Weakly Supervised MRI Slice-Level Deep Learning Classification of Prostate Cancer Approximates Full Voxel- and Slice-Level Annotation: Effect of Increasing Training Set Size.

BACKGROUND: Weakly supervised learning promises reduced annotation effort while maintaining performance. PURPOSE: To compare weakly supervised training with full slice-wise annotated training of a deep convolutional classification network (CNN) for prostate cancer (PC). STUDY TYPE: Retrospective. SUBJECTS: One thousand four hundred eighty-nine consecutive institutional prostate MRI examinations from men with suspicion for PC (65 ± 8 years) between January 2015 and November 2020 were split into training (N = 794, enriched with 204 PROSTATEx examinations) and test set (N = 695). FIELD STRENGTH/SEQUENCE: 1.5 and 3T, T2-weighted turbo-spin-echo and diffusion-weighted echo-planar imaging. ASSESSMENT: Histopathological ground truth was provided by targeted and extended systematic biopsy. Reference training was performed using slice-level annotation (SLA) and compared to iterative training utilizing patient-level annotations (PLAs) with supervised feedback of CNN estimates into the next training iteration at three incremental training set sizes (N = 200, 500, 998). Model performance was assessed by comparing specificity at fixed sensitivity of 0.97 [254/262] emulating PI-RADS ≥ 3, and 0.88-0.90 [231-236/262] emulating PI-RADS ≥ 4 decisions. STATISTICAL TESTS: Receiver operating characteristic (ROC) and area under the curve (AUC) was compared using DeLong and Obuchowski test. Sensitivity and specificity were compared using McNemar test. Statistical significance threshold was P = 0.05. RESULTS: Test set (N = 695) ROC-AUC performance of SLA (trained with 200/500/998 exams) was 0.75/0.80/0.83, respectively. PLA achieved lower ROC-AUC of 0.64/0.72/0.78. Both increased performance significantly with increasing training set size. ROC-AUC for SLA at 500 exams was comparable to PLA at 998 exams (P = 0.28). ROC-AUC was significantly different between SLA and PLA at same training set sizes, however the ROC-AUC difference decreased significantly from 200 to 998 training exams. Emulating PI-RADS ≥ 3 decisions, difference between PLA specificity of 0.12 [51/433] and SLA specificity of 0.13 [55/433] became undetectable (P = 1.0) at 998 exams. Emulating PI-RADS ≥ 4 decisions, at 998 exams, SLA specificity of 0.51 [221/433] remained higher than PLA specificity at 0.39 [170/433]. However, PLA specificity at 998 exams became comparable to SLA specificity of 0.37 [159/433] at 200 exams (P = 0.70). DATA CONCLUSION: Weakly supervised training of a classification CNN using patient-level-only annotation had lower performance compared to training with slice-wise annotations, but improved significantly faster with additional training data. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Prostate cancer risk assessment and avoidance of prostate biopsies using fully automatic deep learning in prostate MRI: comparison to PI-RADS and integration with clinical data in nomograms.

OBJECTIVES: Risk calculators (RCs) improve patient selection for prostate biopsy with clinical/demographic information, recently with prostate MRI using the prostate imaging reporting and data system (PI-RADS). Fully-automated deep learning (DL) analyzes MRI data independently, and has been shown to be on par with clinical radiologists, but has yet to be incorporated into RCs. The goal of this study is to re-assess the diagnostic quality of RCs, the impact of replacing PI-RADS with DL predictions, and potential performance gains by adding DL besides PI-RADS. MATERIAL AND METHODS: One thousand six hundred twenty-seven consecutive examinations from 2014 to 2021 were included in this retrospective single-center study, including 517 exams withheld for RC testing. Board-certified radiologists assessed PI-RADS during clinical routine, then systematic and MRI/Ultrasound-fusion biopsies provided histopathological ground truth for significant prostate cancer (sPC). nnUNet-based DL ensembles were trained on biparametric MRI predicting the presence of sPC lesions (UNet-probability) and a PI-RADS-analogous five-point scale (UNet-Likert). Previously published RCs were validated as is; with PI-RADS substituted by UNet-Likert (UNet-Likert-substituted RC); and with both UNet-probability and PI-RADS (UNet-probability-extended RC). Together with a newly fitted RC using clinical data, PI-RADS and UNet-probability, existing RCs were compared by receiver-operating characteristics, calibration, and decision-curve analysis. RESULTS: Diagnostic performance remained stable for UNet-Likert-substituted RCs. DL contained complementary diagnostic information to PI-RADS. The newly-fitted RC spared 49% [252/517] of biopsies while maintaining the negative predictive value (94%), compared to PI-RADS ≥ 4 cut-off which spared 37% [190/517] (p < 0.001). CONCLUSIONS: Incorporating DL as an independent diagnostic marker for RCs can improve patient stratification before biopsy, as there is complementary information in DL features and clinical PI-RADS assessment. CLINICAL RELEVANCE STATEMENT: For patients with positive prostate screening results, a comprehensive diagnostic workup, including prostate MRI, DL analysis, and individual classification using nomograms can identify patients with minimal prostate cancer risk, as they benefit less from the more invasive biopsy procedure. KEY POINTS: The current MRI-based nomograms result in many negative prostate biopsies. The addition of DL to nomograms with clinical data and PI-RADS improves patient stratification before biopsy. Fully automatic DL can be substituted for PI-RADS without sacrificing the quality of nomogram predictions. Prostate nomograms show cancer detection ability comparable to previous validation studies while being suitable for the addition of DL analysis.

BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study.

Clear cell renal cell carcinoma (ccRCC) is an immunologically vulnerable tumor entity, and immune checkpoint inhibitors are now widely used to treat patients with advanced disease. Whether and to what extent immune responses in ccRCC are shaped by genetic alterations, however, is only beginning to emerge. In this proof-of-concept study, we performed a detailed correlative analysis of the mutational and immunological landscapes in a series of 23 consecutive kidney cancer patients. We discovered that a high infiltration with CD8 + T cells was not dependent on the number of driver mutations but rather on the presence of specific mutational events, namely pathogenic mutations in PTEN or BAP1. This observation encouraged us to compare mechanisms of T cell suppression in the context of four different genetic patterns, i.e., the presence of multiple drivers, a PTEN or BAP1 mutation, or the absence of detectable driver mutations. We found that ccRCCs harboring a PTEN or BAP1 mutation showed the lowest level of Granzyme B positive tumor-infiltrating lymphocytes (TILs). A multiplex immunofluorescence analysis revealed a significant number of CD8 + TILs in the vicinity of CD68 + macrophages/monocytes in the context of a BAP1 mutation but not in the context of a PTEN mutation. In line with this finding, direct interactions between CD8 + TILs and CD163 + M2-polarized macrophages were found in BAP1-mutated ccRCC but not in tumors with other mutational patterns. While an absence of driver mutations was associated with more CD8 + TILs in the vicinity of FOXP3 + Tregs and CD68 + monocytes/macrophages, the presence of multiple driver mutations was, to our surprise, not found to be strongly associated with immunosuppressive mechanisms. Our results highlight the role of genetic alterations in shaping the immunological landscape of ccRCC. We discovered a remarkable heterogeneity of mechanisms that can lead to T cell suppression, which supports the need for personalized immune oncological approaches.

Contribution of Dynamic Contrast-enhanced and Diffusion MRI to PI-RADS for Detecting Clinically Significant Prostate Cancer.

Background Prostate Imaging Reporting and Data System (PI-RADS) version 2.0 requires multiparametric MRI of the prostate, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) imaging sequences; however, the contribution of DCE imaging remains unclear. Purpose To assess whether DCE imaging in addition to apparent diffusion coefficient (ADC) and normalized T2 values improves PI-RADS version 2.0 for prediction of clinically significant prostate cancer (csPCa). Materials and Methods In this retrospective study, clinically reported PI-RADS lesions in consecutive men who underwent 3-T multiparametric MRI (T2-weighted, DWI, and DCE MRI) from May 2015 to September 2016 were analyzed quantitatively and compared with systematic and targeted MRI-transrectal US fusion biopsy. The normalized T2 signal (nT2), ADC measurement, mean early-phase DCE signal (mDCE), and heuristic DCE parameters were calculated. Logistic regression analysis indicated the most predictive DCE parameters for csPCa (Gleason grade group ≥2). Receiver operating characteristic parameter models were compared using the Obuchowski test. Recursive partitioning analysis determined ADC and mDCE value ranges for combined use with PI-RADS. Results Overall, 260 men (median age, 64 years [IQR, 58-69 years]) with 432 lesions (csPCa [n = 152] and no csPCa [n = 280]) were included. The mDCE parameter was predictive of csPCa when accounting for the ADC and nT2 parameter in the peripheral zone (odds ratio [OR], 1.76; 95% CI: 1.30, 2.44; P = .001) but not the transition zone (OR, 1.17; 95% CI: 0.81, 1.69; P = .41). Recursive partitioning analysis selected an ADC cutoff of 0.897 × 10-3 mm2/sec (P = .04) as a classifier for peripheral zone lesions with a PI-RADS score assessed on the ADC map (hereafter, ADC PI-RADS) of 3. The mDCE parameter did not differentiate ADC PI-RADS 3 lesions (P = .11), but classified lesions with ADC PI-RADS scores greater than 3 with low ADC values (less than 0.903 × 10-3 mm2/sec, P < .001) into groups with csPCa rates of 70% and 97% (P = .008). A lesion size cutoff of 1.5 cm and qualitative DCE parameters were not defined as classifiers according to recursive partitioning (P > .05). Conclusion Quantitative or qualitative dynamic contrast-enhanced MRI was not relevant for Prostate Imaging Reporting and Data System (PI-RADS) 3 lesion risk stratification, while quantitative apparent diffusion coefficient (ADC) values were helpful in upgrading PI-RADS 3 and PI-RADS 4 lesions. Quantitative ADC measurement may be more important for risk stratification than current methods in future versions of PI-RADS. © RSNA, 2022 Online supplemental material is available for this article See also the editorial by Goh in this issue.

