Mitochondrial complex I promotes kidney cancer metastasis.

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.

Direct MRI-guided In-Bore Targeted Biopsy of the Prostate: A Step-by-Step How To and Lessons Learned.

Multiparametric MRI-the most accurate imaging technique for detection of prostate cancer-has transformed the landscape of prostate cancer diagnosis by enabling targeted biopsies. In a targeted biopsy, tissue samples are obtained from suspicious regions identified at prebiopsy diagnostic MRI. The authors briefly compare the different strategies available for targeting an MRI-visible suspicious lesion, followed by a step-by-step description of the direct MRI-guided in-bore approach and an illustrated review of its application in challenging clinical scenarios. In this technique, direct visualization of the needle, needle guide, and needle trajectory during the procedure provides a precise and versatile strategy to accurately sample suspicious lesions, improving detection of clinically significant cancers. Published under a CC BY 4.0 license Test Your Knowledge questions for this article are available in the supplemental material.

Preoperative Multiparametric Prostate Magnetic Resonance Imaging Structured Report Informs Risk for Positive Apical Surgical Margins During Radical Prostatectomy.

BACKGROUND: The prostatic apex is the most frequent location of positive surgical margin (PSM) after surgery. Data regarding the ability of multiparametric magnetic resonance imaging (mpMRI) to prospectively identify men at risk for apical PSMs (aPSMs) using a structured report are lacking. OBJECTIVES: The aims of the study are to determine and to compare the rate of aPSM in men with versus without prospectively flagged at-risk prostate lesions during clinical mpMRI interpretation using whole-mount histopathology as the reference standard. METHODS: This single-center, retrospective study of prospectively collected data included treatment-naive men with abnormal 3T mpMRI (PI-RADS v2 score ≥3) between January 2016 and December 2018 followed by surgery. During routine clinical interpretation, radiologists flagged prostate lesions abutting the apical most gland and/or encircling the distal most prostatic urethra using standardized language available as a "pick list" option in the structured report. Logistic regression was used to compare the rate of PSM in 2 groups (flagged vs nonflagged men). Propensity score covariate adjustment corrected for potential selection bias according to age, prostate-specific antigen (PSA), PSA density, grade group, and pT stage. The estimate was further adjusted by including surgeon as a covariate. RESULTS: A total of 428 men were included. A statistically significant higher proportion of aPSMs was noted in flagged (56% [51/91]) compared with nonflagged apical lesions (31% [105/337]; adjusted odds ratio, 2.5; 95% confidence interval, 1.6-4.1; P < 0.01). The difference in aPSM between both groups also varied according to the surgeon performing the RP. Prostate-specific antigen, PSA density, lesion size, apical location, Prostate Imaging Reporting & Data System score, grade group, pT stage, and surgeon's experience were associated with higher PSM rate. Biochemical recurrence, defined as PSA greater than 0.2 ng/mL on 2 measurements after RP, was significantly associated with PSM status (propensity score adjusted odds ratio, 3.1; 95% confidence interval, 1.8-5.3; P < 0.0001); however, patients flagged by radiologists did not have a significant difference in biochemical recurrence rates as compared with nonflagged patients ( P = 0.11). CONCLUSIONS: Standard language built into structured reports for mpMRI of the prostate helps identify preoperatively patients at risk for aPSM. CLINICAL IMPACT: Multiparametric MRI is able to identify patients at increased risk for aPSM, and this information can be conveyed in a structured report to urologists, facilitating patient counseling and treatment decisions.

Outcomes of Lymph Node Dissection in Nephroureterectomy in the Treatment of Upper Tract Urothelial Carcinoma: Analysis of the ROBUUST Registry.

