ISUP Grade Research Articles

Therapy decisions after diagnosis of prostate cancer in men with negative prostate MRI.

To investigate the clinical implications of magnetic resonance imaging(MRI) negative prostate cancer (PCa) in a cohort of men undergoing transperineal prostate biopsy. We included all men without prior diagnosis of PCa undergoing transperineal template saturation ± fusion-guided targeted biopsy of the prostate between November 2014and March 2018. Before biopsy, all patients underwent MRI and biopsies were performed irrespective of imaging results. Baseline characteristics, imaging, biopsy results, and follow-up information were retrieved from the patient charts. Patients were classified as either MRI negative (Prostate Imaging Reporting and Data System[PIRADS] ≤ 2) or positive (PIRADS ≥ 3). ISUP grade group 1 was defined as clinically nonsignificant (nsPCa) and ≥2 as clinically significant PCa (csPCa). Primary outcome was the individual therapeutic decision after diagnosis of PCa stratified according to MRI visibility. Secondary outcomes were the sensitivity and specificity of MRI, and the urooncological outcomes after radical prostatectomy (RP). From 515 patients undergoing prostate biopsy, 171 (33.2%) patients had a negative and 344 (66.8%) a positive MRI. Pathology review stratified for MRI negative and positive cases revealed nsPCa in 27 (15.8%) and 32 (9.3%) and csPCa in 26 (15.2%) and 194 (56.4%) of the patients, respectively. The rate of active treatment in the MRI negative was lower compared with the MRI positive cohort (12.3% vs. 53.2%; odd ratio [OR] = 0.12; p < 0.001). While men with negative MRI were more likely to undergo active surveillance (AS) than MRI positive patients (18.1% vs. 10.8%; OR = 1.84; p = 0.027), they rarely underwent RP (6.4% vs. 40.7%, OR = 0.10; p < 0.001). Logistic regression revealed that a negative MRI was independently protective for active treatment (OR = 0.32, p = 0.014). The specificity, sensitivity, negative, and positive predictive value of MRI for detection of csPCa were 49.2%, 88.2%, 56.4%, and 84.8%, respectively. The rate of adverse clinicopathological outcome features (pT3/4, ISUP ≥4, or prostate-specific antigen[PSA]-persistence) following RP was 4.7% for men with MRI negative compared to 17.4% for men with MRI positive PCa (OR = 3.1, p = 0.19). Only few men with MRI negative PCa need active cancer treatment at the time of diagnosis, while the majority opts for AS. Omitting prostate biopsies and performing a follow-up MRI may be a safe alternative to reduce the number of unnecessary interventions.

The clinical consequences of routine 68Ga-PSMA-11 PET/CT in patients with newly diagnosed prostate cancer, ISUP grade 5 and no metastases based on standard imaging – preliminary results

Aim To evaluate the clinical consequences of prostate specific membrane antigen (PSMA) PET/CT for primary staging in patients with ISUP grade 5 (Gleason score ≥9) prostate cancer (PCa), and no definitive distant metastases based on standard imaging. Methods At our tertial referral center, PSMA PET/CT became standard of care from August 2018 for primary staging of prostate cancer given the following criteria: (1) no prior treatment for prostate cancer, (2) ISUP grade 5, (3) no definitive metastases on standard imaging (contrast enhanced CT and bone scintigraphy), and (4) deemed suitable for treatment with curative intent based on comorbidity and life expectancy. We present the preliminary results of first six months recruitment with 12 months of follow-up. Results Forty-eight patients (mean age 69 years, median PSA 13.0 ng/mL, 20 patients with locally advanced PCa) were included. CT was positive in pelvic lymph nodes in two patients, bone scintigraphy was equivocal in three patients. PSMA PET/CT showed pathological uptake outside the prostatic bed in 22 patients (46%) of which 13 patients (27%) showed lesions confined to regional lymph nodes, and nine patients (19%) showed nonregional lymph node metastases and/or bone metastases. PSMA PET/CT changed the treatment strategy from curatively intended treatment to palliative treatment in 18 patients (38%) Conclusion PMSA PET/CT revealed pathological uptake in a large proportion of high-risk patients at primary staging among patients with no definite metastases on standard imaging leading to change of patient management in 38% of the patients.

Significance of metabolic tumor volume and total lesion uptake measured using Ga-68 labelled prostate-specific membrane antigen PET/CT in primary staging of prostate cancer.