Senescent Tumor Cells Are Frequently Present at the Invasion Front: Implications for Improving Disease Control in Patients with Locally Advanced Prostate Cancer.

INTRODUCTION: Local tumor invasion is a critical factor for the outcome of men with prostate cancer. In particular, seminal vesicle invasion (SVI) has been reported to be associated with a more unfavorable prognosis. A better understanding of the functional state of invading prostate cancer cells is crucial to develop novel therapeutic strategies for patients with locally advanced disease. METHODS: The prognostic impact of local tumor progression was ascertained in over 1,000 men with prostate cancer. Prostate cancer specimens were stained by double-immunohistochemistry for the proliferation marker Ki-67 and the senescence marker p16INK4A. The migratory properties of senescent prostate cancer cells were analyzed in vitro using a wound healing assay and immunofluorescence microscopy for p16INK4A. RESULTS: We confirm the notion that patients with SVI have a more unfavorable prognosis than patients with extraprostatic extension alone. Surprisingly, we found that the tumor invasion front frequently harbors p16INK4A-positive and Ki-67-negative, i.e., senescent, tumor cells. While the intraprostatic tumor periphery was a hotspot for both proliferation and expression of p16INK4A, the area of SVI showed less proliferative activity but was at the same time a hotspot of cells with increased nuclear p16INK4A expression. Senescence was associated with an accelerated migration of prostate cancer cells in vitro. CONCLUSION: This proof-of-concept study shows that invading prostate cancer cells frequently show signs of cellular senescence. This finding may open new avenues for neoadjuvant and adjuvant treatment concepts in men with locally advanced prostate cancer.

CD15 is a risk predictor and a novel target in clear cell renal cell carcinoma.

INTRODUCTION: Tumor cells use adhesion molecules like CD15 or sialylCD15 (sCD15) for metastatic spreading. We analyzed the expression of CD15 and sCD15 in clear cell renal cell carcinoma (ccRCC) regarding prognosis. METHODS: A tissue microarray containing tissue specimens of 763 patients with ccRCC was immunohistochemically stained for CD15 and sCD15, their expression quantified using digital image analysis and the impact on patients' survival analyzed. The cell lines 769p and 786o were stimulated with CD15 or control antibody in vitro and the effects on pathways activating AP-1 and tumor cell migration examined. RESULTS: ccRCC showed a broad range of CD15 and sCD15 expression. A high CD15 expression was significantly associated with favorable outcome (p<0.01) and low-grade tumor differentiation (p<0.001), whereas sCD15 had no significant prognostic value. Tumors with synchronous distant metastasis had a significantly lower CD15 expression compared to tumors without any (p<0.001) or with metachronous metastasis (p<0.01). Tumor cell migration was significantly reduced after CD15 stimulation in vitro, but there were no major effects on activating pathways of AP-1. CONCLUSION: CD15, but not sCD15, qualifies as a biomarker for risk stratification and as an interesting novel target in ccRCC. Moreover, the data indicates a contribution of CD15 to metachronous metastasis. Further research is warranted to decipher the intracellular pathways of CD15 signaling in ccRCC in order to characterize the CD15 effects on ccRCC more precisely.

Evaluation of Gas 6 as a Prognostic Marker in Papillary Renal Cell Carcinoma.

INTRODUCTION: Growth arrest-specific protein 6 (Gas 6) is a ligand that plays a role in proliferation and migration of cells. For several tumor entities, high levels of Gas 6 are associated with poorer survival. We examined the prognostic role of Gas 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), which is still unclear. METHODS: The patients' sample collection is a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Gas 6 was determined by immunohistochemistry. RESULTS: In total, Gas 6 staining was evaluable in 180 of 240 type 1 and 110 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed no significant difference in 5-year overall survival for all pRCC nor either subtype. Also, Gas+ and Gas- groups did not significantly differ in any tumor or patient characteristics. CONCLUSION: Gas 6 was not found to be an independent prognostic marker in pRCC. Future studies are warranted to determine if Gas 6 plays a role as prognostic marker or therapeutic target in pRCC.