PURPOSE: We sought to evaluate outcomes of lymph node dissection (LND) in patients with upper tract urothelial carcinoma. MATERIALS AND METHODS: We performed a multicenter retrospective analysis utilizing the ROBUUST (for RObotic surgery for Upper Tract Urothelial Cancer Study) registry for patients who did not undergo LND (pNx), LND with negative lymph nodes (pN0) and LND with positive nodes (pN+). Primary and secondary outcomes were overall survival (OS) and recurrence-free survival (RFS). Multivariable analyses evaluated predictors of outcomes and pathological node positivity. Kaplan-Meier analyses (KMAs) compared survival outcomes. RESULTS: A total of 877 patients were analyzed (LND performed in 358 [40.8%]/pN+ in 73 [8.3%]). Median nodes obtained were 10.2 for pN+ and 9.8 for pN0. Multivariable analyses noted increasing age (OR 1.1, p <0.001), pN+ (OR 3.1, p <0.001) and pathological stage pTis/3/4 (OR 3.4, p <0.001) as predictors for all-cause mortality. Clinical high-grade tumors (OR 11.74, p=0.015) and increasing tumor size (OR 1.14, p=0.001) were predictive for lymph node positivity. KMAs for pNx, pN0 and pN+ demonstrated 2-year OS of 80%, 86% and 42% (p <0.001) and 2-year RFS of 53%, 61% and 35% (p <0.001), respectively. KMAs comparing pNx, pN0 ≥10 nodes and pN0 <10 nodes showed no significant difference in 2-year OS (82% vs 85% vs 84%, p=0.6) but elicited significantly higher 2-year RFS in the pN0 ≥10 group (60% vs 74% vs 54%, p=0.043). CONCLUSIONS: LND during nephroureterectomy in patients with positive lymph nodes provides prognostic data, but is not associated with improved OS. LND yields ≥10 in patients with clinical node negative disease were associated with improved RFS. In high-grade and large tumors, lymphadenectomy should be considered.

Followup of Men with PI-RADS™ 4 or 5 Abnormality on Prostate Magnetic Resonance Imaging and Nonmalignant Pathological Findings on Initial Targeted Prostate Biopsy.

PURPOSE: A benign magnetic resonance imaging targeted prostate biopsy in the setting of a PI-RADS™ 4/5 abnormality presents a clinical dilemma for future management. We evaluated benign histological features on magnetic resonance imaging targeted prostate biopsy to determine if they predict the likelihood of missed cancer on subsequent biopsy. MATERIALS AND METHODS: Between June 2012 and September 2016, 1,595 men were enrolled in a prospective study of magnetic resonance imaging targeted and systematic biopsy outcomes. We re-reviewed pathology from benign biopsies of PI-RADS 4/5 abnormalities and divided them into 5 groups for comparison to outcomes of clinical followup: inflammation (38%), stroma/glandular hyperplasia (9%), normal prostate tissue (28%), atypical small acinar proliferation/high grade prostatic intraepithelial neoplasia (9%) and cancer in adjacent systematic cores (16%). RESULTS: Of 497 men 88 (18%) with PI-RADS 4/5 abnormality prior to initial biopsy had no cancer on magnetic resonance imaging targeted prostate biopsy. On followup, 45 men underwent repeat magnetic resonance imaging: 12 (27%) had persistent PI-RADS 4/5 abnormalities, 17 (38%) had PI-RADS 2/3, 16 (35%) had PI-RADS 1. On repeat magnetic resonance imaging targeted prostate biopsy, cancer was found in 62.5% of men with PI-RADS 4/5 and 23% of men with PI-RADS 2/3. Histological groups on initial biopsy were not predictive of the likelihood of PI-RADS downgrade on repeat magnetic resonance imaging or cancer detection on repeat biopsy. CONCLUSIONS: Among men with no cancer on magnetic resonance imaging targeted prostate biopsy performed for PI-RADS abnormality, downgrade of PI-RADS score is noted in 73% on repeat magnetic resonance imaging. Persistence of PI-RADS 4/5 predicts a higher risk of missed cancer, warranting prompt re-biopsy. While histological findings such as inflammation may underlie some PI-RADS 4/5 abnormalities, initial histology is a poor predictor of cancer likelihood on repeat biopsy.

Application of the PRECISION Trial Biopsy Strategy to a Contemporary Magnetic Resonance Imaging-Targeted Biopsy Cohort-How Many Clinically Significant Prostate Cancers are Missed?

