Characteristics and outcome of pediatric renal cell carcinoma patients registered in the International Society of Pediatric Oncology (SIOP) 93-01, 2001 and UK-IMPORT database: A report of the SIOP-Renal Tumor Study Group.

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93-01, 2001 and UK-IMPORT databases, were included. Event-free survival (EFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT-RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE-cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5-year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%-80.6%) and 84.5% (95% CI = 77.5%-92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE-testing.

Automated deep-learning system for Gleason grading of prostate cancer using biopsies: a diagnostic study.

BACKGROUND: The Gleason score is the strongest correlating predictor of recurrence for prostate cancer, but has substantial inter-observer variability, limiting its usefulness for individual patients. Specialised urological pathologists have greater concordance; however, such expertise is not widely available. Prostate cancer diagnostics could thus benefit from robust, reproducible Gleason grading. We aimed to investigate the potential of deep learning to perform automated Gleason grading of prostate biopsies. METHODS: In this retrospective study, we developed a deep-learning system to grade prostate biopsies following the Gleason grading standard. The system was developed using randomly selected biopsies, sampled by the biopsy Gleason score, from patients at the Radboud University Medical Center (pathology report dated between Jan 1, 2012, and Dec 31, 2017). A semi-automatic labelling technique was used to circumvent the need for manual annotations by pathologists, using pathologists' reports as the reference standard during training. The system was developed to delineate individual glands, assign Gleason growth patterns, and determine the biopsy-level grade. For validation of the method, a consensus reference standard was set by three expert urological pathologists on an independent test set of 550 biopsies. Of these 550, 100 were used in an observer experiment, in which the system, 13 pathologists, and two pathologists in training were compared with respect to the reference standard. The system was also compared to an external test dataset of 886 cores, which contained 245 cores from a different centre that were independently graded by two pathologists. FINDINGS: We collected 5759 biopsies from 1243 patients. The developed system achieved a high agreement with the reference standard (quadratic Cohen's kappa 0·918, 95% CI 0·891-0·941) and scored highly at clinical decision thresholds: benign versus malignant (area under the curve 0·990, 95% CI 0·982-0·996), grade group of 2 or more (0·978, 0·966-0·988), and grade group of 3 or more (0·974, 0·962-0·984). In an observer experiment, the deep-learning system scored higher (kappa 0·854) than the panel (median kappa 0·819), outperforming 10 of 15 pathologist observers. On the external test dataset, the system obtained a high agreement with the reference standard set independently by two pathologists (quadratic Cohen's kappa 0·723 and 0·707) and within inter-observer variability (kappa 0·71). INTERPRETATION: Our automated deep-learning system achieved a performance similar to pathologists for Gleason grading and could potentially contribute to prostate cancer diagnosis. The system could potentially assist pathologists by screening biopsies, providing second opinions on grade group, and presenting quantitative measurements of volume percentages. FUNDING: Dutch Cancer Society.

Multiparametric magnetic resonance imaging and follow-up to avoid prostate biopsy in 4259 men.

OBJECTIVE: To determine the proportion of men avoiding biopsy because of negative multiparametric magnetic resonance imaging (mpMRI) findings in a prostate MRI expert centre, and to assess the number of clinically significant prostate cancers (csPCa) detected during follow-up. PATIENTS AND METHODS: Retrospective study of 4259 consecutive men having mpMRI of the prostate between January 2012 and December 2017, with either a history of previous negative transrectal ultrasonography-guided biopsy or biopsy naïve. Patients underwent mpMRI in a referral centre. Lesions were classified according to Prostate Imaging Reporting And Data System (PI-RADS) versions 1 and 2. Negative mpMRI was defined as an index lesion PI-RADS ≤2. Follow-up until 13 October 2018 was collected by searching the Dutch Pathology Registry (PALGA). Gleason score ≥3 + 4 was considered csPCa. Kaplan-Meier analysis and univariable logistic regression models were used in the cohort of patients with negative mpMRI and follow-up. RESULTS: Overall, in 53.6% (2281/4259) of patients had a lesion classified as PI-RADS ≤2. In 320 patients with PI-RADS 1 or 2, follow-up mpMRI was obtained after a median (interquartile range) of 57 (41-63) months. In those patients, csPCa diagnosis-free survival (DFS) was 99.6% after 3 years. Univariable logistic regression analysis revealed age as a predictor for csPCa during follow-up (P < 0.05). In biopsied patients, csPCa was detected in 15.8% (19/120), 43.2% (228/528) and 74.5% (483/648) with PI-RADS 3, 4 and 5, respectively. CONCLUSION: More than half of patients having mpMRI of the prostate avoided biopsy. In those patients, csPCa DFS was 99.6% after 3 years.