Cavoatrial hypernephroma resection on cardiopulmonary bypass: Mild/normo-versus moderate hypothermia.

INTRODUCION: Renal cell carcinoma (RCC) is one of the most prevalent malignant tumors. It extends up into the systemic veins and right atrium. Surgical extraction of such extensions is usually carried out using cardiopulmonary bypass (CPB) with moderate hypothermic (MH) being frequently applied in order to obtain a clear surgical field. However, due to obvious disadvantages of hypothermia, approaches with mild/normothermia (NT) during CPB have also been established. The current study aims to compare the outcomes of patients undergoing RCC tumor and extensions resection using MH versus NT. MATERIAL AND METHODS: This is a retrospective, non-randomized study. All patients who underwent RCC tumor and extensions resection for stage III or IV (Staehler) RCC in a single center between 2006 and 2020 were included. During surgery, MH or NT were applied. CPB was realized using aortic and bicaval cannulation. We compared the procedural times, transfusion requirements and postoperative outcomes, respectively between the MH and NT groups. RESULTS: A total of 24 consecutive patients (n(NT) = 12, n(MH) = 12) were included in the study (median age NT 68.5 and MH 66.5). The study only showed a significant difference in heart-lung machine times (median CPB time NT 45.5 min and MH 110.0 min, p = 0.004). All other results, loss of drainage, administration of blood products, as well as the postoperative course and mortality were comparable in both groups. CONCLUSION: The results showed a high perioperative and long-term mortality. The perioperative course was similar after surgery with NT or MH. Therefore, NT which minimizes potential complications of MH should be preferred.

Quality of life after robotic-assisted and laparoscopic radical prostatectomy: Results of a multicenter randomized controlled trial (LAP-01).

BACKGROUND: To explore cross-sectional and longitudinal differences in general health-related and prostate cancer-specific quality of life (QoL) after robotic-assisted (RARP) and laparoscopic (LRP) radical prostatectomy and to analyze predictive variables for QoL outcomes. METHODS: In this multicenter, randomized controlled trial, prostate cancer patients were randomly assigned 3:1 to undergo either RARP or LRP. Patient-reported outcomes were prospectively collected before and 1, 3, 6, 12 months after radical prostatectomy and included QoL as a secondary outcome. Validated questionnaires were used to assess general health-related (EORTC QLQ-C30) and prostate cancer-specific (QLQ-PR25) QoL. Cross-sectional and longitudinal contrasts were analyzed through linear mixed models. Predictive variables for QoL outcomes were identified by general linear modeling. RESULTS: Of 782 randomized patients, QoL was evaluable in 681 patients. In terms of general QoL, the cross-sectional analysis showed only small differences between study arms, whereas longitudinal comparison indicated an advantage of RARP on recovery: RARP patients reported an earlier return to baseline in global health status (3 vs. 6 months) and social functioning (6 vs. 12 months). In role functioning, only the RARP arm regained baseline scores. Regarding prostate-specific QoL, LRP patients experienced more urinary symptoms and reported 3.2 points (95% confidence interval 0.4-6, p = 0.024) higher mean scores at 1-month follow-up and in mean 2.9 points (0.1-5, p = 0.042) higher urinary symptoms scores at 3-month follow-up than RARP patients. There were no other significant differences between treatment groups. Urinary symptoms, sexual activity, and sexual function remained significantly worse compared with baseline at all time points in both arms. CONCLUSIONS: Compared with LRP, the robotic approach led to an earlier return to baseline in several domains of general health-related QoL and better short-term recovery of urinary symptoms. Predictive variables such as the scale-specific baseline status and bilateral nerve-sparing were confirmed.

Age-stratified outcomes after radical prostatectomy in a randomized setting (LAP-01): do younger patients have more to lose?

OBJECTIVE: Age is known to have an impact on outcomes after radical prostatectomy (RP). However, age differences can be investigated from a cross-sectional as well as from a longitudinal perspective. This study combines both perspectives. MATERIALS AND METHODS: LAP-01 is the first multicenter randomized patient blinded trial comparing outcomes after robotic-assisted and laparoscopic RP. This study stratified the entire population that received nerve-sparing surgery and was potent at baseline by the following ages: ≤ 60 years, 61-65 years, and > 65 years. Potency was assessed using the IIEF-5. The EORTC QLQ-C30 was used for global health perception and the EORTC QLQ-PR25 for urinary symptoms. Continence was assessed by the number of pads used. Longitudinal change was assessed using either validated anchor-based criteria or the 1 or 0.5-standard-deviation criterion. Worsening of continence was measured by increasing numbers of pads. RESULTS: 310 patients were included into this study. Older patients had a significantly higher risk for worsening of continence at 3 and 6 months (OR 2.21, 95% CI [1.22, 4.02], p = 0.009 and OR 2.00, 95% CI [1.16, 3.46], p = 0.013, respectively); at 12 months, the odds of worsening did not differ significantly between age groups. Potency scores were better in younger patients from a cross-sectional perspective, but longitudinal change did not differ between the age groups. In contrast, global health perception was better in older patients from a cross-sectional perspective and longitudinal decreases were significantly more common among the youngest patients, at 12 months (36.9% vs. 24.4%, p = 0.038). CONCLUSION: From a cross-sectional perspective, function scores were better in younger patients, but from a longitudinal perspective, age differences were found in continence only. In contrast, global health scores were better in older patients from a cross-sectional and longitudinal perspective. TRIAL REGISTRATION: The LAP-01 trial was registered with the U.S. National Library of Medicine clinical trial registry (clinicaltrials.gov), NCT number: NCT03682146, and with the German Clinical Trial registry (Deutsches Register Klinischer Studien), DRKS ID number: DRKS00007138.

