Claudia Kesch

Multiparametric Magnetic Resonance Imaging (MRI) and MRI–Transrectal Ultrasound Fusion Biopsy for Index Tumor Detection: Correlation with Radical Prostatectomy Specimen

BACKGROUND Multiparametric magnetic resonance imaging (mpMRI) and MRI fusion targeted biopsy (FTB) detect significant prostate cancer (sPCa) more accurately than conventional biopsies alone. OBJECTIVE To evaluate the detection accuracy of mpMRI and FTB on radical prostatectomy (RP) specimen. DESIGN, SETTING AND PARTICIPANTS From a cohort of 755 men who underwent transperineal MRI and transrectal ultrasound fusion biopsy under general anesthesia between 2012 and 2014, we retrospectively analyzed 120 consecutive patients who had subsequent RP. All received saturation biopsy (SB) in addition to FTB of lesions with Prostate Imaging Reporting and Data System (PI-RADS) score ≥2. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The index lesion was defined as the lesion with extraprostatic extension, the highest Gleason score (GS), or the largest tumor volume (TV) if GS were the same, in order of priority. GS 3+3 and TV ≥1.3ml or GS ≥3+4 and TV ≥0.55ml were considered sPCa. We assessed the detection accuracy by mpMRI and different biopsy approaches and analyzed lesion agreement between mpMRI and RP specimen. RESULTS AND LIMITATIONS Overall, 120 index and 71 nonindex lesions were detected. Overall, 107 (89%) index and 51 (72%) nonindex lesions harbored sPCa. MpMRI detected 110 of 120 (92%) index lesions, FTB (two cores per lesion) alone diagnosed 96 of 120 (80%) index lesions, and SB alone diagnosed 110 of 120 (92%) index lesions. Combined SB and FTB detected 115 of 120 (96%) index foci. FTB performed significantly less accurately compared with mpMRI (p=0.02) and the combination for index lesion detection (p=0.002). Combined FTB and SB detected 97% of all sPCa lesions and was superior to mpMRI (85%), FTB (79%), and SB (88%) alone (p<0.001 each). Spearmans rank correlation coefficient for index lesion agreement between mpMRI and RP was 0.87 (p<0.001). Limitations included the retrospective design, multiple operators, and nonblinding of radiologists. CONCLUSIONS MpMRI identified 92% of index lesions compared with RP histopathology. The combination of FTB and SB was superior to both approaches alone, reliably detecting 97% of sPCa lesions. PATIENT SUMMARY Multiparametric magnetic resonance imaging detects the index lesion accurately in 9 of 10 patients; however, the combined biopsy approach, while missing less significant cancer, comes at the cost of detecting more insignificant cancer.

Multicentre evaluation of targeted and systematic biopsies using magnetic resonance and ultrasound image-fusion guided transperineal prostate biopsy in patients with a previous negative biopsy.

To evaluate the detection rates of targeted and systematic biopsies in magnetic resonance imaging (MRI) and ultrasound (US) image‐fusion transperineal prostate biopsy for patients with previous benign transrectal biopsies in two high‐volume centres.

Combined Clinical Parameters and Multiparametric Magnetic Resonance Imaging for Advanced Risk Modeling of Prostate Cancer—Patient-tailored Risk Stratification Can Reduce Unnecessary Biopsies