MRI as a tool to assess surgical margins and pseudocapsule features directly following partial nephrectomy for small renal masses.

PURPOSE: To evaluate the feasibility of ex vivo 7T MRI to assess surgical margins (SMs) and pseudocapsule (PC) features after partial nephrectomy (PN). MATERIALS AND METHODS: In this prospective, IRB-approved study, seven patients undergoing a PN for nine tumours between November 2014 and July 2015 were included for analysis after obtaining informed consent. MRI of the specimen was acquired using a 7T small bore scanner. The imaging protocol consisted of anatomical T1-, T2- and diffusion-weighted imaging. After formalin fixation, specimens were cut for pathology work-up in the same orientation as the MR images were obtained. The entire specimen was processed into H&E slides that were digitally scanned, annotated and correlated with radiological findings for negative SMs, PC presence, PC continuity and extra-PC-extension (EPCE). Sensitivity and specificity of MRI for assessment of these endpoints were calculated. RESULTS: The sensitivity and specificity for assessment of the SM were 100% and 75%, respectively. Two false-positive outcomes were reported, both in case of EPCE and a SM ≤0.5 mm. For the presence of a PC, sensitivity and specificity were 100% and 33%, respectively. Two false-positive scans with anatomical structures mimicking the presence of a PC occurred. If a PC was present, continuity and EPCE were assessed with a sensitivity and specificity of 75% and 100% and 67% and 100%, respectively. CONCLUSION: Ex vivo 7T MRI is a feasible tool for perioperative evaluation of SMs, and if present, PC features after PN. This may facilitate maximal sparing of renal parenchyma without compromising oncological outcomes. KEY POINTS: • Ex vivo MRI may contribute to improvement of negative surgical margins during partial nephrectomy. • Due to the assessment of surgical margins within a limited time span from obtaining the partial nephrectomy specimen, surgery for more complex tumours is possible with maximum sparing of healthy renal parenchyma without compromising oncological outcomes. • The intra operative assessment of pseudocapsule continuity along the resection margin enables maximal sparing of healthy renal parenchyma without delayed diagnosis of incomplete resection.

Ex vivo MRI evaluation of prostate cancer: Localization and margin status prediction of prostate cancer in fresh radical prostatectomy specimens.

PURPOSE: To investigate the ability of high field ex vivo magnetic resonance imaging (MRI) to localize prostate cancer (PCa) and to predict the margin status in fresh radical prostatectomy (RP) specimens using histology as the reference standard. MATERIALS AND METHODS: This Institutional Review Board (IRB)-approved study had written informed consent. Patients with biopsy-proved PCa and a diagnostic multiparametric 3T MRI examination of the prostate prior to undergoing RP were prospectively included. A custom-made container provided reference between the 7T ex vivo MRI obtained from fresh RP specimens and histological slicing. On ex vivo MRI, PCa was localized and the presence of positive surgical margins was determined in a double-reading session. These findings were compared with histological findings obtained from completely cut, whole-mount embedded, prostate specimens. RESULTS: In 12 RP specimens, histopathology revealed 36 PCa lesions, of which 17 (47%) and 20 (56%) were correlated with the ex vivo MRI in the first and second reading session, respectively. Nine of 12 (75%) index lesions were localized in the first session, in the second 10 of 12 (83%). Seven and 8 lesions of 11 lesions with Gleason score >6 and >0.5 cc were localized in the first and second session, respectively. In the first session none of the four histologically positive surgical margins (sensitivity 0%) and 9 of 13 negative margins (specificity 69%) were detected. In second session the sensitivity and specificity were 25% and 88%, respectively. CONCLUSION: Ex vivo MRI enabled accurate localization of PCa in fresh RP specimens, and the technique provided information on the margin status with high specificity. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:439-448.

A placebo-controlled efficacy study of the intravesical immunomodulators TMX-101 and TMX-202 in an orthotopic bladder cancer rat model.