Interleukin-2 and Interferon-α for Advanced Renal Cell Carcinoma: Patient Outcomes, Sexual Dimorphism of Responses, and Multimodal Treatment Approaches over a 30-Year Period.

INTRODUCTION: Cytokine-based immunotherapy (IT) has been the mainstay of systemic treatment of advanced renal cell carcinoma (RCC) from the late 1980s until 2007. With the introduction of immune checkpoint inhibitors, a renaissance of immune oncological approaches is rapidly unfolding. MATERIALS AND METHODS: In the present study, we revisited survival outcomes, sexual dimorphism of treatment responses, and the relevance of multimodal treatment approaches over a 30-year period in 156 patients with advanced RCC treated with subcutaneous (s.c.) interleukin-2 (IL-2) and interferon-α (IFN-α) between 1990 and 2009. RESULTS: The median progression-free survival following the first IT was 5.8 months with a wide range from 0 to 197 months. The median overall survival (OS) was 25.8 months and the median cancer-specific survival after tumor nephrectomy was 24.6 months. A group of 29 patients (18.6%) and 11 patients (7.1%) survived longer than 5 and 10 years after surgery, respectively. A difference in the 5-year OS rate between male and female patients was detected (men, 21.6%; women, 11.1%). However, no sex-specific survival advantage was observed after 10 years. CONCLUSIONS: We provide evidence that IT with s.c. IL-2 and IFN-α played a vital role in long-term survivors either by inducing lasting complete remissions or as part of multimodal approaches that allowed patients to survive until novel therapies became available. The implications for current immune oncological treatment approaches are being discussed.

The Prognostic Impact of PD-L2 in Papillary Renal-Cell Carcinoma.

INTRODUCTION: Programmed death-1 ligand (PD-L1) has been often studied in different types of renal-cell carcinoma (RCC). For example, in clear-cell renal carcinoma it is well established that programmed death-1 receptor and PD-L1 are important prognostic markers. In contrast, the role of programmed death-2 ligand (PD-L2) as prognostic marker remains unclear. The aim of this study was to evaluate if PD-L2 expression could play a role as a prognostic marker for papillary RCC (pRCC). METHODS: The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of PD-L2 was determined by immunohistochemistry. In total, PD-L2 staining was evaluable in 185 of 240 type 1 and 99 of 128 type 2 pRCC cases. RESULTS: PD-L2 staining was positive in 67 (36.2%) of type 1 and in 31 (31.3%) of type 2 pRCC specimens. The prevalence of PD-L2+ cells was significantly higher in high-grade type 1 tumors (p = 0.019) and in type 2 patients with metastasis (p = 0.002). Kaplan-Meier analysis disclosed significant differences in 5-year overall survival (OS) for patients with PD-L2- compared to PD-L2+ in pRCC type 1 of 88.4% compared to 73.6% (p = 0.039) and type 2 of 78.8% compared to 39.1% % (p < 0.001). However, multivariate analysis did not identify the presence of PD-L2+ cells neither in type 1 nor type 2 pRCC as an independent predictor of poor OS. DISCUSSION/CONCLUSION: PD-L2 expression did not qualify as an independent prognostic marker in pRCC. Future studies will have to determine whether anti-PD-L2-targeted treatment may play a role in pRCC and expression can potentially serve as a predictive marker for these therapeutic approaches.

PARP inhibition in prostate cancer.

Defects in DNA damage repair genes are more common in prostate cancer than previously thought. These alterations provide an opportunity for precision oncology approaches and a number of studies have now shown that PARP inhibitors can have significant antitumor activity in men with DNA damage repair-deficient metastatic castration-resistant prostate cancer. This review summarizes the key clinical trials related to the use of PARP inhibitors in prostate cancer. Besides clinical outcomes, toxicity, and PARP inhibitor resistance, the role of different DNA repair genes in the response to PARP inhibition will be discussed.