PURPOSE: To demonstrate the generalizability of PRECISION findings and apply the PRECISION biopsy strategy to a contemporary cohort to characterize cancers missed by employing this strategy. MATERIALS AND METHODS: A total of 629 men biopsied between February 2015 and September 2018 met PRECISION inclusion criteria. Men with PI-RADS™ 1-2 magnetic resonance imaging were only biopsied if high clinical suspicion for cancer. Missed cancers were defined as prostate cancer identified uniquely on systematic biopsy in men with PI-RADS 3-5 magnetic resonance imaging, or on either systematic biopsy or magnetic resonance imaging-targeted prostate biopsy in men with PI-RADS 1-2 magnetic resonance imaging. Outcomes included 1) clinically significant prostate cancer, Gleason grade group 2 or greater, detection rate, 2) missed clinically significant prostate cancer rate upon application of PRECISION biopsy strategy, 3) Gleason grade group distribution, core size, spatial orientation and oncologic risk among missed cancers. RESULTS: Application of the PRECISION biopsy strategy to the study cohort resulted in avoidance of biopsy in 28%, similar magnetic resonance imaging-targeted prostate biopsy detection rate to PRECISION, reduction of Gleason grade group 1 detection rate by 60% and reduction of clinically significant prostate cancer detection rate by 19%. Missed clinically significant prostate cancers were often smaller than 6 mm (54.5%), Gleason grade group 2 (67.3%) and low risk by clinical nomogram (74.6%). Gleason grade group 1 cancers identified uniquely on systematic biopsy were often contralateral to magnetic resonance imaging target (46.4%), while missed clinically significant prostate cancer was predominantly ipsilateral (81%). Limitations include biopsy of only men with high risk clinical features among PI-RADS 1-2 magnetic resonance imaging, potentially overestimating the clinically significant prostate cancer detection rate. CONCLUSIONS: The study cohort demonstrated generalizability of PRECISION findings. Applying the PRECISION biopsy strategy greatly reduces Gleason grade group 1 detection rate, while missing a small number of clinically significant prostate cancer, typically small volume, low risk, and Gleason grade group 2. Missed clinically significant prostate cancer is predominantly ipsilateral to magnetic resonance imaging target, possibly representing targeting error.

Real-World Application of Pre-Orchiectomy miR-371a-3p Test in Testicular Germ Cell Tumor Management.

PURPOSE: Current serum tumor markers for testicular germ cell tumor are limited by low sensitivity. Growing evidence supports the use of circulating miR-371a-3p as a superior marker for malignant (viable) germ cell tumor management. We evaluated the real-world application of serum miR-371a-3p levels in detecting viable germ cell tumor among patients undergoing partial or radical orchiectomy. MATERIALS AND METHODS: Serum samples were collected from 69 consecutive patients before orchiectomy. Performance characteristics of serum miR-371a-3p were compared with conventional serum tumor markers (⍺-fetoprotein/ß-human chorionic gonadotropin/lactate dehydrogenase) between patients with viable germ cell tumor and those without viable germ cell tumor on orchiectomy pathology. Relative miR-371a-3p levels were correlated with clinical course. The Kruskal-Wallis test and linear and ordinal regression models were used for analysis. RESULTS: For detecting viable germ cell tumor, combined conventional serum tumor markers had a specificity of 100%, sensitivity of 58% and AUC of 0.79. The miR-371a-3p test showed a specificity of 100%, sensitivity of 93% and AUC of 0.978. Median relative expression of miR-371a-3p in viable germ cell tumor cases was more than 6,800-fold higher than in those lacking viable germ cell tumor. miR-371a-3p levels correlated with composite stage (p=0.006) and, among composite stage I cases, independently associated with embryonal carcinoma percentage (p=0.0012) and tumor diameter (p <0.0001). Six patients underwent orchiectomy after chemotherapy and were correctly predicted to have presence or absence of viable germ cell tumor by the miR-371a-3p test. CONCLUSIONS: If validated, the miR-371a-3p test can be used in conjunction with conventional serum tumor markers to aid clinical decision making. A positive miR-371a-3p test in patients after preoperative chemotherapy or with solitary testes could potentially guide subsequent orchiectomy or observation.

Prospective evaluation of blue-light flexible cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer.

