were available for pathological central review, including patients who had protocol deviations. This study is registered with ClinicalTrials.gov, number NCT02485379, and is closed to new participants. FINDINGS: Between July 15, 2015, and Aug 11, 2016, we enrolled 275 patients. 24 (9%) were excluded from the analysis. 53 (21%) of 251 analysed patients had negative (Likert ≤2) multiparametric MRI. csPCa-A was detected in 94 (37%) of 251 patients. 13 (14%) of these 94 patients were diagnosed by systematic biopsy only, 19 (20%) by targeted biopsy only, and 62 (66%) by both techniques. Detection of csPCa-A by systematic biopsy (29·9%, 95% CI 24·3-36·0) and targeted biopsy (32·3%, 26·5-38·4) did not differ significantly (p=0·38). csPCa-A would have been missed in 5·2% (95% CI 2·8-8·7) of patients had systematic biopsy not been done, and in 7·6% (4·6-11·6) of patients had targeted biopsy not been done. Four grade 3 post-biopsy adverse events were reported (3 cases of prostatitis, and 1 case of urinary retention with haematuria). INTERPRETATION: There was no difference between systematic biopsy and targeted biopsy in the detection of ISUP grade group 2 or higher prostate cancer; however, this detection was improved by combining both techniques and both techniques showed substantial added value. Thus, obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer but does not seem to avoid the need for systematic biopsy. FUNDING: French National Cancer Institute.

Characterization of Prostate Cancer with Gleason Score of at Least 7 by Using Quantitative Multiparametric MR Imaging: Validation of a Computer-aided Diagnosis System in Patients Referred for Prostate Biopsy.

Purpose To determine the performance of a computer-aided diagnosis (CAD) system trained at characterizing cancers in the peripheral zone (PZ) with a Gleason score of at least 7 in patients referred for multiparametric magnetic resonance (MR) imaging before prostate biopsy. Materials and Methods Two institutional review board-approved prospective databases of patients who underwent multiparametric MR imaging before prostatectomy (database 1) or systematic and targeted biopsy (database 2) were retrospectively used. All patients gave informed consent for inclusion in the databases. A CAD combining the 10th percentile of the apparent diffusion coefficient and the time to peak of enhancement was trained to detect cancers in the PZ with a Gleason score of at least 7 in 106 patients from database 1. The CAD was tested in 129 different patients from database 2. All targeted lesions were prospectively scored at biopsy by using a five-level Likert score. The CAD scores were retrospectively calculated. Biopsy results were used as the reference standard. Areas under the receiver operating characteristic curves (AUCs) were computed for CAD and Likert scores by using binormal smoothing for per-lesion and per-lobe analyses, and a density function for per-patient analysis. Results The CAD outperformed the Likert score in the overall population and all subgroups, except in the transition zone. The difference was statistically significant for the overall population (AUC, 0.95 [95% confidence interval {CI}: 0.90, 0.98] vs 0.88 [95% CI: 0.68, 0.96]; P = .02) at per-patient analysis, and for less-experienced radiologists (<1 year) at per-lesion (AUC, 0.90 [95% CI: 0.81, 0.95] vs 0.83 [95% CI: 0.73, 0.90]; P = .04) and per-lobe (AUC, 0.92 [95% CI: 0.80, 0.96] vs 0.84 [95% CI: 0.72, 0.91]; P = .04) analysis. Conclusion The CAD outperformed the Likert score prospectively assigned at biopsy in characterizing cancers with a Gleason score of at least 7. © RSNA, 2018 Online supplemental material is available for this article.

Diagnostic value and relative weight of sequence-specific magnetic resonance features in characterizing clinically significant prostate cancers.