Simulated clinical deployment of fully automatic deep learning for clinical prostate MRI assessment.

OBJECTIVES: To simulate clinical deployment, evaluate performance, and establish quality assurance of a deep learning algorithm (U-Net) for detection, localization, and segmentation of clinically significant prostate cancer (sPC), ISUP grade group ≥ 2, using bi-parametric MRI. METHODS: In 2017, 284 consecutive men in active surveillance, biopsy-naïve or pre-biopsied, received targeted and extended systematic MRI/transrectal US-fusion biopsy, after examination on a single MRI scanner (3 T). A prospective adjustment scheme was evaluated comparing the performance of the Prostate Imaging Reporting and Data System (PI-RADS) and U-Net using sensitivity, specificity, predictive values, and the Dice coefficient. RESULTS: In the 259 eligible men (median 64 [IQR 61-72] years), PI-RADS had a sensitivity of 98% [106/108]/84% [91/108] with a specificity of 17% [25/151]/58% [88/151], for thresholds at ≥ 3/≥ 4 respectively. U-Net using dynamic threshold adjustment had a sensitivity of 99% [107/108]/83% [90/108] (p > 0.99/> 0.99) with a specificity of 24% [36/151]/55% [83/151] (p > 0.99/> 0.99) for probability thresholds d3 and d4 emulating PI-RADS ≥ 3 and ≥ 4 decisions respectively, not statistically different from PI-RADS. Co-occurrence of a radiological PI-RADS ≥ 4 examination and U-Net ≥ d3 assessment significantly improved the positive predictive value from 59 to 63% (p = 0.03), on a per-patient basis. CONCLUSIONS: U-Net has similar performance to PI-RADS in simulated continued clinical use. Regular quality assurance should be implemented to ensure desired performance. KEY POINTS: • U-Net maintained similar diagnostic performance compared to radiological assessment of PI-RADS ≥ 4 when applied in a simulated clinical deployment. • Application of our proposed prospective dynamic calibration method successfully adjusted U-Net performance within acceptable limits of the PI-RADS reference over time, while not being limited to PI-RADS as a reference. • Simultaneous detection by U-Net and radiological assessment significantly improved the positive predictive value on a per-patient and per-lesion basis, while the negative predictive value remained unchanged.

Evaluation of new motorized articulating laparoscopic instruments by laparoscopic novices using a standardized laparoscopic skills curriculum.

BACKGROUND: Motorized articulating laparoscopic instruments (ALI) offer more degrees of freedom than conventional laparoscopic instruments (CLI). However, a difficult learning curve and complex instrument handling are still a problem of ALI. We compared the performance of new prototypes of motorized ALI with CLI in a series of standardized laparoscopic tasks performed by laparoscopic novices. Further, usability of the new ALI was assessed. METHODS: A randomized cross-over study with 50 laparoscopic novices who either started with CLI and then changed to ALI (CA) or vice versa (AC) was conducted. All participants performed the European training in basic laparoscopic urological skills (E-BLUS) with each instrument in given order. Time and errors were measured for each exercise. Instrument usability was assessed. RESULTS: Overall, using CLI was significantly faster (CLI 4:27 min vs. ALI 4:50 min; p-value 0.005) and associated with fewer exercise failures in needle guidance (CLI 0 vs. ALI 12; p-value 0.0005) than ALI. Median amount of errors was similar for both instruments. Instrument sequence did not matter, as CA and AC showed comparable completion times. Regarding the learning effect, participants were significantly faster in the second attempt of exercises than in the first. In the needle guidance task, participants using CLI last demonstrated a significant speed improvement, whereas ALI were significantly slower in the second run. Regarding usability, CLI were preferred over ALI due to lighter weight and easier handling. Nevertheless, participants valued ALI's additional degrees of freedom. CONCLUSION: Using new motorized ALI in the E-BLUS examination by laparoscopic novices led to a worse performance compared to CLI. An explanation could be that participants felt overwhelmed by ALI and that ALI have an own distinct learning curve. As participants valued ALI's additional degrees of freedom, however, a future application of ALI could be for training purposes, ideally in combination with CLI.

Recovery of pad-free continence in elderly men does not differ from younger men undergoing robot-assisted radical prostatectomy for aggressive prostate cancer.