OBJECTIVES: To evaluate the utility of blue-light flexible cystoscopy (BLFC) for surveillance of non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Prospective cohort of consecutive patients who underwent office-based BLFC for NMIBC. Clinical information was collected including cystoscopic findings and pathological data. RESULTS: A total of 322 cases were performed on 190 patients. The mean age was 71 years and 83% were men. The highest stage prior to BLFC was Ta, carcinoma in situ (CIS), T1, and T2 in 45.3%, 18.4%, 30% and 2%, respectively. Prior to BLFC, 16.8%, 60.5%, and 16.8% were low grade (LG), high grade (HG), and CIS, respectively. Intravesical bacille Calmette-Guérin and intravesical chemotherapy were used in 54.2% and 18.4%, respectively. White-light cystoscopy (WLC) and BLFC were both normal in 173 (53.7%) of cases. WLC was normal and BLFC was abnormal in 26 (8%) cases. Of these, 15 had office-based biopsy and cancer was detected in 13 (87%; six CIS, four HG Ta, three LG Ta). Both WLC and BLFC were positive in 83 (25.8%) cases and 33% had additional tumours found. Cancer was found in 27 (75%) of WLC+/BLFC+ who underwent office-based biopsy including 19 LG Ta, six HG Ta, and two CIS. CONCLUSIONS: Incorporation of BLFC in clinical practice has potential advantages of finding cancer in cases with normal WLC. BLFC detected additional cancers in 33% of patients with positive WLC and BLFC, which can improve surveillance and performance of office-based biopsy. Further research is needed to determine cost-effectiveness and impact on recurrence rates.

Overcoming sociodemographic factors in the care of patients with testicular cancer at a safety net hospital.

BACKGROUND: The objective of this study was to determine whether standardized treatment of germ cell tumors (GCTs) could overcome sociodemographic factors limiting patient care. METHODS: The records of all patients undergoing primary treatment for GCTs at both a public safety net hospital and an academic tertiary care center in the same metropolitan area were analyzed. Both institutions were managed by the same group of physicians in the context of multidisciplinary cancer care. Patients were grouped by care center; clinicopathologic features and outcomes were analyzed. RESULTS: Between 2006 and 2018, 106 and 95 patients underwent initial treatment for GCTs at the safety net hospital and the tertiary care center, respectively. Safety net patients were younger (29 vs 33 years; P = .005) and were more likely to be Hispanic (79% vs 11%), to be uninsured (80% vs 12%; P < .001), to present via the emergency department (76% vs 8%; P < .001), and to have metastatic (stage II/III) disease (42% vs 26%; P = .025). In a multivariable analysis, an absence of lymphovascular invasion (odds ratio [OR], 0.30; P = .008) and an embryonal carcinoma component (OR, 0.36; P = .02) were associated with decreased use of adjuvant treatment for stage I patients; hospital setting was not (OR, 0.67; P = .55). For patients with stage II/III nonseminomatous GCTs, there was no difference in the performance of postchemotherapy retroperitoneal lymph node dissection between the safety net hospital and the tertiary care center (52% vs 64%; P = .53). No difference in recurrence rates was observed between the cohorts (5% vs 6%; P = .76). CONCLUSIONS: Sociodemographic factors are often associated with adverse clinical outcomes in the treatment of GCTs; they may be overcome with integrated, standardized management of testicular cancer.

Necl-4/Cadm4 recruits Par-3 to the Schwann cell adaxonal membrane.

Interactions between axons and Schwann cells are essential for the acquisition of Schwann cell radial and longitudinal polarity and myelin sheath assembly. In the internode, the largest of these longitudinal domains, axon-Schwann cell interactions are mediated by the Nectin-like (Necl) cell adhesion proteins, also known as SynCAMs or Cadms. In particular, Necl-1/Cadm3 expressed on the axon surface binds to Necl-4/Cadm4 expressed along the adaxonal membrane of myelinating Schwann cells. Necl-4 promotes myelination in vitro and is required for the timely onset of myelination and the fidelity of the organization of the myelin sheath and the internode in vivo. A key question is the identity of the downstream effectors of Necl-4 that mediate its effects. The cytoplasmic terminal region (CTR) of Necl-4 contains a PDZ-domain binding motif. Accordingly, we used the CTR of Necl-4 in an unbiased proteomic screen of PDZ-domain proteins. We identify Par-3, a multi-PDZ domain containing protein of the Par-aPKC polarity complex previously implicated in myelination, as an interacting protein. Necl-4 and Par-3 are colocalized along the inner Schwann cell membrane and coprecipitate from Schwann cell lysates. The CTR of Necl-4 binds to the first PDZ domain of Par-3 thereby recruiting Par-3 to sites of Necl-4/Necl-1 interaction. Knockdown of Necl-4 perturbs Par-3 localization to the inner membrane of Schwann cells in myelinating co-cultures. These findings implicate interactions of Necl-1/Necl-4 in the recruitment of Par-3 to the Schwann cell adaxonal membrane and the establishment of Schwann cell radial polarity.