PURPOSE: To assess the diagnostic weight of sequence-specific magnetic resonance features in characterizing clinically significant prostate cancers (csPCa). MATERIALS AND METHODS: We used a prospective database of 262 patients who underwent T2-weighted, diffusion-weighted, and dynamic contrast-enhanced (DCE) imaging before prostatectomy. For each lesion, two independent readers (R1, R2) prospectively defined nine features: shape, volume (V_Max), signal abnormality on each pulse sequence, number of pulse sequences with a marked (S_Max) and non-visible (S_Min) abnormality, likelihood of extracapsular extension (ECE) and PSA density (dPSA). Overall likelihood of malignancy was assessed using a 5-level Likert score. Features were evaluated using the area under the receiver operating characteristic curve (AUC). csPCa was defined as Gleason ≥7 cancer (csPCa-A), Gleason ≥7(4+3) cancer (csPCa-B) or Gleason ≥7 cancer with histological extraprostatic extension (csPCa-C). RESULTS: For csPCa-A, the Signal1 model (S_Max+S_Min) provided the best combination of signal-related variables, for both readers. The performance was improved by adding V_Max, ECE and/or dPSA, but not shape. All models performed better with DCE findings than without. When moving from csPCa-A to csPCa-B and csPCa-C definitions, the added value of V_Max, dPSA and ECE increased as compared to signal-related variables, and the added value of DCE decreased. For R1, the best models were Signal1+ECE+dPSA (AUC = 0,805 [95%CI:0,757-0,866]), Signal1+V_Max+dPSA (AUC = 0.823 [95%CI:0.760-0.893]) and Signal1+ECE+dPSA [AUC = 0.840 (95%CI:0.774-0.907)] for csPCa-A, csPCA-B and csPCA-C respectively. The AUCs of the corresponding Likert scores were 0.844 [95%CI:0.806-0.877, p = 0.11], 0.841 [95%CI:0.799-0.876, p = 0.52]) and 0.849 [95%CI:0.811-0.884, p = 0.49], respectively. For R2, the best models were Signal1+V_Max+dPSA (AUC = 0,790 [95%CI:0,731-0,857]), Signal1+V_Max (AUC = 0.813 [95%CI:0.746-0.882]) and Signal1+ECE+V_Max (AUC = 0.843 [95%CI: 0.781-0.907]) for csPCa-A, csPCA-B and csPCA-C respectively. The AUCs of the corresponding Likert scores were 0. 829 [95%CI:0.791-0.868, p = 0.13], 0.790 [95%CI:0.742-0.841, p = 0.12]) and 0.808 [95%CI:0.764-0.845, p = 0.006]), respectively. CONCLUSION: Combination of simple variables can match the Likert score's results. The optimal combination depends on the definition of csPCa.

p16/Ki-67 dual labeling and urinary cytology results according to the New Paris System for Reporting Urinary Cytology: Impact of extended follow-up.

BACKGROUND: Overexpression of p16INK4a has been identified in urothelial malignancies both cytologically and histologically. In addition, p16/Ki-67 dual labeling has been shown to identify high-grade urothelial cancer cells and some progression cases within a 12-month delay. The Paris System for Reporting Urinary Cytology (TPS) was published in late 2015. Its aim is to clarify the criteria for diagnosing or, conversely, excluding high-grade urothelial carcinoma (HGUC). METHODS: Dual labeling was performed on archived ThinPrep-based Papanicolaou slides. A total of 208 samples (negative for high-grade urothelial carcinoma [NHGUC], 59; consistent with low-grade urothelial neoplasia [LGUN], 24; atypical urothelial cells [AUC], 15; and suspicious for or showing HGUC, 110) were analyzed for p16/Ki-67 after reclassification according to TPS. We assessed the oncologic status of the patients with cystoscopy, urinary cytology, histology, and prolonged 36-month follow-up data. RESULTS: The sensitivity of p16/Ki-67 for life-threatening lesions was not different from that of urinary cytology (82.8% vs 83.6%; P = 1). However, among patients with samples classified as NHGUC and AUC, disease-free survival was significantly shorter for dual-labeled cases versus cases with negative dual labeling (P < .0001). The same tendency was observed in patients with histologically proven LGUN (P < .0001). As for specificity in patients with negative cystoscopy and cytology combined, prolonged follow-up showed 90% overall survival at 24 months. CONCLUSIONS: A long-term evaluation of p16/Ki-67 dual labeling may identify HGUC and progression in cases with negative/low-grade urinary cytology results, and there are potential implications for the clinical management of patients after the conservative treatment of non-muscle-invasive urothelial carcinoma. Cancer Cytopathol 2017;125:552-62. © 2017 American Cancer Society.

Can pre- and postoperative magnetic resonance imaging predict recurrence-free survival after whole-gland high-intensity focused ablation for prostate cancer?