PURPOSE: To analyze urinary continence outcome following robot-assisted radical prostatectomy (RARP) for aggressive prostate cancer in men aged ≥ 70 and < 70 years. METHODS: Retrospective analyses of prospectively collected long-term data from a monocentric cohort of 350 men with D'Amico high-risk prostate cancer undergone robot-assisted radical prostatectomy at a single institution between 2005 and 2016. The association between time since operation and zero-pad urinary continence recovery was comparatively analyzed by separate pre-operative and post-operative Cox proportional-hazard regression models. RESULTS: Median age in the age group ≥ 70 years was 73 years compared with 62 years in the < 70 year age group. Distribution of men receiving adjuvant and salvage radiotherapy/hormonal therapy was similar in both age groups. Urinary continence recovery rate at 12, 24, and 36 months after surgery of men aged ≥ 70 years was 66, 79 and 83%, respectively, and statistically similar to that of men < 70 years: 71, 81, and 85% (log-rank test p = 0.24). Multivariable analyses demonstrated no significant difference in return to continence between the two age groups (p = 0.28 and p = 0.17). In addition, clinical stage and type of nerve sparing (unilateral, bilateral or non-nerve sparing) were found to be independently predictive of pad-free continence recovery. CONCLUSIONS: Regardless of age, return to continence in men with aggressive prostate cancer undergoing RARP continues to improve way beyond the first 12 months after surgery. Considering the dire effects of post-operative radiotherapy on continence in this aggressive cancer cohort, advanced age alone should not discourage recommending multimodal therapy involving RARP.

Microenvironment-Derived FGF-2 Stimulates Renal Cell Carcinoma Cell Proliferation through Modulation of p27Kip1: Implications for Spatial Niche Formation and Functional Intratumoral Heterogeneity.

BACKGROUND/OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is characterized by a high degree of functional intratumoral heterogeneity (ITH). This is highlighted by the finding that tumor cell proliferation and intracellular signaling occur preferentially in the tumor periphery. The driving forces for such a spatial organization are largely unknown. Herein, we investigate the role of the tumor microenvironment in the control of tumor cell proliferation and functional ITH. METHODS: Conditioned media (CM) derived from nonmalignant peritumoral kidney tissue were used to stimulate RCC cells in vitro. A neutralization assay was used to characterize the role of FGF-2 in the CM. The molecular mechanisms underlying the action of CM on RCC cells were investigated using immunoblotting, flow cytometry and immunofluorescence microscopy. Lastly, a series of ccRCCs were stained for Ki-67 and p27Kip1, and expression was analyzed in both tumor periphery and center. RESULTS: We show that CM derived from nonmalignant kidney cells adjacent to an RCC can downregulate the expression of the CDK inhibitor p27Kip1 through enhanced protein degradation in an FGF-2-dependent fashion. FGF-2 functions mainly through the PI3K/AKT pathway downstream of its receptors, and RCC cells with constitutively high AKT activity show not only an enhanced degradation of p27Kip1 through the Emi1-Skp2 axis, but also a subcellular mislocalization of p27Kip1 to the cytoplasmic compartment. Such a mislocalization was also detected in the tumor periphery in vivo suggesting that p27Kip1 plays an important role in shaping this spatial niche. CONCLUSIONS: Our results suggest that the tumor microenvironment is involved in shaping the tumor peripheral niche by stimulating the enhanced proliferation that is characteristic for this zone.

The BRCA2 mutation status shapes the immune phenotype of prostate cancer.

Defects in DNA damage repair caused by mutations in BRCA1/2, ATM or other genes have been shown to play an important role in the development and progression of prostate cancer. The influence of such mutations on anti-tumor immunity in prostate cancer, however, is largely unknown. To better understand the correlation between BRCA1/2 mutations and the immune phenotype in prostate cancer, we characterized the immune infiltrate of eight BRCA2-mutated tumors in comparison with eight BRCA1/2 wild-type patients by T-cell receptor sequencing and immunohistochemistry for CD45, CD4, CD8, FOXP3, and CD163. In addition, we analyzed seven prostate cancer biopsies that were either BRCA2 or ATM-mutated in comparison with wild-type tumors. Whereas in BRCA1/2 wild-type tumors, immune cells were found predominantly extratumorally, most BRCA2-mutated tumors including one biopsy showed a significantly increased intratumoral immune cell infiltration. The ratio of intratumoral to extratumoral immune cells was considerably higher in BRCA2-mutated tumors for all markers and reached statistical significance for CD4 (p = 0.007), CD8 (p = 0.006), and FOXP3 (p = 0.001). However, the intratumoral CD8 to FOXP3 ratio showed a trend to be lower in BRCA2-mutated tumors suggesting a more suppressed tumor immune microenvironment. Our findings provide a rationale for the future use of immune oncological approaches in BRCA2-mutated prostate cancer and may encourage efforts to target immunosuppressive T-cell populations to prime tumors for immunotherapy.

Classification of Cancer at Prostate MRI: Deep Learning versus Clinical PI-RADS Assessment.