PURPOSE: TMX-101 and TMX-202 are formulations of toll-like receptor 7 (TLR-7) agonists, under investigation for the treatment of urothelial carcinoma. Our goal was to evaluate the efficacy of intravesical instillations of TMX-101 or TMX-202 in an orthotopic bladder cancer rat model. METHODS: Four groups of 14 rats received an instillation with isogenic AY-27 tumor cells on day 0, starting tumor development. On day 2 and 5, the rats were treated with an intravesical instillation of TMX-101 0.1%, TMX-202 0.38%, vehicle solution or NaCl. On day 12 the rats were sacrificed and the bladders were evaluated histopathologically. RESULTS: No signs of toxicity were seen. The number of tumor-positive rats was 11 of 14 (79%) in the vehicle control group and in the NaCl control group, versus 9 of 14 (64%) in the TMX-101-treated group, and 8 of 14 (57%) in the TMX-20-treated group. The difference between tumor-bearing rats in the treated and control groups was not significant (p = 0.12). Bladder weight was significantly lower for TMX-202-treated rats compared to vehicle (p = 0.005). CONCLUSIONS: TMX-101 and TMX-202 are TLR-7 agonists with antitumor activity. Treatment with TMX-101 and TMX-202 resulted in less tumor-bearing rats compared to vehicle or saline control groups, although not statistically significant. In this aggressive bladder cancer model, a lower number of tumor-positive rats after treatment with TLR-7 agonists indicates activity for the treatment of non-muscle invasive bladder cancer.

A urinary biomarker-based risk score correlates with multiparametric MRI for prostate cancer detection.

BACKGROUND: Prostate cancer (PCa) diagnostics would greatly benefit from more accurate, non-invasive techniques for the detection of clinically significant disease, leading to a reduction of over-diagnosis and over-treatment. The aim of this study was to determine the association between a novel urinary biomarker-based risk score (SelectMDx), multiparametric MRI (mpMRI) outcomes, and biopsy results for PCa detection. METHODS: This retrospective observational study used data from the validation study of the SelectMDx score, in which urine was collected after digital rectal examination from men undergoing prostate biopsies. A subset of these patients also underwent a mpMRI scan of the prostate. The indications for performing mpMRI were based on persistent clinical suspicion of PCa or local staging after PCa was found upon biopsy. All mpMRI images were centrally reviewed in 2016 by an experienced radiologist blinded for the urine test results and biopsy outcome. The PI-RADS version 2 was used. RESULTS: In total, 172 patients were included for analysis. Hundred (58%) patients had PCa detected upon prostate biopsy, of which 52 (52%) had high-grade disease correlated with a significantly higher SelectMDx score (P < 0.01). The median SelectMDx score was significantly higher in patients with a suspicious significant lesion on mpMRI compared to no suspicion of significant PCa (P < 0.01). For the prediction of mpMRI outcome, the area-under-the-curve of SelectMDx was 0.83 compared to 0.66 for PSA and 0.65 for PCA3. There was a positive association between SelectMDx score and the final PI-RADS grade. There was a statistically significant difference in SelectMDx score between PI-RADS 3 and 4 (P < 0.01) and between PI-RADS 4 and 5 (P < 0.01). CONCLUSIONS: The novel urinary biomarker-based SelectMDx score is a promising tool in PCa detection. This study showed promising results regarding the correlation between the SelectMDx score and mpMRI outcomes, outperforming PCA3. Our results suggest that this risk score could guide clinicians in identifying patients at risk for significant PCa and selecting patients for further radiological diagnostics to reduce unnecessary procedures.

MRI-guided focal laser ablation for prostate cancer followed by radical prostatectomy: correlation of treatment effects with imaging.

PURPOSE: To correlate treatment effects of MRI-guided focal laser ablation in patients with prostate cancer with imaging using prostatectomy as standard of reference. METHODS: This phase I study was approved by the Institutional Review Board. Three weeks prior to prostatectomy, five patients with histopathologically proven, low/intermediate grade prostate cancer underwent transrectal MRI-guided focal laser ablation. Per patient, only one ablation was performed to investigate the effect of ablation on the tissue rather than the effectiveness of ablation. Ablation was continuously monitored with real-time MR temperature mapping, and damage-estimation maps were computed. A post-ablation high-resolution T1-weighted contrast-enhanced sequence was acquired. Ablation volumes were contoured and measured on histopathology specimens (with a shrinkage factor of 1.15), T1-weighted contrast-enhanced images, and damage-estimation maps, and were compared. RESULTS: A significant volume correlation was seen between the ablation zone on T1-weighted contrast-enhanced images and the whole-mount histopathology section (r = 0.94, p = 0.018). The damage-estimation maps and histopathology specimen showed a correlation of r = 0.33 (p = 0.583). On histopathology, the homogeneous necrotic area was surrounded by a reactive transition zone (1-5 mm) zone, showing neovascularisation, and an increased mitotic index, indicating increased tumor activity. CONCLUSIONS: The actual ablation zone was better indicated by T1-weighted contrast-enhanced than by damage-estimation maps. Histopathology results highlight the importance of complete tumor ablation with a safety margin.