BACKGROUND Multiparametric magnetic resonance imaging (mpMRI) is gaining widespread acceptance in prostate cancer (PC) diagnosis and improves significant PC (sPC; Gleason score≥3+4) detection. Decision making based on European Randomised Study of Screening for PC (ERSPC) risk-calculator (RC) parameters may overcome prostate-specific antigen (PSA) limitations. OBJECTIVE We added pre-biopsy mpMRI to ERSPC-RC parameters and developed risk models (RMs) to predict individual sPC risk for biopsy-naïve men and men after previous biopsy. DESIGN, SETTING, AND PARTICIPANTS We retrospectively analyzed clinical parameters of 1159 men who underwent mpMRI prior to MRI/transrectal ultrasound fusion biopsy between 2012 and 2015. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariate regression analyses were used to determine significant sPC predictors for RM development. The prediction performance was compared with ERSPC-RCs, RCs refitted on our cohort, Prostate Imaging Reporting and Data System (PI-RADS) v1.0, and ERSPC-RC plus PI-RADSv1.0 using receiver-operating characteristics (ROCs). Discrimination and calibration of the RM, as well as net decision and reduction curve analyses were evaluated based on resampling methods. RESULTS AND LIMITATIONS PSA, prostate volume, digital-rectal examination, and PI-RADS were significant sPC predictors and included in the RMs together with age. The ROC area under the curve of the RM for biopsy-naïve men was comparable with ERSPC-RC3 plus PI-RADSv1.0 (0.83 vs 0.84) but larger compared with ERSPC-RC3 (0.81), refitted RC3 (0.80), and PI-RADS (0.76). For postbiopsy men, the novel RMs discrimination (0.81) was higher, compared with PI-RADS (0.78), ERSPC-RC4 (0.66), refitted RC4 (0.76), and ERSPC-RC4 plus PI-RADSv1.0 (0.78). Both RM benefits exceeded those of ERSPC-RCs and PI-RADS in the decision regarding which patient to receive biopsy and enabled the highest reduction rate of unnecessary biopsies. Limitations include a monocentric design and a lack of PI-RADSv2.0. CONCLUSIONS The novel RMs, incorporating clinical parameters and PI-RADS, performed significantly better compared with RMs without PI-RADS and provided measurable benefit in making the decision to biopsy men at a suspicion of PC. For biopsy-naïve patients, both our RM and ERSPC-RC3 plus PI-RADSv1.0 exceeded the prediction performance compared with clinical parameters alone. PATIENT SUMMARY Combined risk models including clinical and imaging parameters predict clinically relevant prostate cancer significantly better than clinical risk calculators and multiparametric magnetic resonance imaging alone. The risk models demonstrate a benefit in making a decision about which patient needs a biopsy and concurrently help avoid unnecessary biopsies.

The Value of PSA Density in Combination with PI-RADS™ for the Accuracy of Prostate Cancer Prediction

Purpose: Multiparametric magnetic resonance imaging has an emerging role in prostate cancer diagnostics. In addition, clinical information is a reliable predictor of significant prostate cancer. We analyzed whether the negative predictive value of multiparametric magnetic resonance imaging to rule out significant prostate cancer could be improved using clinical factors, especially prostate specific antigen density. Materials and Methods: A total of 1,040 consecutive men with suspicion of prostate cancer underwent multiparametric magnetic resonance imaging first, followed by transperineal systematic and magnetic resonance imaging‐transrectal ultrasound fusion guided biopsy. Logistic regression analyses were performed to test different clinical factors as predictors of significant prostate cancer and build nomograms. To simplify these nomograms for clinical use patients were stratified into 3 prostate specific antigen density groups, including group 1—less than 0.07, group 2—0.07 to 0.15 and group 3—greater than 0.15 ng/ml/ml. After stratification we calculated the negative predictive value of a PI‐RADS (Prostate Imaging Reporting and Data System) Likert score of less than 3. Significant prostate cancer was defined as a Gleason score of 3 + 4 or greater. High grade prostate cancer was defined as a Gleason score of 4 + 3 or greater. Results: Overall 451 men were diagnosed with significant prostate cancer, including 187 with a Gleason score of 4 + 3 or greater. On ROC curve analyses the predictive power of the developed nomogram for significant prostate cancer showed a higher AUC than that of PI‐RADS alone (0.79 vs 0.75, p <0.001). The negative predictive value of harboring significant prostate cancer increased in men with unsuspicious magnetic resonance imaging from 79% up to 89% when prostate specific antigen density was 0.15 ng/ml/ml or less. In the repeat biopsy setting the negative predictive value of significant prostate cancer increased from 83% to 93%. The negative predictive value to harbor high grade prostate cancer increased from 92% up to 98% in the entire cohort. Conclusions: Using prostate specific antigen density combined with multiparametric magnetic resonance imaging improved the negative predictive value of PI‐RADS scoring. By increasing the probability of ruling out significant prostate cancer approximately 20% of unnecessary biopsies could be avoided safely.