OBJECTIVES: Our aim was to assess whether magnetic resonance imaging (MRI) features predict recurrence-free survival (RFS) after prostate cancer high-intensity focused ultrasound (HIFU) ablation. METHODS: We retrospectively selected 81 patients who underwent (i) whole-gland HIFU ablation between 2007 and 2011 as first-line therapy or salvage treatment after radiotherapy or brachytherapy, and (ii) pre- and postoperative MRI. On preoperative imaging, two senior (R1, R2) and one junior (R3) readers assessed the number of sectors invaded by the lesion with the highest Likert score (dominant lesion) using a 27-sector diagram. On postoperative imaging, readers assessed destruction of the dominant lesion using a three-level score. Multivariate analysis included the number of sectors invaded by the dominant lesion, its Likert and destruction scores, the pre-HIFU prostate-specific antigen (PSA) level, Gleason score, and the clinical setting (primary/salvage). RESULTS: The most significant predictor was the number of prostate sectors invaded by the dominant lesion for R2 and R3 (p≤0.001) and the destruction score of the dominant lesion for R1 (p = 0.011). The pre-HIFU PSA level was an independent predictor for R2 (p = 0.014), but with only marginal significance for R1 (p = 0.059) and R3 (p = 0.053). CONCLUSION: The dominant lesion's size and destruction assessed by MRI provide independent prognostic information compared with usual predictors. KEY POINTS: • The size of the MR-dominant lesion significantly influences post-HIFU recurrence-free survival. • The destruction score of the MR-dominant lesion predicts post-HIFU recurrence-free survival. • Patients with a completely devascularized MR-dominant lesion show better recurrence-free survival • Pre- and post-HIFU MRI provide prognostic information independent of usual predictors.

Stiffness of benign and malignant prostate tissue measured by shear-wave elastography: a preliminary study.

OBJECTIVES: To measure benign and malignant prostate tissue stiffness using shear-wave elastography (SWE). METHODS: Thirty consecutive patients underwent transrectal SWE in the axial and sagittal planes before prostatectomy. After reviewing prostatectomy specimens, two radiologists measured stiffness in regions corresponding to cancers, lateral and median benign peripheral zone (PZ) and benign transition zone (TZ). RESULTS: Cancers were stiffer than benign PZ and TZ. All tissue classes were stiffer on sagittal than on axial imaging, in TZ than in PZ, and in median PZ than in lateral PZ. At multivariate analysis, the nature of tissue (benign or malignant; P < 0.00001), the imaging plane (axial or sagittal; P < 0.00001) and the location within the prostate (TZ, median PZ or lateral PZ; P = 0.0065) significantly and independently influenced tissue stiffness. On axial images, the thresholds maximising the Youden index in TZ, lateral PZ and median PZ were respectively 62 kPa, 33 kPa and 49 kPa. On sagittal images, the thresholds were 76 kPa, 50 kPa and 72 kPa, respectively. CONCLUSIONS: SWE can distinguish prostate malignant and benign tissues. Tissue stiffness is influenced by the imaging plane and the location within the gland. KEY POINTS: • Prostate cancers were stiffer than the benign peripheral zone • All tissue classes were stiffer on sagittal than on axial imaging • All tissue classes were stiffer in the transition zone than in the peripheral zone • All tissue classes were stiffer in the median than in the lateral peripheral zone • Taking into account imaging plane and zonal anatomy can improve cancer detection.

Quantitative Analysis of Prostate Multiparametric MR Images for Detection of Aggressive Prostate Cancer in the Peripheral Zone: A Multiple Imager Study.