Apparent diffusion coefficient as it relates to histopathology findings in post-chemotherapy nephroblastoma: a feasibility study.

BACKGROUND: Nephroblastomas represent a group of heterogeneous tumours with variable proportions of distinct histopathological components. OBJECTIVE: The purpose of this study was to investigate whether direct comparison of apparent diffusion coefficient (ADC) measurements with post-resection histopathology subtypes is feasible and whether ADC metrics are related to histopathological components. MATERIALS AND METHODS: Twenty-three children were eligible for inclusion in this retrospective study. All children had MRI including diffusion-weighted imaging (DWI) after preoperative chemotherapy, just before tumour resection. A pathologist and radiologist identified corresponding slices at MRI and postoperative specimens using tumour morphology, the upper/lower calyx and hilar vessels as reference points. An experienced reader performed ADC measurements, excluding non-enhancing areas. A pathologist reviewed the corresponding postoperative slides according to the international standard guidelines. We tested potential associations with the Spearman rank test. RESULTS: Side-by-side comparison of MRI-DWI with corresponding histopathology slides was feasible in 15 transverse slices in 9 lesions in 8 patients. Most exclusions were related to extensive areas of necrosis/haemorrhage. In one lesion correlation was not possible because of the different orientation of sectioning of the specimen and MRI slices. The 25% ADC showed a strong relationship with percentage of blastema (Spearman rho=-0.71, P=0.003), whereas median ADC was strongly related to the percentage stroma (Spearman rho=0.74, P=0.002) at histopathology. CONCLUSION: Side-by-side comparison of MRI-DWI and histopathology is feasible in the majority of patients who do not have massive necrosis and hemorrhage. Blastemal and stromal components have a strong linear relationship with ADC markers.

Contribution of Histopathologic Tissue Composition to Quantitative MR Spectroscopy and Diffusion-weighted Imaging of the Prostate.

PURPOSE: To determine associations of metabolite levels derived from magnetic resonance (MR) spectroscopic imaging (ie, hydrogen 1 [(1)H] MR spectroscopic imaging) and apparent diffusion coefficients (ADCs) from diffusion-weighted imaging with prostate tissue composition assessed by digital image analysis of histologic sections. MATERIALS AND METHODS: Institutional ethical review board approved this retrospective study and waived informed consent. Fifty-seven prostate cancer patients underwent an MR examination followed by prostatectomy. One hematoxylin and eosin-stained section of the resected prostate per patient was digitized and computationally segmented into nuclei, lumen, and combination of epithelial cytoplasm and stroma. On each stained section, regions of interest (ROIs) were chosen and matched to the corresponding ADC map and (1)H MR spectroscopic imaging voxels. ADC and two metabolite ratios (citrate [Cit], spermine [Spm], and creatine [Cr] to choline [Cho] and Cho to Cr plus Spm) were correlated with percentage areas of nuclei, lumen, and cytoplasm and stroma for peripheral zone (PZ), transition zone (TZ), and tumor tissue in both zones of the prostate by using a linear mixed-effect model and Spearman correlation coefficient (ρ). RESULTS: ADC and (Cit + Spm + Cr)/Cho ratio showed positive correlation with percentage area of lumen (ρ = 0.43 and 0.50, respectively) and negative correlation with percentage area of nuclei (ρ = -0.29 and -0.26, respectively). The Cho/(Cr + Spm) ratio showed negative association with percentage area of lumen (ρ = -0.40) and positive association with area of nuclei (ρ = 0.26). Percentage areas of lumen and nuclei, (Cit + Spm + Cr)/Cho ratio, and ADC were significantly different (P < .001) between benign PZ (23.7 and 7.7, 8.83, and 1.58 × 10(-3) mm(2)/sec, respectively) and tumor PZ tissue (11.4 and 12.5, 5.13, and 1.20 × 10(-3) mm(2)/sec, respectively). These parameters were also significantly different between benign TZ (20.0 and 8.2, 6.50, and 1.26 × 10(-3) mm(2)/sec, respectively) and tumor TZ tissue (9.8 and 11.2, 4.36, and 1.03 × 10(-3) mm(2)/sec, respectively). CONCLUSION: The observed correlation of (Cit + Spm + Cr)/Cho ratio and ADC of the prostate with its tissue composition indicates that components of this composition, such as percentage luminal area, contribute to the value of these MR parameters.