18F-PSMA-1007 PET/CT Detects Micrometastases in a Patient With Biochemically Recurrent Prostate Cancer

To date, several radioactive tracers for imaging primary and recurrent prostate cancer are undergoing active investigation. In this case report fluorine-18 (F)eprostate-specific membrane antigen (PSMA)-1007 positron emission tomography (PET)/computed tomography imaging was performed, to our knowledge, for the first time in a patient with biochemical recurrence (prostate-specific antigen [PSA] 0.08 mg/L) after radical prostatectomy and adjuvant radiation. Seventeen lymph nodes with increased tracer uptake along the retroperitoneum and iliac arteries were detected. Therefore, early treatment with intermittent androgen deprivation was initiated instead of locoregional salvage therapy. Hence, F-PSMA-1007 PET imaging at very low PSA levels provided critical information to correctly restage disease.

Multicentre evaluation of magnetic resonance imaging supported transperineal prostate biopsy in biopsy‐naïve men with suspicion of prostate cancer

To analyse the detection rates of primary magnetic resonance imaging (MRI)‐fusion transperineal prostate biopsy using combined targeted and systematic core distribution in three tertiary referral centres.

68Ga or 18F for Prostate Cancer Imaging

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein with enzymatic carboxypeptidase activity. Expression is seen at low levels in the brain, kidneys, salivary glands, small intestines, and normal prostatic tissue (4,5). However, the function of this enzyme, also called glutamate carboxypeptidase II, in prostate cancer is still unclear (4). Compared with its normal expression, PSMA is highly overexpressed in prostate cancer cells. The level of PSMA expression rises with increasing tumor dedifferentiation as well as in metastatic and hormone-refractory cancer (5–7), making PSMA an ideal imaging and therapeutic target for prostate cancer. Several radiolabeled small-molecule inhibitors of PSMA have been designed (8). Currently, the most widely used PET tracer is the lowmolecular-weight PSMA inhibitor 68Ga-PSMA-11 (9), but it may have some disadvantages with respect to production capacity and nuclear decay properties. Its main advantage is the commercial availability of 68Ga via 68Ge generators, allowing convenient batch production of approximately 2–4 patient doses per generator elution. For centers that do not have access to a cyclotron and have a moderate number of examinations, these generators present a reasonably priced upfront investment. PSMA-11 contains the chelator HBED-CC (N,N9-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N9-diacetic acid), which allows labeling with kit formulations at ambient temperature without critical radiochemistry demands (10,11). However, 68Ga has a physical half-life of only 68 min. Therefore, 68Ga-PSMA-PET scans are preferably performed in house, and delivery of sufficient tracer activities to remote centers is challenging. Consequently, in large centers with many patients, several productions per day are required (12), or multiple generators need to be operated simultaneously, multiplying costs. To meet the quantitative demand of those centers, the use of 18F-labeled PSMA tracers may overcome these limitations. PET radiopharmacies with an on-site cyclotron can produce high activities of 18F at moderate costs. The physical half-life (110 min) of 18F-labeled PSMA tracers such as PSMA-1007 (((3S,10S,14S)-1-(4-(((S)-4-carboxy-2-((S)4-carboxy-2-(6-18F-fluoronicotinamido)butanamido)butanamido) methyl)phenyl)-3-(naphthalen-2-ylmethyl)-1,4,12-trioxo-2,5,11,13tetraazahexadecane-10,14,16-tricarboxylic acid)) and DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}ureido)-pentanedioic acid) may also enable centralized production and delivery to distant satellite centers. 18F also has a lower positron energy than 68Ga (0.65 vs. 1.90 MeV), theoretically resulting in an improved spatial resolution (13). Table 1 compares PET tracers labeled with 18F and 68Ga. Two promising 18F-labeled PSMA tracers are under clinical investigation: 18F-DCFPyL and 18F-PSMA-1007. A few studies have evaluated 18F-DCFPyL in the setting of recurrent prostate cancer or biochemical relapse (14–16), but there are no published data on primary prostate cancer, and in only a subgroup of patients were the imaging results confirmed by histopathologic evaluation. For 18F-PSMA-1007, one proof-of-concept study examined the tracer in 10 patients with primary high-risk prostate cancer, most of whom had lymph node metastases, which were systematically evaluated histopathologically (17). Only case reports—although interesting— have been published, one in a patient with biochemical relapse (17) and another in an advanced-stage patient who required tailoring of PSMA radioligand therapy (18). 18F-PSMA-1007 was reported favorable for primary tumors and local relapse because of low clearance via the urinary tract (1.2 percentage injected dose over 2 h). In contrast, urinary excretion of 18F-DCFPyL, 68Ga-PSMA-11, and 68Ga-PSMA-617 is remarkably higher (.10 percentage injected dose over 2 h) (1,16,19). However, this improvement is related less to the radiolabeling moiety than to the optimized structure of the overall molecule. Thus, the published experience with 18F-PSMA ligands is still limited to about 100 patients in different clinical settings. In contrast, confirmative publications from different centers, reporting on several thousand patients examined with 68GaPSMA-11, present a robust basis by which to gauge the value and limitations of these radionuclide–ligand combinations (3,20). Intraindividual comparisons between 68Gaand 18F-labeled ligands is limited to 25 patients (21); a separate cohort of 62 patients with biochemical relapse who were examined with 18F-DCFPyL performed comparably to literature values for 68Ga-PSMA-11 and even slightly better than the intrainstitutional 68Ga-PSMA controls (21). As promising as these preliminary results are, they also demonstrate that larger, prospective clinical trials evaluating 18F-labeled PSMA tracers in different clinical settings are mandatory. It is too early to answer the question of whether 68Ga or 18F should be used for prostate cancer imaging. Both should be considered widely exchangeable for most clinical indications (Table 1). Today the question is more one of whether it is decentralized or centralized production that is needed to adequately meet the clinical demand.