Background Men suspected of having clinically significant prostate cancer (sPC) increasingly undergo prostate MRI. The potential of deep learning to provide diagnostic support for human interpretation requires further evaluation. Purpose To compare the performance of clinical assessment to a deep learning system optimized for segmentation trained with T2-weighted and diffusion MRI in the task of detection and segmentation of lesions suspicious for sPC. Materials and Methods In this retrospective study, T2-weighted and diffusion prostate MRI sequences from consecutive men examined with a single 3.0-T MRI system between 2015 and 2016 were manually segmented. Ground truth was provided by combined targeted and extended systematic MRI-transrectal US fusion biopsy, with sPC defined as International Society of Urological Pathology Gleason grade group greater than or equal to 2. By using split-sample validation, U-Net was internally validated on the training set (80% of the data) through cross validation and subsequently externally validated on the test set (20% of the data). U-Net-derived sPC probability maps were calibrated by matching sextant-based cross-validation performance to clinical performance of Prostate Imaging Reporting and Data System (PI-RADS). Performance of PI-RADS and U-Net were compared by using sensitivities, specificities, predictive values, and Dice coefficient. Results A total of 312 men (median age, 64 years; interquartile range [IQR], 58-71 years) were evaluated. The training set consisted of 250 men (median age, 64 years; IQR, 58-71 years) and the test set of 62 men (median age, 64 years; IQR, 60-69 years). In the test set, PI-RADS cutoffs greater than or equal to 3 versus cutoffs greater than or equal to 4 on a per-patient basis had sensitivity of 96% (25 of 26) versus 88% (23 of 26) at specificity of 22% (eight of 36) versus 50% (18 of 36). U-Net at probability thresholds of greater than or equal to 0.22 versus greater than or equal to 0.33 had sensitivity of 96% (25 of 26) versus 92% (24 of 26) (both P > .99) with specificity of 31% (11 of 36) versus 47% (17 of 36) (both P > .99), not statistically different from PI-RADS. Dice coefficients were 0.89 for prostate and 0.35 for MRI lesion segmentation. In the test set, coincidence of PI-RADS greater than or equal to 4 with U-Net lesions improved the positive predictive value from 48% (28 of 58) to 67% (24 of 36) for U-Net probability thresholds greater than or equal to 0.33 (P = .01), while the negative predictive value remained unchanged (83% [25 of 30] vs 83% [43 of 52]; P > .99). Conclusion U-Net trained with T2-weighted and diffusion MRI achieves similar performance to clinical Prostate Imaging Reporting and Data System assessment. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Padhani and Turkbey in this issue.

Histopathological to multiparametric MRI spatial mapping of extended systematic sextant and MR/TRUS-fusion-targeted biopsy of the prostate.

PURPOSE: MRI has limited ability to detect multifocal disease or the full extent of prostate involvement with clinically significant prostate cancer (sPC). We compare the spatial co-localization at sextant resolution of MRI lesions and histopathological mapping by combined targeted and extended systematic biopsies. MATERIALS AND METHODS: Sextants were mapped for sPC (ISUP group ≥ 2) by 24-core transperineal systematic biopsies in 316 patients with suspicion for sPC and by MR lesions of PI-RADS score of ≥ 3. The gold standard is combined systematic (median 23 cores) and targeted biopsies. RESULTS: Of 316 men, 121 (38%) harbored sPC. Of these 121 patients, 4 (3%) had a negative MRI. MRI correctly identified 117/121 (97%) patients with sPC. In these patients, mpMRI missed no additional sPC in 96 (82%), while MRI-negative sPC lesions were present in 21 patients (18%). Of 1896 sextants, 379 (20%) harbored sPC. MR-positive sextants contained sPC in 26% (337/1275), compared to 7% (42/621) in MR-negative sextants. On a patient basis, sensitivity was 0.97, specificity 0.22, positive predictive value 0.43, and negative predictive value 0.91. On a sextant basis, sensitivity was 0.73, specificity 0.38, positive predictive value 0.26, and negative predictive value 0.93. CONCLUSION: MpMRI mapping agreed well with histopathology with, at the observed sPC prevalence and on a patient basis, excellent sensitivity and negative predictive value, and acceptable specificity and positive predictive value for sPC. However, 18% of sPC was outside the mpMRI mapped region, quantifying limitations of MRI for complete localization of disease extent. KEY POINTS: • Currently, exclusive MRI mapping of the prostate for focal treatment planning cannot be recommended, as significant prostate cancer may remain untreated in a substantial number of cases. • At the observed sPC prevalence and on a patient basis, mpMRI has excellent sensitivity and NPV, and acceptable specificity and PPV for detection of prostate cancer, supporting its use to detect suspicious lesions before biopsy. • Despite the excellent global performance, 18% of sPC was outside the mpMRI mapped region even when a security margin of 10 mm was considered, indicating that prostate MRI has limited ability to completely map all cancer foci within the prostate.