Computer-extracted Features Can Distinguish Noncancerous Confounding Disease from Prostatic Adenocarcinoma at Multiparametric MR Imaging.

PURPOSE: To determine the best features to discriminate prostate cancer from benign disease and its relationship to benign disease class and cancer grade. MATERIALS AND METHODS: The institutional review board approved this study and waived the need for informed consent. A retrospective cohort of 70 patients (age range, 48-70 years; median, 62 years), all of whom were scheduled to undergo radical prostatectomy and underwent preoperative 3-T multiparametric magnetic resonance (MR) imaging, including T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced imaging, were included. The digitized prostatectomy slides were annotated for cancer and noncancerous disease and coregistered to MR imaging with an interactive deformable coregistration scheme. Computer-identified features for each of the noncancerous disease categories (eg, benign prostatic hyperplasia [BPH], prostatic intraepithelial neoplasia [PIN], inflammation, and atrophy) and prostate cancer were extracted. Feature selection was performed to identify the features with the highest discriminatory power. The performance of these five features was evaluated by using the area under the receiver operating characteristic curve (AUC). RESULTS: High-b-value diffusion-weighted images were more discriminative in distinguishing BPH from prostate cancer than apparent diffusion coefficient, which was most suitable for distinguishing PIN from prostate cancer. The focal appearance of lesions on dynamic contrast-enhanced images may help discriminate atrophy and inflammation from cancer. Which imaging features are discriminative for different benign lesions is influenced by cancer grade. The apparent diffusion coefficient appeared to be the most discriminative feature in identifying high-grade cancer. Classification results showed increased performance by taking into account specific benign types (AUC = 0.70) compared with grouping all noncancerous findings together (AUC = 0.62). CONCLUSION: The best features with which to discriminate prostate cancer from noncancerous benign disease depend on the type of benign disease and cancer grade. Use of the best features may result in better diagnostic performance.

Adherence to guideline recommendations for management of clinical T1 renal cancers in the Netherlands: a population-based study.

PURPOSE: For decades, small renal cancers are treated by radical nephrectomy (RN). Current guidelines recommend partial nephrectomy (PN) to preserve renal function and minimize cardiovascular comorbidity. As adherence to guidelines is largely unknown and international comparison to evaluate quality of health care is lacking, an pre-specified guideline evaluation of quality indicators concerning management of cT1 renal cancers was performed. METHODS: We performed a cohort study including patients with cT1 renal cancer between 2010 and 2014, identified through the Netherlands Cancer Registry. Time trends and variation in treatment were described. Factors associated with PN in cT1a and laparoscopic RN in cT1b were evaluated with logistic regression analyses. RESULTS: An increase in nephron-sparing treatment strategies (NSS) of cT1a patients (N total = 2436) was observed; in 2014, 67 % underwent NSS (62 % PN and 5 % thermal ablation). Age, a non-central tumor localization and being treated in a high-volume hospital were associated with PN. Although NSS were applied more frequently over time, the majority (70 %) of cT1b patients (N total = 2205) underwent RN in 2014, mainly performed laparoscopically. Increasing tumor size, tumor localization in the right kidney and being treated in a university hospital were associated with a lower probability of a laparoscopic RN versus open. Treatment in a high-volume hospital was associated with a higher probability of laparoscopic RN. CONCLUSIONS: Dutch patients with cT1 renal cancer are predominantly treated according to current guidelines. Data of this pre-specified quality indicator analysis of a urological national guideline may serve as a model for international comparison of treatment of cT1 renal cancers.

Prostate Cancer: The European Society of Urogenital Radiology Prostate Imaging Reporting and Data System Criteria for Predicting Extraprostatic Extension by Using 3-T Multiparametric MR Imaging.