Gallium-68 or Fluorine-18 for prostate cancer imaging?

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein with enzymatic carboxypeptidase activity. Expression is seen at low levels in the brain, kidneys, salivary glands, small intestines, and normal prostatic tissue (4,5). However, the function of this enzyme, also called glutamate carboxypeptidase II, in prostate cancer is still unclear (4). Compared with its normal expression, PSMA is highly overexpressed in prostate cancer cells. The level of PSMA expression rises with increasing tumor dedifferentiation as well as in metastatic and hormone-refractory cancer (5–7), making PSMA an ideal imaging and therapeutic target for prostate cancer. Several radiolabeled small-molecule inhibitors of PSMA have been designed (8). Currently, the most widely used PET tracer is the lowmolecular-weight PSMA inhibitor 68Ga-PSMA-11 (9), but it may have some disadvantages with respect to production capacity and nuclear decay properties. Its main advantage is the commercial availability of 68Ga via 68Ge generators, allowing convenient batch production of approximately 2–4 patient doses per generator elution. For centers that do not have access to a cyclotron and have a moderate number of examinations, these generators present a reasonably priced upfront investment. PSMA-11 contains the chelator HBED-CC (N,N9-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N9-diacetic acid), which allows labeling with kit formulations at ambient temperature without critical radiochemistry demands (10,11). However, 68Ga has a physical half-life of only 68 min. Therefore, 68Ga-PSMA-PET scans are preferably performed in house, and delivery of sufficient tracer activities to remote centers is challenging. Consequently, in large centers with many patients, several productions per day are required (12), or multiple generators need to be operated simultaneously, multiplying costs. To meet the quantitative demand of those centers, the use of 18F-labeled PSMA tracers may overcome these limitations. PET radiopharmacies with an on-site cyclotron can produce high activities of 18F at moderate costs. The physical half-life (110 min) of 18F-labeled PSMA tracers such as PSMA-1007 (((3S,10S,14S)-1-(4-(((S)-4-carboxy-2-((S)4-carboxy-2-(6-18F-fluoronicotinamido)butanamido)butanamido) methyl)phenyl)-3-(naphthalen-2-ylmethyl)-1,4,12-trioxo-2,5,11,13tetraazahexadecane-10,14,16-tricarboxylic acid)) and DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}ureido)-pentanedioic acid) may also enable centralized production and delivery to distant satellite centers. 18F also has a lower positron energy than 68Ga (0.65 vs. 1.90 MeV), theoretically resulting in an improved spatial resolution (13). Table 1 compares PET tracers labeled with 18F and 68Ga. Two promising 18F-labeled PSMA tracers are under clinical investigation: 18F-DCFPyL and 18F-PSMA-1007. A few studies have evaluated 18F-DCFPyL in the setting of recurrent prostate cancer or biochemical relapse (14–16), but there are no published data on primary prostate cancer, and in only a subgroup of patients were the imaging results confirmed by histopathologic evaluation. For 18F-PSMA-1007, one proof-of-concept study examined the tracer in 10 patients with primary high-risk prostate cancer, most of whom had lymph node metastases, which were systematically evaluated histopathologically (17). Only case reports—although interesting— have been published, one in a patient with biochemical relapse (17) and another in an advanced-stage patient who required tailoring of PSMA radioligand therapy (18). 18F-PSMA-1007 was reported favorable for primary tumors and local relapse because of low clearance via the urinary tract (1.2 percentage injected dose over 2 h). In contrast, urinary excretion of 18F-DCFPyL, 68Ga-PSMA-11, and 68Ga-PSMA-617 is remarkably higher (.10 percentage injected dose over 2 h) (1,16,19). However, this improvement is related less to the radiolabeling moiety than to the optimized structure of the overall molecule. Thus, the published experience with 18F-PSMA ligands is still limited to about 100 patients in different clinical settings. In contrast, confirmative publications from different centers, reporting on several thousand patients examined with 68GaPSMA-11, present a robust basis by which to gauge the value and limitations of these radionuclide–ligand combinations (3,20). Intraindividual comparisons between 68Gaand 18F-labeled ligands is limited to 25 patients (21); a separate cohort of 62 patients with biochemical relapse who were examined with 18F-DCFPyL performed comparably to literature values for 68Ga-PSMA-11 and even slightly better than the intrainstitutional 68Ga-PSMA controls (21). As promising as these preliminary results are, they also demonstrate that larger, prospective clinical trials evaluating 18F-labeled PSMA tracers in different clinical settings are mandatory. It is too early to answer the question of whether 68Ga or 18F should be used for prostate cancer imaging. Both should be considered widely exchangeable for most clinical indications (Table 1). Today the question is more one of whether it is decentralized or centralized production that is needed to adequately meet the clinical demand.