To evaluate the accuracy of Ga-68 prostate-specific membrane antigen positron-emission-tomography and computed-tomography(PSMA-PET/CT) in primary nodal staging of prostate cancer (PCa), and the predictive value of volumetric parameters derived from Ga-68- PSMA-PET/CT data in lymph node(LN) metastasis and correlation with histopathological and surgical outcomes. Seventy-seven patients with newly diagnosed, biopsy-proven PCa who underwent Ga-68-PSMA-PET/CT for primary staging of disease and underwent radical prostatectomy with extendend pelvic LN dissection were evaluated retrospectively. 2 experienced nuclear medicine specialists have retrospectively reviewed PET/CT images blinded to all histopathological and clinical data. Sensitivity, specificity, positive predictive value(PPV), and negative predictive value(NPV) for the detection of LN metastases were analyzed per-patient. Volumetric and semiquantitative PET parameters of the primary prostate lesions including SUVmax,metabolic tumor volume(MTV), and total lesion uptake(TLU) were measured and recorded. Primary tumor SUVmax, MTV and TLU were found significantly higher in patients who were in higher ISUP Grade groups 3,4,5 after surgical treatment (P = 0.021,P = 0.049,P = 0.032, respectively). The sensitivity, specificity, PPV and NPV on LN metastasis detection of Ga-68-PSMA-PET/CT was found 60%, 91%, 82% and 78% respectively. Although the distribution of the measured primary tumor MTV and TLU values were higher in histopathologically proven LN metastasis positive patients compared to negative patients, only TLU was statistically significant(P = 0.023). Increase in primary tumor TLU values were correlated with higher pT stages and surgical margin positivity(P = 0.034). Ga-68-PSMA-PET/CT is of clinically valuable for primary staging. Measuring and adding these 2 parameters in routine clinical evaluation may increase the prediction power of high-grade disease confirmed by surgery.

Tissue immunostaining of candidate prognostic proteins in metastatic and non-metastatic prostate cancer.

Prostate cancer (PCa) lacks specific markers capable of distinguishing aggressive tumors from those with indolent behavior. Therefore, the aim of this study was to evaluate the immunostaining of candidate proteins (PTEN, AKT, TRPM8, and NKX3.1) through the immunohistochemistry technique (IHC) on patients with metastatic and non-metastatic PCa. Tissues from 60 patients were divided into three groups categorized according to prognostic parameters: better prognosis (n = 20), worse prognosis (n = 23), and metastatic (n = 17). Immunostaining was analyzed by a pathologist and staining classifications were considered according to signal intensity: (0) no staining, (+) weak, and (++ and +++) intermediate to strong. AKT protein was associated (p = 0.012) and correlated (p = 0.014; Tau = -0.288) with the prognostic groups. The immunostaining for TRPM8 (p = 0.010) and NKX3.1 (p = 0.003) proteins differed between malignant tumor and non-tumoral adjacent tissue as well as for proteins in cellular locations (nucleus and cytoplasm). TRPM8 was independently associated with the ISUP grade ≥ 4 (p = 0.024; OR = 8.373; 95% CI = 1.319-53.164). The NKX3.1 showed positive and predominantly strong immunostaining in all patients in both tumoral and non-tumoral adjacent tissues. All metastatic samples had positive immunostaining, with strong intensity for NKX3.1 (p = 0.021; Tau = -0.302). In the non-metastatic group, this strong protein staining was not observed in any patients. This study confirmed that NKX3.1 is highly specific for prostate tissue and indicated that NKX3.1, AKT, and TRPM8 may be candidate markers for prostate cancer prognosis.