The Institutional Learning Curve of Magnetic Resonance Imaging-Ultrasound Fusion Targeted Prostate Biopsy: Temporal Improvements in Cancer Detection in 4 Years.

PURPOSE: While magnetic resonance imaging-ultrasound fusion targeted biopsy allows for improved detection of clinically significant prostate cancer, a concerning amount of clinically significant disease is still missed. We hypothesized that a number of these misses are due to the learning curve associated with magnetic resonance imaging-ultrasound fusion targeted biopsy. We report the results of repeat magnetic resonance imaging-ultrasound fusion targeted biopsy in men with continued suspicion for cancer and the institutional learning curve in the detection of clinically significant prostate cancer with time. MATERIALS AND METHODS: We analyzed the records of 1,813 prostate biopsies in a prospectively acquired cohort of men who presented for prostate biopsy in a 4-year period. All men were offered prebiopsy magnetic resonance imaging and were assigned a maximum PI-RADS™ (Prostate Imaging Reporting and Data System version 2) score. Biopsy outcomes in men with a suspicious region of interest were compared. The relationship between time and clinically significant prostate cancer detection was analyzed. RESULTS: The clinically significant prostate cancer detection rate increased 26% with time in men with a PI-RADS 4/5 region of interest. On repeat magnetic resonance imaging-ultrasound fusion targeted biopsy in men with continued suspicion for cancer 53% of those with a PI-RADS 4/5 region of interest demonstrated clinically significant discordance from the initial magnetic resonance imaging-ultrasound fusion targeted biopsy compared to only 23% with a PI-RADS 1/2 region of interest. Significantly less clinically significant prostate cancer was missed or under graded in the most recent biopsies compared to the earliest biopsies. CONCLUSIONS: The high upgrade rate on repeat magnetic resonance imaging-ultrasound fusion targeted biopsy and the increasing cancer detection rate with time show the significant learning curve associated with magnetic resonance imaging-ultrasound fusion targeted biopsy. Men with low risk or negative biopsies with a persistent, concerning region of interest should be promptly rebiopsied. Improved targeting accuracy with operator experience can help decrease the number of missed cases of clinically significant prostate cancer.

Discordance between Ureteroscopic Biopsy and Final Pathology for Upper Tract Urothelial Carcinoma.

PURPOSE: We evaluated the discordance between ureteroscopic biopsy and surgical pathology findings for grading and staging upper tract urothelial carcinoma. We also sought to establish preoperative predictors of aggressive tumors. MATERIALS AND METHODS: We retrospectively reviewed the records of 314 patients who underwent ureteroscopic biopsy followed by surgical management of upper tract urothelial carcinoma from 2000 to 2016 at a total of 3 institutions. Our primary outcomes were muscle invasive (pT2 or greater) disease at surgical pathology and upgrading of clinical low grade tumors to pathological high grade. RESULTS: At biopsy 61% of the patients had clinical high grade tumors and 21% had subepithelial connective tissue invasion (cT1+). On final pathology 79% of the patients had pathological high grade tumors and 45% had stage pT2 or greater. On multivariate analysis advanced patient age, clinical high grade and cT1+ were independently associated with pT2 or greater. The combined presence of clinical high grade and cT1+ had 86% positive predictive value for muscle invasion while the combined absence of clinical high grade and cT1+ had 80% negative predictive value. The likelihood of missing invasion on biopsy in patients with muscle invasive disease was increased when biopsy fragments were limited to 1 mm or less. Of clinical low grade cases on biopsy 51% were upgraded at surgery. The presence of positive urine cytology was associated with an increased risk of upgrading but this was not statistically significant. CONCLUSIONS: Clinical high grade, cT1+ on biopsy and advanced patient age are independent risk factors for muscle invasive upper tract urothelial carcinoma. There is a significant risk of upgrading in patients with clinical low grade tumors on biopsy, especially when urine cytology is positive. The predictive value of biopsy can likely be improved by more extensive ureteroscopic sampling.

Akt Regulates Axon Wrapping and Myelin Sheath Thickness in the PNS.

