PCa Patients Research Articles

Abstract LB032: CXCR7 drives prostate cancer growth through AURKA activation

Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer among males in the United States. The mainstay treatment for metastatic PCa patients is androgen-deprivation therapies, including high-affinity androgen receptor antagonists, such as enzalutamide. Unfortunately, most patients develop resistance and relapse with castration-resistant PCa (CRPC). We have previously reported up-regulation of CXCR7, an atypical chemokine receptor, in CRPC. CXCR7 interacts with beta-arrestin (ARRB2), a cytoplasmic scaffold protein, and translocates to the cytoplasm to induce signal transduction and PCa progression. However, much remains to be known regarding CXCR7-driven downstream signaling and its therapeutic targeting in advanced PCa. To unveil CXCR7-downstream signaling, we utilized RNA-seq to profile gene expression. Gene ontology analyses revealed remarkable enrichment of CXCR7-regulated genes in G2/M cell cycle progression. Comprehensive phospho-proteomics analysis of CXCR7-knockdown PCa cells showed markedly reduced phosphorylation of AURKA substrates. AURKA, a serine/threonine-protein kinase, is a key regulator of mitosis and G2/M progression and is frequently upregulated in CRPC and the late-stage neuroendocrine PCa (NEPC). Activated AURKA experiences autophosphorylation and phosphorylates downstream substrates, e.g., TACC3, that mediate proper cell division. Immunoblotting confirmed that CXCR7 depletion reduces phosphorylation of AURKA and TACC3. Co-immunoprecipitation revealed protein-protein interaction between CXCR7 and AURKA, which is mediated by ARRB2. Accordingly, ARRB2-knockdown similarly inhibits AURKA phosphorylation and arrests cell proliferation. Immunofluorescence coupled with confocal imaging demonstrated that CXCR7 is packed into clathrin-coated vesicles and locates in the plasma membrane, cytoplasm, and perinuclear Golgi complex, which surrounds the centrosomal AURKA and ARRB2. We found that CXCR7 translocates to the Golgi complex along microtubule-dependent trafficking. Finally, we found that pharmacological inhibitors of AURKA abolish CXCR7-driven PCa cell proliferation in vitro and tumor growth in vivo. Conclusions: Our results describe for the first time that the CXCR7-ARRB2 complex interacts with AURKA and promotes its activation. Our data suggest that AURKA-targeting is a promising therapeutic strategy for CRPC and NEPC with CXCR7 up-regulation. Citation Format: Galina Gritsina, Zhuoyuan Lin, Ka Wing Fong, Xiaodong Lu, Changsheng Zhao, Jindan Yu. CXCR7 drives prostate cancer growth through AURKA activation [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 LB032.

Abstract 462: Using attention-based deep multiple instance learning to identify key genetic alterations in prostate cancer from whole slide images

Abstract Prostate cancer (PCa) is associated with several genetic alterations which play an important role in the disease heterogeneity and clinical outcome. These alterations involve gene fusion between TMPRSS2 and members of the ETS family of transcription factors like ERG, ETV1, and ETV4 together with mutations or deletions in tumor suppressors like TP53 and PTEN. The expanding wealth of digital whole slide images (WSIs) and the increasing adoption of deep learning approaches offer a unique opportunity for pathologists to streamline the detection of these alterations. Here, we used 736 haematoxylin and eosin-stained WSIs from 494 primary PCa patients to identify several key genetic alterations including ERG, ETV1, and ETV4 fusion, PTEN loss, and TP53 and SPOP mutations. Using a custom segmentation pipeline, we identified tissue regions and tiled them into high-resolution (10X magnification) patches (256X256 pixels) which were passed to our deep multiple instance learning framework. Using a pre-trained ResNet50 model, we extracted informative features which were subsequently used for training to predict slide-level labels and to detect slide regions with high diagnostic relevance. Using a 10-folds cross validation approach, we divided the data into training (80%), validation (10%) and testing (10%) sets. The training and validation data were used for training the model and hyperparameters tuning, respectively while the testing data was used to provide an unbiased evaluation of the models’ performance using the mean Area Under the Receiver Operating Characteristic (AUROC) across the ten testing folds as evaluation metric. We managed to accurately detect key molecular alterations including ERG fusion, ETV1 fusion, ETV4 fusion, and PTEN loss. Additionally, we were able to detect mutations in TP53 and SPOP together with the presence of androgen-receptor splice variant 7 (ARv7). In addition to slide-level classification, we also identified subregions with high attention score which can help pathologists identify the distinct morphological features associated with each genetic alteration. Finally, in order to examine the cellular structure associated with each genetic alteration, we used Hover-Net model to segment and classify the nuclei in the high-attention tiles. Our work highlights the utility of using WSIs to accurately identify key molecular alteration in cancer and their associated morphological and cellular features on the slide which would streamline the diagnostic process. To the best of our knowledge, this is the first study that uses routine WSIs to predict and characterize key genetic alterations in PCa. Citation Format: Mohamed Omar, Zhuoran Xu, Ryan Carelli, Jacob Rosenthal, David Brundage, Daniela C. Salles, Eddie L. Imada, Renato Umeton, Edward M. Schaeffer, Brian D. Robinson, Tamara L. Lotan, Massimo Loda, Luigi Marchionni. Using attention-based deep multiple instance learning to identify key genetic alterations in prostate cancer from whole slide images [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 462.