PURPOSE: To retrospectively assess the use of the European Society of Urogenital Radiology (ESUR) Prostate Imaging Reporting and Data System (PI-RADS) criteria and 3-T multiparametric magnetic resonance (MR) imaging for detection of extraprostatic extension (EPE) of prostate cancer. MATERIALS AND METHODS: The institutional review board approval requirement was waived. Consecutive patients with prostate cancer (n = 133) underwent 3-T multiparametric MR imaging before prostatectomy. Lesions were assessed by using ESUR/PI-RADS criteria for T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced imaging, and by using the sum of these scores. Zonal dominant parameters corresponding to the score of diffusion-weighted imaging for peripheral zone lesions and to T2-weighted imaging scores for transitional zone lesions were calculated. In addition, the presence of EPE in each patient was evaluated on the basis of subjective multiparametric MR imaging features. Histopathologic examination of whole-mount radical prostatectomy specimens was used as the reference standard. Sensitivity, specificity, positive predictive, and negative predictive values; likelihood ratios; and areas under the receiver operating characteristic curve were calculated for each parameter on the basis of its usefulness for prediction of EPE. RESULTS: EPE was found in 60 of 133 (45%) patients. Receiver operating characteristic curve analysis for the prediction of EPE revealed an area under the curve of 0.72 for T2-weighted, 0.67 for diffusion-weighted, and 0.64 for dynamic contrast-enhanced imaging; 0.74 for the dominant parameter; and 0.74 for the sum of the PI-RADS scores, and a score of 5 was defined as the best threshold for the individual parameters, with a score greater than or equal to 13 as the threshold for the sum of the PI-RADS scores. By applying these thresholds, sensitivity, negative predictive value, and negative likelihood ratio (ruling out EPE) were 77%, 77%, and 0.36, respectively, and specificity, positive predictive value, and positive likelihood ratio (ruling in EPE) were 64%, 64%, and 2.15, respectively, for the dominant parameter. Feature analysis showed an area under the curve of 0.72; sensitivity, negative predictive value, and negative likelihood ratio of 63%, 72%, and 0.56, respectively, and specificity, positive predictive value, and positive likelihood ratio of 78%, 70%, and 3.77, respectively. CONCLUSION: ESUR/PI-RADS criteria showed moderate overall accuracy for use in the prediction of EPE, and these results were similar to those of multiparametric MR imaging assessment of features in this study sample.

Location of Prostate Cancers Determined by Multiparametric and MRI-Guided Biopsy in Patients With Elevated Prostate-Specific Antigen Level and at Least One Negative Transrectal Ultrasound-Guided Biopsy.

OBJECTIVE: The purpose of this article is to identify histopathologically proven prostate cancer locations using MRI followed by MRI-guided biopsy in patients with elevated prostate-specific antigen (PSA) levels and at least one negative transrectal ultrasound (TRUS)-guided biopsy session. Our hypothesis is that in this patient group most cancers are located in the anterior portion of the prostate. This may have implications for the biopsy strategy regarding the location of sampling. MATERIALS AND METHODS: This retrospective study consisted of 872 consecutive men who had undergone MRI-guided prostate biopsy. Inclusion criteria were PSA level greater than or equal to 4 ng/mL, one or more negative TRUS-guided biopsy session, the presence of suspicious lesions on previous multiparametric MRI, and prostate cancer histopathologically proven by MRI-guided biopsy. Thereafter, the location of intermediate- or high-risk cancers and cancers with a maximum cancer core length of 6 mm or longer were determined. The proportion of cancer locations was compared using a chi-square test. One-way ANOVA analyses were performed to compare patient characteristics. RESULTS: Results were presented on both a patient and lesion basis because a single patient can have multiple lesions. In total, 176 of 872 patients met the inclusion criteria. Prostate cancer was detected in 202 of 277 (73%) suspicious lesions. In total, 76% of patients had cancer of the transition zone and anterior fibromuscular stroma. Peripheral zone cancers were found in 30% of the patients, and 6% had cancers in both zones. In 70% of cases (141/202; 95%, CI, 63-76%), lesions were located anteriorly; this included 75% (132/176; 95%, CI, 69-81%) of patients. Intermediate- or high-risk prostate cancer was found in 93% (128/138; 95%, CI, 88-96%) of patients. Of these patients, 73% (94/128; 95%, CI, 66-81%) had anterior involvement. Cancers with a maximum cancer core length of 6 mm or more were more likely to be located in the anterior part of the prostate than were cancers with a core length of less than 6 mm (66% vs 6%). Most cancers 58% (102/176; 95% CI, 51-65%) were found in the mid prostate. Anterior involvement of prostate cancer detected by MRI-guided biopsy was statistically significantly (p = 0.04) higher in patients with two or more negative TRUS-guided biopsy sessions (79%) than in those with one negative TRUS-guided biopsy session (55%). CONCLUSION: Anterior involvement was high (76%) in patients with an elevated PSA level and one or more negative TRUS-guided biopsy session, and the majority of these cancers (93%) were intermediate or high risk.

Correlation between dynamic contrast-enhanced MRI and quantitative histopathologic microvascular parameters in organ-confined prostate cancer.