Purpose To assess the intermanufacturer variability of quantitative models in discriminating cancers with a Gleason score of at least 7 among peripheral zone (PZ) lesions seen at 3-T multiparametric magnetic resonance (MR) imaging. Materials and Methods An institutional review board-approved prospective database of 257 patients who gave written consent and underwent T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced imaging before prostatectomy was retrospectively reviewed. It contained outlined lesions found to be suspicious for malignancy by two independent radiologists and classified as malignant or benign after correlation with prostatectomy whole-mount specimens. One hundred six patients who underwent imaging with 3-T MR systems from two manufacturers were selected (data set A, n = 72; data set B, n = 34). Eleven parameters were calculated in PZ lesions: normalized T2-weighted signal intensity, skewness and kurtosis of T2-weighted signal intensity, T2 value, wash-in rate, washout rate, time to peak (TTP), mean apparent diffusion coefficient (ADC), 10th percentile of the ADC, and skewness and kurtosis of the histogram of the ADC values. Parameters were selected on the basis of their specificity for a sensitivity of 0.95 in diagnosing cancers with a Gleason score of at least 7, and the area under the receiver operating characteristic curve (AUC) for the models was calculated. Results The model of the 10th percentile of the ADC with TTP yielded the highest AUC in both data sets. In data set A, the AUC was 0.90 (95% confidence interval [CI]: 0.85, 0.95) or 0.89 (95% CI: 0.82, 0.94) when it was trained in data set A or B, respectively. In data set B, the AUC was 0.84 (95% CI: 0.74, 0.94) or 0.86 (95% CI: 0.76, 0.95) when it was trained in data set A or B, respectively. No third variable added significantly independent information in any data set. Conclusion The model of the 10th percentile of the ADC with TTP yielded accurate results in discriminating cancers with a Gleason score of at least 7 among PZ lesions at 3 T in data from two manufacturers. (©) RSNA, 2016 Online supplemental material is available for this article.

Low glucose microenvironment of normal kidney cells stabilizes a subset of messengers involved in angiogenesis.

As glucose is a mandatory nutrient for cell proliferation and renewal, it is suspected that glucose microenvironment is sensed by all cell types to regulate angiogenesis. Several glucose-sensing components have been partially described to respond to high glucose levels. However, little is known about the response to low glucose. Here, we used well-differentiated isolated normal rat renal tubules under normal oxygenation conditions to assess the angiogenic response to low glucose. In apparent paradox, but confirming observations made separately in other models, high glucose but also low glucose increased mRNA level of vascular endothelial growth factor A (VEGFA). A subset of mRNAs including hypoxia-inducible factor 1A (HIF1A), angiopoietin receptor (TIE-2), and VEGF receptor 2 (FLK1) were similarly glucose-sensitive and responded to low glucose by increased stability independently of HIF1A and HIF2A proteins. These results contribute to gain some insights as to how normal cells response to low glucose may play a role in the tumor microenvironment.

How accurate is multiparametric MR imaging in evaluation of prostate cancer volume?

PURPOSE: To assess the factors influencing multiparametric (MP) magnetic resonance (MR) imaging accuracy in estimating prostate cancer histologic volume (Vh). MATERIALS AND METHODS: A prospective database of 202 patients who underwent MP MR imaging before radical prostatectomy was retrospectively used. Institutional review board approval and informed consent were obtained. Two independent radiologists delineated areas suspicious for cancer on images (T2-weighted, diffusion-weighted, dynamic contrast material-enhanced [DCE] pulse sequences) and scored their degree of suspicion of malignancy by using a five-level Likert score. One pathologist delineated cancers on whole-mount prostatectomy sections and calculated their volume by using digitized planimetry. Volumes of MR true-positive lesions were measured on T2-weighted images (VT2), on ADC maps (VADC), and on DCE images [VDCE]). VT2, VADC, VDCE and the greatest volume determined on images from any of the individual MR pulse sequences (Vmax) were compared with Vh (Bland-Altman analysis). Factors influencing MP MR imaging accuracy, or A, calculated as A = Vmax/Vh, were evaluated using generalized linear mixed models. RESULTS: For both readers, Vh was significantly underestimated with VT2 (P < .0001, both), VADC (P < .0001, both), and VDCE (P = .02 and P = .003, readers 1 and 2, respectively), but not with Vmax (P = .13 and P = .21, readers 1 and 2, respectively). Mean, 25th percentile, and 75th percentile, respectively, for Vmax accuracy were 0.92, 0.54, and 1.85 for reader 1 and 0.95, 0.57, and 1.77 for reader 2. At generalized linear mixed (multivariate) analysis, tumor Likert score (P < .0001), Gleason score (P = .009), and Vh (P < .0001) significantly influenced Vmax accuracy (both readers). This accuracy was good in tumors with a Gleason score of 7 or higher or a Likert score of 5, with a tendency toward underestimation of Vh; accuracy was poor in small (<0.5 cc) or low-grade (Gleason score ≤6) tumors, with a tendency toward overestimation of Vh. CONCLUSION: Vh can be estimated by using Vmax in aggressive tumors or in tumors with high Likert scores.

p16(INK4a) overexpression is not linked to oncogenic human papillomaviruses in patients with high-grade urothelial cancer cells.