The signaling pathways that regulate myelination in the PNS remain poorly understood. Phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, activated in Schwann cells by neuregulin and the extracellular matrix, has an essential role in the early events of myelination. Akt/PKB, a key effector of phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, was previously implicated in CNS, but not PNS myelination. Here we demonstrate that Akt plays a crucial role in axon ensheathment and in the regulation of myelin sheath thickness in the PNS. Pharmacological inhibition of Akt in DRG neuron-Schwann cell cocultures dramatically decreased MBP and P0 levels and myelin sheath formation without affecting expression of Krox20/Egr2, a key transcriptional regulator of myelination. Conversely, expression of an activated form of Akt in purified Schwann cells increased expression of myelin proteins, but not Krox20/Egr2, and the levels of activated Rac1. Transgenic mice expressing a membrane-targeted, activated form of Akt under control of the 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter, exhibited thicker PNS and CNS myelin sheaths, and PNS myelin abnormalities, such as tomacula and myelin infoldings/outfoldings, centered around the paranodes and Schmidt Lanterman incisures. These effects were corrected by rapamycin treatmentin vivo Importantly, Akt activity in the transgenic mice did not induce myelination of nonmyelinating Schwann cells in the sympathetic trunk or Remak fibers of the dorsal roots, although, in those structures, they wrapped membranes redundantly around axons. Together, our data indicate that Akt is crucial for PNS myelination driving axonal wrapping by unmyelinated and myelinated Schwann cells and enhancing myelin protein synthesis in myelinating Schwann cells. SIGNIFICANCE STATEMENT: Although the role of the key serine/threonine kinase Akt in promoting CNS myelination has been demonstrated, its role in the PNS has not been established and remains uncertain. This work reveals that Akt controls several key steps of the PNS myelination. First, its activity promotes membrane production and axonal wrapping independent of a transcriptional effect. In myelinated axons, it also enhances myelin thickness through the mTOR pathway. Finally, sustained Akt activation in Schwann cells leads to hypermyelination/dysmyelination, mimicking some features present in neuropathies, such as hereditary neuropathy with liability to pressure palsies or demyelinating forms of Charcot-Marie-Tooth disease. Together, these data demonstrate the role of Akt in regulatory mechanisms underlying axonal wrapping and myelination in the PNS.

Likert score 3 prostate lesions: Association between whole-lesion ADC metrics and pathologic findings at MRI/ultrasound fusion targeted biopsy.

BACKGROUND: To assess associations between whole-lesion apparent diffusion coefficient (ADC) metrics and pathologic findings of Likert score 3 prostate lesions at MRI/ultrasound fusion targeted biopsy. METHODS: This retrospective Institutional Review Board-approved study received a waiver of consent. We identified patients receiving a highest lesion score of 3 on 3 Tesla multiparametric MRI reviewed by a single experienced radiologist using a 5-point Likert scale and who underwent fusion biopsy. A total of 188 score 3 lesions in 158 patients were included. Three-dimensional volumes-of-interest encompassing each lesion were traced on ADC maps. Logistic regression was used to predict biopsy results based on whole-lesion ADC metrics and patient biopsy history. Biopsy yield was compared between metrics. RESULTS: By lesion, targeted biopsy identified tumor in 22.3% and Gleason score (GS) > 6 tumor in 8.5%, although results varied by biopsy history: biopsy-naïve (n = 80), 20.0%/8.8%; prior negative biopsy (n = 53), 9.4%/1.9%; prior positive biopsy (n = 55): 40.0%/14.5%. Biopsy history, whole-lesion mean ADC, whole-lesion ADC10-25 , and whole-lesion ADC25-50 were each significantly associated with tumor or GS > 6 tumor at fusion biopsy (P ≤ 0.047). In men without prior negative prostate biopsy, whole-lesion ADC25-50 ≤ 1.04*10(-3) mm2 /s achieved 90.0% sensitivity and 50.0% specificity for GS > 6 tumor, which was significantly higher (P < 0.001) than specificity of PSA (17.5%) at identical sensitivity. CONCLUSION: For score 3 lesions in patients without prior negative biopsy, whole-lesion ADC metrics help detect GS > 6 cancer while avoiding negative biopsies. However, deferral of fusion biopsy may be considered for score 3 lesions in patients with prior negative biopsy (without applying whole-lesion ADC metrics) given exceedingly low (∼ 2%) frequency of GS > 6 tumor in this group.