OBJECTIVES: To correlate pharmacokinetic parameters of 3-T dynamic contrast-enhanced (DCE-)MRI with histopathologic microvascular and lymphatic parameters in organ-confined prostate cancer. METHODS: In 18 patients with unilateral peripheral zone (pT2a) tumours who underwent DCE-MRI prior to radical prostatectomy (RP), the following pharmacokinetic parameters were assessed: permeability surface area volume transfer constant (K (trans)), extravascular extracellular volume (Ve) and rate constant (K ep). In the RP sections blood and lymph vessels were visualised immunohistochemically and automatically examined and analysed. Parameters assessed included microvessel density (MVD), area (MVA) and perimeter (MVP) as well as lymph vessel density (LVD), area (LVA) and perimeter (LVP). RESULTS: A negative correlation was found between age and K (trans) and K ep for tumour (r = -0.60, p = 0.009; r = -0.67, p = 0.002) and normal (r = -0.54, p = 0.021; r = -0.46, p = 0.055) tissue. No correlation existed between absolute values of microvascular parameters from histopathology and DCE-MRI. In contrast, the ratio between tumour and normal tissue (correcting for individual microvascularity variations) significantly correlated between K ep and MVD (r = 0.61, p = 0.007) and MVP (r = 0.54, p = 0.022). The lymphovascular parameters showed only a correlation between LVA and K ep (r = -0.66, p = 0.003). CONCLUSIONS: Significant correlations between DCE-MRI and histopathologic parameters were found when correcting for interpatient variations in microvascularity. KEY POINTS: • Normal prostate tissue shows strong heterogeneity in microvascularity. • Peripheral zone prostate cancer shows increased and less heterogeneous microvascularity. • Normal and tumour tissue shows considerable variation in microvascularity between patients. • DCE-MRI should take into account the interprostatic heterogeneity of microvasculature between patients.

European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.

Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.

Microvascularity in transition zone prostate tumors resembles normal prostatic tissue.

BACKGROUND: The objective of this study was comparison of characteristics of the microvasculature in transition zone tumor (TZT) and benign nodular hyperplasia (BPH) with normal prostatic transition zone (NTZ), applying accurate and objective quantification based on digital image analysis. Results of this study may increase understanding of prostate dynamic contrast enhanced (DCE) MRI analysis. METHODS: Radical prostatectomy specimens of 28 patients containing TZT ranging from pT2-pT4 were used. In 11 patients a concomitant peripheral zone tumor (PZT) was present. Microvessels were visualized by CD31 immunohistochemistry. Specimens were scanned using a computer-controlled microscope with automatic recognition of microvessels. Pseudocolor maps were produced displaying microvessel density, perimeter, and area of an entire prostate transection. Mean, 75th percentile (p75) and coefficient of variation (CV) were calculated automatically in manually indicated areas of the tumor and corresponding contralateral normal tissue, and BPH. RESULTS: Large variability was seen in TZT microvascular parameters, indicating presence of patients having both hypo and hypervascularized tumors compared to NTZ. In contrast, areas of BPH showed a more consistent increase in vascular parameters, with decreased CV. Analysis of PZT confirmed results of our previous study, with mean and p75 of all vascular parameters being significantly increased and a decrease in CV. No correlation was found for clinicopathological parameters and microvascular parameters. CONCLUSION: Microvasculature of transition zone tumor showed increased heterogeneity compared to BPH and peripheral zone tumors, possibly explaining the difficulty of TZT detection on DCE-MRI.

Prostate cancer: computer-aided diagnosis with multiparametric 3-T MR imaging--effect on observer performance.

PURPOSE: To determine the effect of computer-aided diagnosis (CAD) on less-experienced and experienced observer performance in differentiation of benign from malignant prostate lesions at 3-T multiparametric magnetic resonance (MR) imaging. MATERIALS AND METHODS: The institutional review board waived the need for informed consent. Retrospectively, 34 patients were included who had prostate cancer and had undergone multiparametric MR imaging, including T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced MR imaging prior to radical prostatectomy. Six radiologists less experienced in prostate imaging and four radiologists experienced in prostate imaging were asked to characterize different regions suspicious for cancer as benign or malignant on multiparametric MR images first without and subsequently with CAD software. The effect of CAD was analyzed by using a multiple-reader, multicase, receiver operating characteristic analysis and a linear mixed-model analysis. RESULTS: In 34 patients, 206 preannotated regions, including 67 malignant and 64 benign regions in the peripheral zone (PZ) and 19 malignant and 56 benign regions in the transition zone (TZ), were evaluated. Stand-alone CAD had an overall area under the receiver operating characteristic curve (AUC) of 0.90. For PZ and TZ lesions, the AUCs were 0.92 and 0.87, respectively. Without CAD, less-experienced observers had an overall AUC of 0.81, which significantly increased to 0.91 (P = .001) with CAD. For experienced observers, the AUC without CAD was 0.88, which increased to 0.91 (P = .17) with CAD. For PZ lesions, less-experienced observers increased their AUC from 0.86 to 0.95 (P < .001) with CAD. Experienced observers showed an increase from 0.91 to 0.93 (P = .13). For TZ lesions, less-experienced observers significantly increased their performance from 0.72 to 0.79 (P = .01) with CAD and experienced observers increased their performance from 0.81 to 0.82 (P = .42). CONCLUSION: Addition of CAD significantly improved the performance of less-experienced observers in distinguishing benign from malignant lesions; when less-experienced observers used CAD, they reached similar performance as experienced observers. The stand-alone performance of CAD was similar to performance of experienced observers.