840 PSMA PET/CT in Prostate Cancer (PCa) Management: Outcomes from a high-volume tertiary NHS centre

Abstract Introduction PSMA PET-CT (PSMA) is a relatively new development in PCa imaging. We report the role and impact of PSMA in the management of both primary and recurrent PCa since our service's inception in January 2020. Method A retrospective analysis of PSMA database was conducted. All patients underwent conventional imaging (CI) [CT/MRI &amp; Bone scan] as well. Indications for PSMA were: Data collected included demographics, PSA, ISUP grade, D'Amico risk classification, and TNM staging. Data are expressed as median (range) and analysed using SPSS v25. Results Overall, 454 scans were reviewed; 175 (38.5%) and 279 (61.5%) scans were offered to evaluate primary and recurrent disease, respectively. On reassessment with PSMA, 54.2% of all scans showed nodal or metastatic involvement that led to re-staging. More specifically, 56%% of primary cases and 77.1% of recurrent cases had their stage, and consequentially, management plan modified. ISUP, cT3 stage, and D’Amico risk classification were not associated with upstaging (p &amp;gt;0.05). Overall, there was poor agreement between CI and PSMA when evaluating nodal (k = 0.216, p &amp;lt;0.005) and metastases (k= 0.171, p&amp;lt;0.005) in staging either primary or recurrent disease. Conclusions PSMA is superior to CI in staging PCa and significantly alters management in these patients. It should be offered as the first line of staging imaging for primary (high-risk) and prior to salvage therapy.

Advanced age portends poorer prognosis after radical prostatectomy: a single center experience

Introduction and objectiveAlthough advanced age doesn’t seem to impair oncological outcomes after robot-assisted radical prostatectomy (RARP), elderly patients have increased rates of prostate cancer (PCa) related deaths due to a higher incidence of high-risk disease. The potential unfavorable impact of advanced age on oncological outcomes following RARP remains an unsettled issue. We aimed to evaluate the oncological outcome of PCa patients > 69 years old in a single tertiary center.Materials and methods1143 patients with clinically localized PCa underwent RARP from January 2013 to October 2020. Analysis was performed on 901 patients with available follow-up. Patients ≥ 70 years old were considered elderly. Unfavorable pathology included ISUP grade group > 2, seminal vesicle, and pelvic lymph node invasion. Disease progression was defined as biochemical and/or local recurrence and/or distant metastases.Results243 cases (27%) were classified as elderly patients (median age 72 years). Median (IQR) follow-up was 40.4 (38.7–42.2) months. Disease progression occurred in 159 cases (17.6%). Elderly patients were more likely to belong to EAU high-risk class, have unfavorable pathology, and experience disease progression after surgery (HR = 5.300; 95% CI 1.844–15.237; p = 0.002) compared to the younger patients.ConclusionsElderly patients eligible for RARP are more likely to belong to the EAU high-risk category and to have unfavorable pathology that are independent predictors of disease progression. Advanced age adversely impacts on oncological outcomes when evaluated inside these unfavorable categories. Accordingly, elderly patients belonging to the EAU high-risk should be counseled about the increased risk of disease progression after surgery.

Prostate Cancer Detection with mpMRI According to PI-RADS v2 Compared with Systematic MRI/TRUS-Fusion Biopsy: A Prospective Study.

Background: mpMRI assesses prostate lesions through their PI-RADS score. The primary goal of this prospective study was to demonstrate the correlation of PI-RADS v2 score and the volume of a lesion with the presence and clinical significance of prostate cancer (PCa). The secondary goal was to determine the extent of additionally PCa in inconspicuous areas. Methods: All 157 patients underwent a perineal MRI/TRUS-fusion prostate biopsy. Targeted biopsies as well as a systematic biopsy were performed. The presence of PCa in the probes was specified by the ISUP grading system. Results: In total, 258 lesions were biopsied. Of the PI-RADS 3 lesions, 24% were neoplastic. This was also true for 36.9% of the PI-RADS 4 lesions and for 59.5% of the PI-RADS 5 lesions. Correlation between ISUP grades and lesion volume was significant (p < 0.01). In the non-suspicious mpMRI areas carcinoma was revealed in 19.7% of the patients. Conclusions: The study shows that the PI-RADS v2 score and the lesion volume correlate with the presence and clinical significance of PCa. However, there are two major points to consider: First, there is a high number of false positive findings. Second, inconspicuous mpMRI areas revealed PCa.

Comparison of 68Ga-PSMA PET/CT and mp-MRI in regard to local staging for prostate cancer with histopathological results: A retrospective study.