BACKGROUND: p16(INK4a) Is overexpressed in almost all precancerous and carcinomatous lesions of the uterine cervix, secondary to interference between high-risk human papillomaviruses (hr-HPVs) and the retinoblastoma gene product. Overexpression of p16(INK4a) has also been identified in patients with high-grade urothelial lesions, both cytologically and histologically. However, the etiological role of HPV has not been documented except in inverted papillomas, low-grade bladder tumors, and younger patients. We therefore attempted to verify if HPV DNA was detectable in p16(INK4a) -positive urothelial tumors. METHODS: A total of 90 urinary cytology samples (33 negative/low-grade cases and 57 high-grade proliferations) were analyzed for p16(INK4a) and HPV DNA. HPV genotyping was performed by polymerase chain reaction using a low-density DNA microarray enabling the detection of 35 HPVs. A reasoned approach combining tissue genotyping and in situ hybridization (ISH) for hr-HPVs was used in patients with urinary HPV. RESULTS: Low-risk HPV (HPV-84) and hr-HPVs (HPV-16, -31, and -70) were detected. The prevalence of hr-HPVs in the urine was low: 5 of 82 patients (6.1%) and only 4 of 50 patients (8.0%) with high-grade urothelial malignancy. p16(INK4a) overexpression was noted in 49 high-grade samples (85.9%). In patients with p16(INK4a) -positive tumor cells and hr-HPV in the urine, HPV genotyping and ISH for hr-HPVs were negative in matched tissue sections. CONCLUSIONS: Our study shows a low prevalence of hr-HPVs in the urine of patients with high-grade urothelial malignancy. In those, p16(INK4a) overexpression occurs in the absence of demonstrable HPV DNA in the tissue sections, contrary to what is noted in gynecopathology.

Characterization of prostate lesions as benign or malignant at multiparametric MR imaging: comparison of three scoring systems in patients treated with radical prostatectomy.

PURPOSE: To compare the subjective Likert score to the Prostate Imaging Reporting and Data System (PIRADS) and morphology-location-signal intensity (MLS) scores for categorization of prostate lesions as benign or malignant at multiparametric magnetic resonance (MR) imaging. MATERIALS AND METHODS: Two hundred fifteen patients who underwent T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced multiparametric MR imaging of the prostate before radical prostatectomy were included in a prospective database after they signed the institutional review board-approved forms. Senior readers 1 and 2 prospectively noted the location, shape, and signal intensity of lesions on MR images from individual pulse sequences and scored each for likelihood of malignancy by using a Likert scale (range, 1-5). A junior reader (reader 3) retrospectively reviewed the database and did the same analysis. The MLS score (range, 1-13) was computed by using the readers' descriptions of the lesions. Then, the three readers again scored the lesions they described by using the PIRADS score (range, 3-15). MLS and PIRADS scores were compared with the Likert score by using their areas under the receiver operating characteristic curves. RESULTS: Areas under the receiver operating characteristic curves of the Likert, MLS, and PIRADS scores were 0.81, 0.77 (P = .03), and 0.75 (P = .01) for reader 1; 0.88, 0.74 (P < .0001), and 0.76 (P < .0001) for reader 2; and 0.81, 0.78 (P = .23), and 0.75 (P = .01) for reader 3. For diagnosing cancers with Gleason scores greater than or equal to 7, the Likert score was significantly more accurate than the others, except for the MLS score for reader 3. Weighted κ values were 0.470-0.524, 0.405-0.430, and 0.378-0.441 for the Likert, MLS, and PIRADS scores, respectively. CONCLUSION: The Likert score allowed significantly more accurate categorization of prostate lesions on MR images than did the MLS and PIRADS scores.

Prostate focal peripheral zone lesions: characterization at multiparametric MR imaging--influence of a computer-aided diagnosis system.