Transition zone prostate cancer: detection and localization with 3-T multiparametric MR imaging.

PURPOSE: To retrospectively compare transition zone (TZ) cancer detection and localization accuracy of 3-T T2-weighted magnetic resonance (MR) imaging with that of multiparametric (MP) MR imaging, with radical prostatectomy specimens as the reference standard. MATERIALS AND METHODS: The informed consent requirement was waived by the institutional review board. Inclusion criteria were radical prostatectomy specimen TZ cancer larger than 0.5 cm(3) and 3-T endorectal presurgery MP MR imaging (T2-weighted imaging, diffusion-weighted [DW] imaging apparent diffusion coefficient [ADC] maps [b < 1000 sec/mm(2)], and dynamic contrast material-enhanced [DCE] MR imaging). From 197 patients with radical prostatectomy specimens, 28 patients with TZ cancer were included. Thirty-five patients without TZ cancer were randomly selected as a control group. Four radiologists randomly scored T2-weighted and DW ADC images, T2-weighted and DCE MR images, and T2-weighted, DW ADC, and DCE MR images. TZ cancer suspicion was rated on a five-point scale in six TZ regions of interest (ROIs). A score of 4-5 was considered a positive finding. A score of 4 or higher for any ROI containing TZ cancer was considered a positive detection result at the patient level. Generalized estimating equations were used to analyze detection and localization accuracy by using ROI-receiver operating characteristics (ROC) curve analyses for the latter. Gleason grade (GG) 4-5 and GG 2-3 cancers were analyzed separately. RESULTS: Detection accuracy did not differ between T2-weighted and MP MR imaging for all TZ cancers (68% vs 66%, P = .85), GG 4-5 TZ cancers (79% vs 72%-75%, P = .13), and GG 2-3 TZ cancers (66% vs 62%-65%, P = .47). MP MR imaging (area under the ROC curve, 0.70-0.77) did not improve T2-weighted imaging localization accuracy (AUC = 0.72) (P > .05). CONCLUSION: Use of 3-T MP MR imaging, consisting of T2-weighted imaging, DW imaging ADC maps (b values, 50, 500, and 800 sec/mm(2)), and DCE MR imaging may not improve TZ cancer detection and localization accuracy compared with T2-weighted imaging. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120281/-/DC1.

An interobserver reproducibility study on invasiveness of bladder cancer using virtual microscopy and heatmaps.

AIMS: The distinction between non-invasive (pTa) and invasive (pT1) non-muscle invasive bladder cancer (NMIBC) is subject to considerable interobserver variation. We aimed to generate a teaching set of images based on the diagnostic opinions of a panel of expert genitourinary pathologists. METHODS AND RESULTS: Twenty-five transurethral resection specimens initially reported as pT1 NMIBC from two university hospitals were selected on the basis of potential uncertainty of stromal invasion. Digitized slides were reviewed independently by a panel of eight genitourinary pathologists, who annotated any invasive area if present. Annotations were reviewed by the lead panel, and heatmaps of annotated areas were constructed. Reasons for discrepancies were analysed, and kappa scores were calculated to determine agreement among the eight panellists. Full agreement by the eight panellists was obtained in 11 of 25 cases (44%), with a multi-rater (Fleiss) kappa of 0.47 (P < 0.0001). After joint review of the seven discordant (agreement <75% of panellists) cases, consensus was obtained for six cases, and a teaching set of images was generated. CONCLUSIONS: Interobserver agreement among the panellists in the selected cases was moderate, but consensus could be reached in almost all cases. Heatmaps proved to be instrumental in generating a teaching set of images for standardization of histological criteria for NMIBC invasion.