Imaging modalities are used to diagnose and clinical grading of clinically significant prostate cancer. In this study, 68Ga-PSMA PET/CT (PSMA) and multiparametric prostate MRI (mp-MRI) were compared in regard to locating intraprostatic tumor and locoregional staging. After ethics committee approval, a total of 49 patients with prostate cancer who had mp-MRI and PSMA before radical prostatectomy were included. Preoperative and postoperative PSA, transrectal ultrasound-guided prostate biopsy (TRUS-Bx) ISUP grade, radical prostatectomy ISUP grade, body mass index (BMI), TRUS prostate volume, mp-MRI tumor mapping, PSMAtumor mapping, pathologic tumor mapping, extraprostatic extension (EPE), seminal vesicle invasion (SVI), lymph node invasion (LNI), and bladder neck invasion (BNI)were retrospectively evaluated. Index tumor was located by uroradiologist, nuclear medicine specialist, and uropathologist on a 12-sector prostate pathology map and compared with each other in terms of accuracy and locoregional clinical staging. Mean age of the patients was 66.18 ± 6.67 years and the mean of preoperative PSA results was 21.11 ± 32.56 ng/ml. Nearly half of the patients' (44.9%) pathology was reported as ISUP grade 4 and 5% and 18.4% of patients were surgical margin positive. According to the pathological findings, 362 out of 588 sectors were tumor-positive, 174 out of 362 sectors were tumor-positive in mp-MRI, and 175 out of 362 sectors were tumor-positive in PSMA. Both PSMA and mp-MRI were comparable (p = 0.823) and accurate to detect the location of the intraprostatic index tumor (AUC = 0.66 vs. 0.69 respectively, p = 0.82). The sensitivity and the specificity of the PSMA and mp-MRI for localizing intraprostatic index tumors were 42.5% versus 49.5% and 90.7% versus 88.6% respectively. mp-MRI was more accurate than PSMA in terms of EPE (AUC = 0.8 vs. AUC = 0.57 respectively, p = 0.027) and both methods were comparable in terms of SVI (AUC = 0.75 vs. AUC = 0.75, p = 0.886) and BNI (AUC = 0.51 vs. AUC = 0.59, p = 0.597). PSMA and mp-MRI were comparable in terms of LNI (AUC = 0.76 vs. AUC = 0.64, p = 0.39). mp-MRI should be considered for its high accuracy in the diagnosis of EPE, especially before decision-making for nerve-sparing surgery in high-risk patients. Both imaging modalities were accurate for localizing intraprostatic index tumor. PSMA is accurate for detecting LNI.

Prognostic Gene Expression-Based Signature in Clear-Cell Renal Cell Carcinoma.

Simple SummaryIn this study, we identified molecular markers for disease progression from ccRCC tissue samples. Using the selected biomarkers and clinical data from the TCGA cohort, we developed a gene expression-based signature which enhances the prognostic prediction of clinicopathological variables and could help to provide personalized disease management.The inaccuracy of the current prognostic algorithms and the potential changes in the therapeutic management of localized ccRCC demands the development of an improved prognostic model for these patients. To this end, we analyzed whole-transcriptome profiling of 26 tissue samples from progressive and non-progressive ccRCCs using Illumina Hi-seq 4000. Differentially expressed genes (DEG) were intersected with the RNA-sequencing data from the TCGA. The overlapping genes were used for further analysis. A total of 132 genes were found to be prognosis-related genes. LASSO regression enabled the development of the best prognostic six-gene panel. Cox regression analyses were performed to identify independent clinical prognostic parameters to construct a combined nomogram which includes the expression of CERCAM, MIA2, HS6ST2, ONECUT2, SOX12, TMEM132A, pT stage, tumor size and ISUP grade. A risk score generated using this model effectively stratified patients at higher risk of disease progression (HR 10.79; p < 0.001) and cancer-specific death (HR 19.27; p < 0.001). It correlated with the clinicopathological variables, enabling us to discriminate a subset of patients at higher risk of progression within the Stage, Size, Grade and Necrosis score (SSIGN) risk groups, pT and ISUP grade. In summary, a gene expression-based prognostic signature was successfully developed providing a more precise assessment of the individual risk of progression.

2 - Focal high-intensity focused ultrasound vs. active surveillance for ISUP grade 1 prostate cancer: Medium-term results of a prospective matched-pair comparison

2 - Focal high-intensity focused ultrasound vs. active surveillance for ISUP grade 1 prostate cancer: Medium-term results of a prospective matched-pair comparison

The association between PI3K, JAK/STAT pathways with the PDL-1 expression in prostate cancer.