PURPOSE: To assess the impact of a computer-aided diagnosis (CAD) system in the characterization of focal prostate lesions at multiparametric magnetic resonance (MR) imaging. MATERIALS AND METHODS: Formal institutional review board approval was not required. Thirty consecutive 1.5-T multiparametric MR imaging studies (with T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced imaging) obtained before radical prostatectomy in patients between September 2008 and February 2010 were reviewed. Twelve readers assessed the likelihood of malignancy of 88 predefined peripheral zone lesions by using a five-level (level, 0-4) subjective score (SS) in reading session 1. This was repeated 5 weeks later in reading session 2. The CAD results were then disclosed, and in reading session 3, the readers could amend the scores assigned during reading session 2. Diagnostic accuracy was assessed by using a receiver operating characteristic (ROC) regression model and was quantified with the area under the ROC curve (AUC). RESULTS: Mean AUCs were significantly lower for less experienced (<1 year) readers (P < .02 for all sessions). Seven readers improved their performance between reading sessions 1 and 2, and 12 readers improved their performance between sessions 2 and 3. The mean AUCs for reading session 1 (83.0%; 95% confidence interval [CI]: 77.9%, 88.0%) and reading session 2 (84.1%; 95% CI: 78.1%, 88.7%) were not significantly different (P = .76). Although the mean AUC for reading session 3 (87.2%; 95% CI: 81.0%, 92.0%) was higher than that for session 2, the difference was not significant (P = .08). For an SS positivity threshold of 3, the specificity of reading session 2 (79.0%; 95% CI: 71.1%, 86.4%) was not significantly different from that of session 1 (78.7%; 95% CI: 70.5%, 86.8%) but was significantly lower than that of session 3 (86.2%; 95% CI: 77.1%, 93.1%; P < .03). The sensitivity of reading session 2 (68.4%; 95% CI: 57.5%, 77.7%) was significantly higher than that of session 1 (64.0%; 95% CI: 52.9%, 73.9%; P = .003) but was not significantly different from that of session 3 (71.4%; 95% CI: 58.3%, 82.7%). CONCLUSION: A CAD system may improve the characterization of prostate lesions at multiparametric MR imaging by increasing reading specificity.

p16 INK4a overexpression and p16/Ki-67 dual labeling versus conventional urinary cytology in the evaluation of urothelial carcinoma.

BACKGROUND: Taking into consideration the known overexpression of p16(INK4a) in histologically demonstrated high-grade urothelial malignancies, the objective of the current study was to examine the value of p16(INK4a) overexpression and of p16/Ki-67 dual labeling versus urinary cytology in the detection of urothelial lesions. METHODS: Immunolabeling was performed on demounted and destained Papanicolaou slides after liquid-based ThinPrep processing. Actual diagnoses were ascertained by cystoscopy controls and histopathology. Negative cases, papillary urothelial neoplasia of low malignant potential/low-grade tumor, and high-grade lesions were considered separately. RESULTS: A total of 216 urine samples were collected from new patients with symptoms who were referred for cystoscopy (92 cases) or patients who were being followed after conservative treatment for lesions involving the bladder (117 cases) or the upper urinary tract (7 cases). p16(INK4a) positivity was assessed in 171 of the 216 cases (79.2%) and in 93 of 99 high-grade cases with positive cytology (93.9%). Coexpression of p16/Ki-67 in the same cells was observed in 119 of 216 cases (55.1%) and was noted in 18 of 51 cases of negative or papillary urothelial neoplasia of low malignant potential/low-grade tumor (35.3%) and in 80 of 101 high-grade tumors (79.2%) (P < .0001). Thirteen of 14 high-grade intraurothelial lesions (92.8%) were dual labeled. When high-grade tumors, disease progression (increased grade, muscle infiltration, and extension into the upper urinary tract), and cancer-related death were grouped together as an endpoint, dual labeling demonstrated a sensitivity that was slightly higher than that of urinary cytology (82.5% vs 80.8%; P = .8), with 94.9% overall specificity. CONCLUSIONS: When applied to the search for high-grade and aggressive disease, p16/Ki-67 dual labeling and urinary cytology appear to demonstrate comparable performance.