Predictive value of negative 3T multiparametric magnetic resonance imaging of the prostate on 12-core biopsy results.

OBJECTIVES: To evaluate the cancer detection rates for men undergoing 12-core systematic prostate biopsy with negative prebiopsy multiparametric magnetic resonance imaging (mpMRI) results. MATERIALS AND METHODS: Clinical data from consecutive men undergoing prostate biopsy who had undergone prebiopsy 3T mpMRI from December 2011 to August 2014 were reviewed from an institutional review board-approved prospective database. Men with negative prebiospy mpMRI results (negMRI) before biopsy were identified for the present analysis. Clinical features, cancer detection rates and negative predictive values were summarized. RESULTS: Seventy five men with negMRI underwent systematic 12-core biopsy during the study period. In the entire cohort, men with no previous biopsy, men with previously negative biopsy and men enrolled in active surveillance protocols, the overall cancer detection rates were 18.7, 13.8, 8.0 and 38.1%, respectively, and the detection rates for Gleason score (GS) ≥7 cancer were 1.3, 0, 4.0 and 0%, respectively. The NPVs for all cancers were 81.3, 86.2, 92.0, and 61.9, and for GS ≥7 cancer they were 98.7, 100, 96.0 and 100%, respectively. CONCLUSIONS: A negative prebiopsy mpMRI confers an overall NPV of 82% on 12-core biopsy for all cancer and 98% for GS ≥7 cancer. Based on biopsy indication, these findings assist in prebiopsy risk stratification for detection of high-risk disease and may provide guidance in the decision to pursue biopsy.

Magnetic Resonance Imaging-Ultrasound Fusion Targeted Prostate Biopsy in a Consecutive Cohort of Men with No Previous Biopsy: Reduction of Over Detection through Improved Risk Stratification.

PURPOSE: MRF-TB (magnetic resonance imaging-ultrasound fusion targeted prostate biopsy) may improve the detection of prostate cancer in men presenting for prostate biopsy. We report clinical outcomes of 12-core systematic biopsy and MRF-TB in men who presented for primary biopsy and further describe pathological characteristics of cancers detected by systematic biopsy and not by MRF-TB. MATERIALS AND METHODS: Clinical outcomes of 452 consecutive men who underwent prebiopsy multiparametric magnetic resonance imaging followed by MRF-TB and systematic biopsy at our institution between June 2012 and June 2015 were captured in an institutional review board approved database. Clinical characteristics, biopsy results and magnetic resonance imaging suspicion scores were queried from the database. RESULTS: Prostate cancer was detected in 207 of 382 men (54.2%) with a mean±SD age of 64±8.5 years and mean±SEM prostate specific antigen 6.8±0.3 ng/ml who met study inclusion criteria. The cancer detection rate of systematic biopsy and MRF-TB was 49.2% and 43.5%, respectively (p=0.006). MRF-TB detected more Gleason score 7 or greater cancers than systematic biopsy (117 of 132 or 88.6% vs 102 of 132 or 77.3%, p=0.037). Of 41 cancers detected by systematic biopsy but not by MRF-TB 34 (82.9%) demonstrated Gleason 6 disease, and 26 (63.4%) and 34 (82.9%) were clinically insignificant by Epstein criteria and a UCSF CAPRA (University of California-San Francisco-Cancer of the Prostate Risk Assessment) score of 2 or less, respectively. CONCLUSIONS: In men presenting for primary prostate biopsy MRF-TB detects more high grade cancers than systematic biopsy. Most cancers detected by systematic biopsy and not by MRF-TB are at clinically low risk. Prebiopsy magnetic resonance imaging followed by MRF-TB decreases the detection of low risk cancers while significantly improving the detection and risk stratification of high grade disease.

Using multiparametric MRI to 'personalize' biopsy for men.