Programmed cell death protein-1/programmed death-ligand-1 (PD-1/PDL-1) signalling pathway has gained attention in prostate cancer. The relationship between pSTAT-1, pSTAT-3 expressions and PTEN loss with PDL-1 expression was assessed and the effects of the pathways on prostate cancer prognosis were evaluated. Patients who underwent radical prostatectomy between 2011 and 2017 were included in our study. Prostatectomy materials were evaluated using immunohistochemical staining of pSTAT-1, pSTAT-3, PTEN, and PDL-1. The relationship between PDL-1 and pSTAT-1, pSTAT-3 expressions and PTEN loss was evaluated. Additionally, factors affecting biochemical recurrence-free survival and clinical progression-free survival were analysed. Within100 patients, 9 of 11 patients with PDL-1 expression also had intermediate-high pSTAT-1 staining intensity, and those with PDL-1 expression had higher pSTAT-1 staining intensity than those without (81.9% vs. 56.2%, p=0.014). In univariate analysis, pSTAT-1, pSTAT-3 and PDL-1 expressions had significant impact on biochemical recurrence-free and clinical progression-free survival. In multivariate analysis, pSTAT-1 staining intensity with radical prostatectomy ISUP grade in terms of biochemical recurrence-free survival and the pSTAT-1 H-score with radical prostatectomy ISUP grade in terms of clinical progression-free survival were independent risk factors. Moderate-high expression of pSTAT-1 was closely associated with PDL-1 expression, and pSTAT-1 was also a predictor of biochemical recurrence and clinical progression.

Homologous recombination deficiency (HRD) score in aggressive prostatic adenocarcinoma with or without intraductal carcinoma of the prostate (IDC-P)

BackgroundIntraductal carcinoma of the prostate (IDC-P) is a subtype of prostate cancer featured by poor prognosis. Previous studies suggested IDC-P could have a potentially unstable genome. Homologous recombination deficiency (HRD) score is a result-oriented method to describe the genomic instability status. This study investigates the association of HRD scores with IDC-P and other clinicopathological factors and the prognostic implication of HRD scores in an aggressive prostate cancer cohort.MethodsThis study involved 123 PCa patients, including high-risk localized (M0) and de novo metastatic (M1) diseases. HRD score is calculated based on over 10,000 single-nucleotide polymorphisms distributed across the human genome. We explored the association between HRD scores and clinicopathological characteristics, genomic alterations, and patients’ prognoses using rank-sum tests, chi-square tests, Kaplan-Meier curves, and Cox proportional hazards method.ResultsThe median HRD score of this cohort is 21.0, with 65 (52.8%) patients showing HRD score≥21. Tumors with IDC-P displayed higher HRD scores than adenocarcinoma (P=0.002); other high HRD score-related factors included M1 (P =0.008) and high ISUP grades (4–5) (P=0.001). MYC mutations were associated with high HRD scores (P<0.001) in the total cohort. TP53 mutations (P=0.010) and HRR pathway mutations (P=0.028) corresponded to high HRD scores in IDC-P positive and non-IDC-P patients, respectively, but not vice versa. HRD scores higher than 21 indicated significantly worse survival in the total cohort.ConclusionsM1, high Gleason score, and IDC-P pathology represent higher HRD scores in PCa. Tumors with IDC-P might have different driven mechanisms for high HRD scores than non-IDC-P. HRD score displayed prognostic value in this aggressive prostate cancer cohort.

Performance of CT radiomics in predicting the overall survival of patients with stage III clear cell renal carcinoma after radical nephrectomy.

To investigate the performance of CT radiomics in predicting the overall survival (OS) of patients with stage III clear cell renal carcinoma (ccRCC) after radical nephrectomy. The 132 patients with stage III ccRCC undergoing radical nephrectomy were collected, and the patients were divided into training set (n = 79) and validation set (n = 53). The ccRCC was segmented and 396 radiomics features were extracted. After dimensionality reduction, radiomics score (RS) was obtained. COX regression was used to construct Model 1 (clinical variables + CT findings) and Model 2 (clinical variables + CT findings + RS) in the training set to predict the OS of patients, and then, the performance of the two models in the two data sets was compared. In the training set, Akaike information criterion, C-index, and corrected C-index were 295.51, 0.744, and 0.728 for Model 1, and 271.78, 0.805, and 0.799 for Model 2, respectively. In the validation set, the corresponding values were 185.68, 0.701, and 0.699 for Model 1, and 175.99, 0.768, and 0.768 for Model 2. The calibration curves showed that both models had good calibration degrees in the validation set. Compared with Model 1, the continuous net reclassification index and integrated discrimination improvement index of Model 2 in the two data sets were positively improved. The two prediction models showed high performance in the evaluation of OS of stage III ccRCC patients after radical nephrectomy, among which Model 2 based on ISUP grade and RS was more concise and efficient.