Whole-gland ablation of localized prostate cancer with high-intensity focused ultrasound: oncologic outcomes and morbidity in 1002 patients.

BACKGROUND: High-intensity focused ultrasound (HIFU) is a nonsurgical therapy for selected patients with localized prostate cancer (PCa). OBJECTIVE: The long-term oncologic and morbidity outcomes of primary HIFU therapy for localized PCa were evaluated in a prospective, single-arm, single-institution cohort study. DESIGN, SETTING, AND PARTICIPANTS: Participants were patients treated with HIFU for localized PCa from 1997 to 2009. Excluded were patients with local recurrence following radiotherapy. A second HIFU session was systematically performed in patients with biopsy-proven local recurrence. INTERVENTION: Whole-gland prostate ablation with transrectal HIFU. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incontinence was assessed using the Ingelman-Sundberg score, and potency was assessed using the five-item version of the International Index of Erectile Function (IIEF-5) scores. Primary outcomes were survival rates (biochemical-free, cancer-specific, metastasis-free, and overall survival). Secondary outcomes were morbidity rates. Median follow-up was 6.4 yr (range: 0.2-13.9). The Kaplan-Meier method was used to determine survival estimates, and multivariate analysis was used to determine predictive factors of biochemical progression. RESULTS AND LIMITATIONS: A total of 1002 patients were included. The median nadir prostate-specific antigen (PSA) was 0.14 ng/ml, with 63% of patients reaching a nadir PSA ≤0.3 ng/ml. Sixty percent of patients received one HIFU session, 38% received two sessions, and 2% received three sessions. The 8-yr biochemical-free survival rates (Phoenix definition) were 76%, 63%, and 57% for low-, intermediate-, and high-risk patients, respectively (p < 0.001). At 10 yr, the PCa-specific survival rate and metastasis-free survival rate (MFSR) were 97% and 94%, respectively. Salvage therapies included external-beam radiation therapy (EBRT) (13.8%), EBRT plus androgen-deprivation therapy (ADT) (9.7%), and ADT alone (12.1%). Severe incontinence and bladder outlet obstruction decreased with refinement in the technology, from 6.4% and 34.9% to 3.1% and 5.9%, respectively. Limitations included the fact that the study was a single-arm study without a comparison group, technological improvements, changes in surgical protocol during the study, and the use of ADT to downsize the prostate in 39% of patients. CONCLUSIONS: HIFU is a potentially effective treatment of localized PCa, with a low PCa-specific mortality rate and a high MFSR at 10 yr as well as acceptable morbidity.

Hybrid oncocytic/chromophobe renal cell tumours do not display genomic features of chromophobe renal cell carcinomas.

Hybrid oncocytic/chromophobe tumours (HOCT) are renal tumours recently described displaying histological features of both renal oncocytoma (RO) and chromophobe renal cell carcinoma (ChRCC), raising the question of their precise signification in the RO/ChRCC group. This study aimed to describe clinicopathological features of so called HOCT and to characterise their genomic profile. Five hundred and eighty-three tumours belonging to the ChRCC/RO group were retrospectively reviewed. Twelve tumours that could not be classified as RO or CHRC were considered as HOCT. Hale staining and cytokeratin 7 (CK7) immunostaining were performed. Genomic profile was established by array comparative genomic hybridisation (array-CGH) on frozen samples. Mean age at diagnosis was 70 years (range 46-83). No recurrence was observed (median follow-up: 18 months; range 9-72). Tumour size ranged from 1 to 11 cm. HOCT showed an admixture of RO- and ChRCC-like areas and/or "hybrid" cells with overlapping cytonuclear and/or histochemical features. Hale staining was apical in 50 to 100 % of cells, and CK7 was expressed in 10 to 100 % of cells. Genomic profile was balanced in seven cases or showed a limited number of random imbalances in five cases, as observed in RO. In no instances were observed the characteristic chromosome losses of ChRCC. These results suggest that so called HOCT are not true hybrid tumours and rather could represent a morphological variant of RO. From a diagnostic perspective, an array-CGH analysis could be performed in ambiguous ChRCC/RO cases to formally exclude the diagnosis of ChRCC.