Transcriptome Wide Analysis of Magnetic Resonance Imaging-targeted Biopsy and Matching Surgical Specimens from High-risk Prostate Cancer Patients Treated with Radical Prostatectomy: The Target Must Be Hit

BACKGROUND The most suspicious lesions on multiparametric magnetic resonance imaging (MRI) may be representative of final pathology. OBJECTIVE We connect imaging with high-precision spatial annotation of biopsies and genomic cancer signatures to compare the genomic signals of the index lesion and biopsy cores of adjacent and far away locations. DESIGN, SETTING, AND PARTICIPANTS Eleven patients diagnosed with high-risk prostate cancer on MRI/transrectal ultrasound-fusion biopsy (Bx) and treated with radical prostatectomy (RP). Five tissue specimens were collected from each patient. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Whole transcriptome RNA-expression was profiled for each sample. Genomic signatures were used to compare signals in MRI invisible versus visible foci using Pearsons correlation and to assess intratumoral heterogeneity using hierarchical clustering. RESULTS AND LIMITATIONS Ten RP and 27 Bx-samples passed quality control. Gene expression between RP and index Bx, but not adjacent benign samples, was highly correlated. Genomic Gleason grade classifier features measured across the different samples showed concordant expression across Bx and RP tumor samples, while an inverse expression pattern was observed between tumor and benign samples indicating the lack of a strong field-effect. The distribution of low and high Prostate Imaging Reporting and Data System (PI-RADS) samples was 10 and 11, respectively. Genomics of all low PI-RADS samples resembled benign tissue and most high PI-RADS samples resembled cancer tissue. A strong association was observed between PI-RADS version 2 and Decipher as well as the genomic Gleason grade classifier score. Clustering analysis showed that most samples cluster tightly by patient. One patient showed unique tumor biology in index versus secondary lesion suggesting the presence of intrapatient heterogeneity and the utility in profiling multiple foci identified by MRI. CONCLUSIONS MRI-targeted Bx-genomics show excellent correlation with RP-genomics and confirm the information captured by PI-RADS. Sampling of the target lesion must be precise as correlation between index and benign lesions was not seen. PATIENT SUMMARY In this report, we tested if targeted prostate sampling using magnetic resonance imaging-fusion biopsy allows to genetically describe index tumors of prostate cancer. We found that imaging genomics correlated well with final prostatectomy provided that the target is hit precisely.

Imaging of the Large Prostate

The diagnostic and imaging workflow for patients with enlarged prostates is still unclear. In this abstract we elucidate the role of ultrasound and MRI in diagnostics and treatment follow-up for “the large prostate”.