Transperineal Targeted Microwave Ablation (TMA) of localized prostate cancer guided by MRI-Ultrasound fusion and organ-based tracking: a pilot study.

To investigate the efficacy of transperineal targeted microwave ablation (TMA) in treating localized prostate cancer (PCa). This is a single-centre prospective phase 2 trial recruiting men with low to intermediate-risk localized PCa to undergo transperineal TMA. TMA was performed with MRI-Ultrasound fusion guidance and organ-based tracking. A per-protocol 6-month MRI and biopsy were performed for all patients. The primary outcome was any cancer detected on biopsy of each ablated area. Secondary outcomes included per-patient analysis of positive biopsy, complications, urinary symptom score, erectile function and quality of life (QOL) scores. In the first 15 men, 23 areas were being treated. The median age was 70 years, number of TMA ablations were 5 (range 2-8), and the total ablation time and operating time was 22 (IQR 14-28) and 75 (IQR 65-85) minutes, respectively. PSA level dropped from a median of 7.7to2.4 ng/mL. For the primary outcome, 91.3% (21/23) ablated area had no cancer in 6-month biopsy. In per-patient analysis, 33.3% (5/15) had in or out-of-field positive biopsy at 6 months. Among these five cases, four of them were amenable to active surveillance and 1 (6.7%) case with out-of-field ISUP grade group 2 cancer received radiotherapy. The urinary symptoms, uroflowmetry, erectile function, and QOL scores had no significant difference at 6 months. One patient (out of five patients with normal erection) in the cohort complained of significant worsening of erectile function after TMA. Grade 1 complications including hematuria (33.3%), dysuria (6.7%), and perineal discomfort (13.4%) were observed. In this first pilot study, transperineal TMA guided by MRI-Ultrasound fusion guidance and organ-based tracking was shown to be effective, safe, and easily applicable in men with localized PCa.

Is PSA Still the Best Predictor for Biochemical Recurrence after Radical Prostatectomy in High-Risk Prostate Cancer?

Background Patients with high-risk prostate cancer (PCa) experience heterogeneous oncological outcomes. In this study, we assessed the patients who underwent an RP procedure because of high-risk prostate cancer in subgroups formed according to D’Amico criteria and analyzed the effects of these criteria on biochemical recurrence (BCR) after RP. Methods We retrospectively identified high-risk non-metastatic PCa patients who underwent RP between 2006 and 2020 in our hospital. Groups were formed as follows: group 1 consisted of those with an ISUP grade 4 − 5 biopsy, group 2 consisted of those with a clinical stage T2c, group 3 consisted of those with a tPSA level ≥ 20 ng/ml, and group 4 consisted of those with locally advanced disease. Survival analyses were made by Kaplan–Meier test and Log Rank test. A P value <0.05 was accepted as statistically significant. Results Of all patients, 61.8% were cured by only RP and 38.2% had recurrences. Rates of BCR were significantly different among groups (P = 0.003). In group 1, group 2, group 3, and group 4, BCR rates were 30.8%, 13%, 40.8%, and 70.6%, respectively. Mean BCR-free survival was 82.47 ± 11.64 months. In group 2, BCR-free survival was higher than that in group 3 and group 4 (P1 = 0.020 and P2 = 0.001) and in group 1, BCR-free survival was higher than that in group 4 (P = 0.016). There was no significant difference between group 3 and 4 (P > 0.05). Conclusion Despite the developments in the imaging technology, an elevated tPSA level remains to be an important predictor for BCR-free survival.

Value of T2 Mapping MRI for Prostate Cancer Detection and Classification

ROI Measurements of benign tissue in the peripheral zone (PZ; purple ROI) and transition zone (TZ; orange ROI), and PCA (red ROI). Quantitative T2 map (A), T2 TSE (B), and calculatedadc map of RS-DWI (C). On Radical prostatectomy (RPE), an ISUP grade 5 PCA was confirmed. by Maximilian Klingebiel et al. (413–422)

Reduced CDH16 expression is linked to poor prognosis in clear cell renal cell carcinoma 16.