PURPOSE OF REVIEW: In recent years, multiparametric magnetic resonance imaging (mpMRI) of the prostate has shown promise as a modality to identify areas of suspicion within the gland which correlate with cancer location and disease extent. However, optimal individualization of prostate biopsy using mpMRI relies on aligning the relative benefits of MRI-targeted approaches with the goals of biopsy. RECENT FINDINGS: For men with prior negative biopsies, mpMRI allows improved detection of occult high-grade cancers missed by repeat systematic biopsy but also has the potential to identify men who will not benefit from repeat biopsy due to a low likelihood of significant disease. For men with prior low-grade cancer diagnosis, the addition of MRI-targeted biopsy may identify those who are poor candidates for active surveillance by detecting high-risk disease without serial biopsies. For men without prior biopsy, mpMRI and targeted biopsy may help improve high-grade cancer diagnosis and significantly limit the detection of low-risk disease. SUMMARY: mpMRI of the prostate is a promising tool to address many of the shortcomings of traditional systematic prostate biopsy. Biopsy history plays a critical role in determining how to assess the potential advantages and disadvantages of prostate mpMRI in the context of each patient. Although these benefits have been suggested by published clinical outcomes data, there is a need for prospective validation of mpMRI and MRI-targeted biopsy in comparison with the current approach of systematic biopsy for all men, to define new paradigms for prostate cancer detection and risk stratification.

Optimization of prostate biopsy: the role of magnetic resonance imaging targeted biopsy in detection, localization and risk assessment.

PURPOSE: Optimization of prostate biopsy requires addressing the shortcomings of standard systematic transrectal ultrasound guided biopsy, including false-negative rates, incorrect risk stratification, detection of clinically insignificant disease and the need for repeat biopsy. Magnetic resonance imaging is an evolving noninvasive imaging modality that increases the accurate localization of prostate cancer at the time of biopsy, and thereby enhances clinical risk assessment and improves the ability to appropriately counsel patients regarding therapy. In this review we 1) summarize the various sequences that comprise a prostate multiparametric magnetic resonance imaging examination along with its performance characteristics in cancer detection, localization and reporting standards; 2) evaluate potential applications of magnetic resonance imaging targeting in prostate biopsy among men with no previous biopsy, a negative previous biopsy and those with low stage cancer; and 3) describe the techniques of magnetic resonance imaging targeted biopsy and comparative study outcomes. MATERIALS AND METHODS: A bibliographic search covering the period up to October 2013 was conducted using MEDLINE®/PubMed®. Articles were reviewed and categorized based on which of the 3 objectives of this review was addressed. Data were extracted, analyzed and summarized. RESULTS: Multiparametric magnetic resonance imaging consists of anatomical T2-weighted imaging coupled with at least 2 functional imaging techniques. It has demonstrated improved prostate cancer detection sensitivity up to 80% in the peripheral zone and 81% in the transition zone. A prostate cancer magnetic resonance imaging suspicion score has been developed, and is depicted using the Likert or PI-RADS (Prostate Imaging Reporting and Data System) scale for better standardization of magnetic resonance imaging interpretation and reporting. Among men with no previous biopsy, magnetic resonance imaging increases the frequency of significant cancer detection to 50% in low risk and 71% in high risk patients. In low risk men the negative predictive value of a combination of negative magnetic resonance imaging with prostate volume parameters is nearly 98%, suggesting a potential role in avoiding biopsy and reducing over detection/overtreatment. Among men with a previous negative biopsy 72% to 87% of cancers detected by magnetic resonance imaging guidance are clinically significant. Among men with a known low risk cancer, repeat biopsy using magnetic resonance targeting demonstrates a high likelihood of confirming low risk disease in low suspicion score lesions and of upgrading in high suspicion score lesions. Techniques of magnetic resonance imaging targeted biopsy include visual estimation transrectal ultrasound guided biopsy; software co-registered magnetic resonance imaging-ultrasound, transrectal ultrasound guided biopsy; and in-bore magnetic resonance imaging guided biopsy. Although the improvement in accuracy and efficiency of visual estimation biopsy compared to systematic appears limited, co-registered magnetic resonance imaging-ultrasound biopsy as well as in-bore magnetic resonance imaging guided biopsy appear to increase cancer detection rates in conjunction with increasing suspicion score. CONCLUSIONS: Use of magnetic resonance imaging for targeting prostate biopsies has the potential to reduce the sampling error associated with conventional biopsy by providing better disease localization and sampling. More accurate risk stratification through improved cancer sampling may impact therapeutic decision making. Optimal clinical application of magnetic resonance imaging targeted biopsy remains under investigation.