Prostate cancer diagnosis: multiparametric MR-targeted biopsy with cognitive and transrectal US-MR fusion guidance versus systematic biopsy--prospective multicenter study.

PURPOSE: To compare biopsy performance of two approaches for multiparametric magnetic resonance (MR)-targeted biopsy (TB) with that of extended systematic biopsy (SB) in prostate cancer (PCa) detection. MATERIALS AND METHODS: This institutional review board-approved multicenter prospective study (May 2009 to January 2011) included 95 patients with informed consent who were suspected of having PCa, with a suspicious abnormality (target) at prebiopsy MR. Patients underwent 12-core SB and four-core TB with transrectal ultrasonographic (US) guidance, with two cores aimed visually (cognitive TB [TB-COG]) and two cores aimed using transrectal US-MR fusion software (fusion-guided TB [TB-FUS]). SB and TB positivity for cancer and sampling quality (mean longest core cancer length, Gleason score) were compared. Clinically significant PCa was any 3 mm or greater core cancer length or any greater than 3 Gleason pattern for SB or any cancer length for TB. Statistical analysis included t test, paired χ(2) test, and κ statistic. Primary end point (core cancer length) was calculated (paired t test). RESULTS: Among 95 patients (median age, 65 years; mean prostate-specific antigen level, 10.05 ng/mL [10.05 µg/L]), positivity rate for PCa was 59% (n = 56) for SB and 69% (n = 66) for TB (P = .033); rate for clinically significant PCa was 52% (n = 49) for SB and 67% (n = 64) for TB (P = .0011). Cancer was diagnosed through TB in 16 patients (17%) with negative SB results. Mean longest core cancer lengths were 4.6 mm for SB and 7.3 mm for TB (P < .0001). In 12 of 51 (24%) MR imaging targets with positive SB and TB results, TB led to Gleason score upgrading. In 79 MR imaging targets, positivity for cancer was 47% (n = 37) with TB-COG and 53% (n = 42) with TB-FUS (P = .16). Neither technique was superior for Gleason score assessment. CONCLUSION: Prebiopsy MR imaging combined with transrectal US-guided TB increases biopsy performance in detecting PCa, especially clinically significant PCa. No significant difference was observed between TB-FUS and TB-COG for TB guidance.

Influence of imaging and histological factors on prostate cancer detection and localisation on multiparametric MRI: a prospective study.

OBJECTIVES: To assess factors influencing prostate cancer detection on multiparametric (T2-weighted, diffusion-weighted, and dynamic contrast-enhanced) MRI. METHODS: One hundred and seventy-five patients who underwent radical prostatectomy were included. Pre-operative MRI performed at 1.5 T (n = 71) or 3 T (n = 104), with (n = 58) or without (n = 117) an endorectal coil were independently interpreted by two radiologists. A five-point subjective suspicion score (SSS) was assigned to all focal abnormalities (FAs). MR findings were then compared with whole-mount sections. RESULTS: Readers identified 192-214/362 cancers, with 130-155 false positives. Detection rates for tumours of <0.5 cc (cm(3)), 0.5-2 cc and >2 cc were 33-45/155 (21-29 %), 15-19/35 (43-54 %) and 8-9/12 (67-75 %) for Gleason ≤6, 17/27 (63 %), 42-45/51 (82-88 %) and 34/35 (97 %) for Gleason 7 and 4/5 (80 %), 13/14 (93 %) and 28/28 (100 %) for Gleason ≥8 cancers respectively. At multivariate analysis, detection rates were influenced by tumour Gleason score, histological volume, histological architecture and location (P < 0.0001), but neither by field strength nor coils used for imaging. The SSS was a significant predictor of both malignancy of FAs (P < 0.005) and aggressiveness of tumours (P < 0.00001). CONCLUSIONS: Detection rates were significantly influenced by tumour characteristics, but neither by field strength nor coils used for imaging. The SSS significantly stratified the risk of malignancy of FAs and aggressiveness of detected tumours. KEY POINTS: • Prostate cancer volume, Gleason score, architecture and location are MRI predictors of detection. • Field strength and coils used do not influence the tumour detection rate. • Multiparametric MRI is accurate for detecting aggressive tumours. • A subjective suspicion score can stratify the risk of malignancy and tumour aggressiveness.