Cadherin-16 (CDH16) is a member of the cadherin superfamily which is also termed kidney specific cadherin (ksp-cadherin) because of its preferred expression in the normal kidney where it plays a pivotal role in tubulus formation during embryonal development. However, little is known about the prognostic role of CDH16 in renal cell carcinomas. CDH16 protein was analyzed by immunohistochemistry in more than 1,300 renal cell carcinomas (RCCs) in a tissue microarray format. A CDH16 positivity was found in 81% of 1,115 interpretable tumors. Staining was weak in 34%, moderate in 32% and strong in 15% of tumors. CDH16 positivity was more common in oncocytomas (99% positive) and chromophobe carcinomas (94%) than in papillary (73%) and clear cell RCCs (82%; P < 0.0001). In clear cell RCC, reduced CDH16 staining was significantly linked to high-grade (P < 0.0001), advanced pT stage (P = 0.0452), distant metastasis (P = 0.0003) as well as to shortened recurrence free (P < 0.0001), overall (P = 0.0002), and tumor specific survival (P = 0.0092). In a multivariate analysis including pT, pN, ISUP grade, and M status, CDH16 expression loss was an independent prognostic parameter for overall (P = 0.0016) and tumor specific survival (P = 0.0218) in clear cell RCC. Unequivocal associations with tumor phenotype and prognosis were not seen in papillary RCC. Our data demonstrate that reduction of CDH16 expression is a strong and potentially clinically useful independent predictor of poor prognosis in clear cell RCC.

The prognostic value of mean apparent diffusion coefficient measured with diffusion-weighted magnetic resonance image in patients with prostate cancer treated with definitive radiotherapy

PurposeTo assess the correlation between initial tumor apparent diffusion coefficient (ADC) values and clinicopathological parameters in prostate cancer (PCa) patients treated with definitive radiotherapy (RT). Additionally, the prognostic factors for freedom from biochemical failure (FFBF) and progression-free survival (PFS) in this patient cohort were analyzed. Materials and methodsThe clinical data of 503 patients with biopsy-confirmed PCa were evaluated retrospectively. All patients had clearly evident tumors on diffusion-weighted magnetic resonance imaging (DW-MRI) for ADC values. Univariable and multivariable analyses were used to determine prognostic factors for FFBF and PFS. ResultsThe median follow-up was 72.9 months. The 5-year FFBF and PFS rates were 93.2% and 86.2%, respectively. Significantly lower ADC values were found in patients with a high PSA level; advanced clinical stage; higher ISUP score, and higher risk group than their counterparts. Receiver operating characteristic (ROC) curve analysis revealed an ADC cut-off value of 0.737 × 10−3 mm2/sec for tumor recurrence. Patients who progressed had a lower mean ADC value than those who did not (0.712 ± 0.158 vs. 1.365 ± 0.227 × 10−3 mm2/sec; p < 0.001). There was a significant difference in 5-year FFBF (96.3% vs. 90%; p < 0.001) and PFSrates (83.8% vs. 73.5%; p = 0.002) between patients with higher and lower mean ADC values. The FFBF and PFS were found to be correlated with tumor ADC value and ISUP grades in multivariable analysis. Additionally, older age was found to be a significant predictor of worse PFS. ConclusionsLower ADC values were found in patients with high-risk characteristics such as a high serum PSA level, stage or grade of tumor, or high-risk disease, implying that ADC values could be used to predict prognosis. Lower ADC values and higher ISUP grades were associated with an increased risk of BF and progression, implying that treatment intensification may be required in these patients.

Abstract 2234: Incidence of clinically significant prostate cancer after negative prostate MRI - comparison to general population

Abstract Prostate MRI has high NPV (around 90%) for clinically significant prostate cancer (csPCa, ISUP grade group ≥ 2)1. However, clinicians are still faced with significant uncertainty when considering whether to avoid or to proceed to systematic biopsies in a man with negative MRI (nMRI). When making such an informed decision, information on the risk of subsequent csPCa diagnosis after nMRI in respect to risk of csPCa in general population may be beneficial. Hence, our objective was to compare incidence rate (IR) of csPCa and overdiagnosis rate (diagnosis of ISUP grade group 1 cancer, isPCa) after nMRI (PI-RADS 1-2) to outcomes in general population, and to assess the value of age and PSA-density in stratification. We utilized institutional and national registries to retrospectively identify 1,685 50-79-year-old PCa-free men who underwent a primary nMRI at our institution, of whom 906 men had PSA-D &amp;lt; 0.15 ng/ml/cm3. We compared the IR of csPCa and overdiagnosis rate in relation to general population (n=230,246) during follow-up (up to four years) under clinical routine since December 2015 (PIRADS v2 era). We calculated age-standardized IR ratios (IRR) of csPCa and odds ratios (OR) of overdiagnosis with 95% confidence intervals (95% CI) as age-pooled and among 10-year interval groups (50-59, 60-69 and 70-79 years). Follow-up times in general population cohort, nMRI cohort, and nMRI and low PSA-D cohort were 885,792, 3,363, and 1,821 years and IRs of csPCa were 406, 2,201, and 989 per 100,000 person years. In reference to general population, IRR of csPCa in nMRI cohort was 4.2 (95% CI 3.3-5.4) which reduced to 1.8 (95% CI 1.1-2.9) if PSA-D was &amp;lt; 0.15 ng/ml/cm3. ORs of isPCa were 3.0 (95% CI 2.0-4.6) and 4.6 (95% CI 2.2-9.5), respectively. IRRs of csPCa of 50-59, 60-69 and 70-79-year-old men were 14.1 (95% CI 10.5-25.4), 3.2 (95% CI 2.1-4.6) and 3.4 (95% CI 1.6-3.9). Limitations of this study include retrospective and registry-based design. In conclusion, the risk of subsequent csPCa after nMRI in young men is significant, when compared to population risk. However, with advancing age, these risks converge. For a subgroup of men with PSA-D &amp;lt; 0.15 ng/ml/cm3, the relative risk of csPCa is low in all age groups and comparable to population risk. At the same time, the risk of overdiagnosis after nMRI is substantially higher than in general population. In light of our results, elderly men with nMRI and men at all age groups with nMRI and PSA-D &amp;lt; 0.15 ng/ml/cm3 could be considered candidates for follow-up instead of systematic biopsy.

Abstract 483: Automated Ki67-LI assessment in prostate cancer using artificial intelligence in multiplex fluorescence immunohistochemistry

Abstract The Ki67 labeling index (Ki67-LI) is a strong prognostic marker in prostate cancer. Its analysis requires cumbersome manual quantification of Ki67 immunostaining in at least 200 tumor cells. To enable automated Ki67-LI assessment in routine clinical practice, we have developed and validated a framework for automated Ki67-LI quantification, which comprises three different artificial intelligence analysis steps and an algorithm for cell-distance analysis of multiplex fluorescence immunohistochemistry staining. The prognostic impact of the Ki67-LI was tested on a tissue microarray (TMA) containing one sample each of 12475 prostate cancers. A “heterogeneity TMA” containing 3 to 6 samples from different tumor areas was used to model Ki67 analysis of multiple different biopsies. The Ki67-LI provided strong and independent prognostic information in 11845 successfully analyzed prostate cancers (p&amp;lt;0.001 each). The analysis of the heterogeneity TMA revealed that the Ki67-LI of the sample with the highest Gleason score (AUC:0.68) was similarly prognostic as the mean Ki67-LI of all six foci (AUC:0.71 [p=0.24]). The combined analysis of the Ki67-LI and Gleason grades obtained on identical tissue spots showed that the Ki67-LI added significant additional prognostic information in case of classical ISUP grades (AUC:0.82 [p=0.002]) and quantitative Gleason grades (AUC:0.83 [p=0.018]). The Ki67-LI is a powerful prognostic parameter in prostate cancer, which can be efficiently analyzed in multiplex fluorescence IHC. In case of multiple cancer positive biopsies, the sole analysis of the worst biopsy can be sufficient. Citation Format: Niclas C. Blessin, Tim Mandelkow, Elena Bady, Ronald Simon, Claudia Hube-Magg, Maximilian Lennartz, Guido Sauter, Markus Graefen, Stefan Steurer. Automated Ki67-LI assessment in prostate cancer using artificial intelligence in multiplex fluorescence immunohistochemistry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 483.