Abstract 2348: Contribution of the GR/LEDGFp75 axis to prostate cancer chemoresistance

Abstract Prostate cancer (PCa) is the second leading cause of cancer deaths in the U.S., disproportionally affecting African American (AA) men. Glucocorticoids (GCs) are administered to PCa patients and have been implicated in therapy resistance. This may be critical to AA men with PCa since they have elevated endogenous GCs levels compared to Caucasian American (CA) men. GCs bind to the glucocorticoid receptor (GR) to exert their actions. The mechanisms of GR-mediated chemoresistance, and its possible contribution to PCa mortality disparities are unknown. We demonstrated that GCs upregulate the chemoresistance-associated protein and transcription co-activator LEDGF/p75 in PCa cells and identified consensus GR binding sites in the promoter region of this protein. Given that both GR and LEDGF/p75 are components of the RNA polymerase II transcription complex, we hypothesized that GR transcriptionally upregulates LEDGF/p75 and then interacts with it to enhance taxane resistance in PCa cells. Pharmacological and genetic inhibition of GR in a panel of docetaxel (DTX)-sensitive and -resistant PCa cells decreased the expression of LEDGF/p75, confirming its status as a candidate GR target gene. However, silencing of LEDGF/p75 had no effects on GR expression. Immunoprecipitation studies revealed that GR and LEDGF/p75 interact in DTX-resistant PCa cells. This interaction was confirmed by confocal microscopy. Immunohistochemical analysis of GR and LEDGF/p75 expression in normal and tumor prostate tissues was performed, and the results are currently being analyzed. Our studies use a mechanistic approach to evaluate the potential contribution of the GR-LEDGF/p75 axis to PCa chemoresistance. Evaluating the co-expression of these proteins in racially diverse PCa tissues may also reveal race-related differential expression, providing insights into the potential contribution of this axis to PCa chemoresistance and mortality disparities. Citation Format: Evelyn S. Sanchez Hernandez, Greisha L. Ortiz Hernandez, Pedro T. Ochoa, Christian R. Gomez, Carlos A. Casiano. Contribution of the GR/LEDGFp75 axis to prostate cancer chemoresistance [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 2348.

The Application of Biopsy Density in Transperineal Templated-Guided Biopsy Patients With PI-RADS

BackgroundIn patients with multiparameter magnetic resonance imaging (mpMRI) low-possibility but highly clinical suspicion of prostate cancer, the biopsy core is unclear. Our study aims to introduce the biopsy density (BD; the ratio of biopsy cores to prostate volume) and investigates the BD-predictive value of prostate cancer and clinically significant prostate cancer (csPCa) in PI-RADS<3 patients.MethodsPatients underwent transperineal template–guided prostate biopsy from 2012 to 2022. The inclusion criteria were PI-RADS<3 with a positive digital rectal examination or persistent PSA abnormalities. BD was defined as the ratio of the biopsy core to the prostate volume. Clinical data were collected, and we grouped the patients according to pathology results. Kruskal–Wallis test and chi-square test were used in measurement and enumeration data, respectively. Logistics regression was used to choose the factor associated with positive biospy and csPCa. The receiver operating characteristic (ROC) curve was used to evaluate the ability to predict csPCa.ResultsA total of 115 patients were included in our study. Biopsy was positive in 14 of 115 and the International Society of Urological Pathology grade groups 2–5 were in 7 of all the PCa patients. The BD was 0.38 (0.24-0.63) needles per milliliter. Binary logistics analysis suggested that PSAD and BD were correlated with positive biopsy. Meanwhile, BD and PSAD were associated with csPCa. The ROC curve illustrated that BD was a good parameter to predict csPCa (AUC=0.80, 95% CI: 0.69-0.91, p<0.05). The biopsy density combined with PSAD increased the prediction of csPCa (AUC=0.90, 95% CI: 0.85-0.97, p<0.05). The cut-off value of the BD was 0.42 according to the Youden index.ConclusionIn PI-RADS<3 patients, BD and PSAD are related to csPCa. A biopsy density of more than 0.42 needles per millimeter can increase the csPCa detection rate, which should be considered as an alternative biopsy method when we perform prostate biopsy in patients with PI-RADS<3.

EPA Modulates KLK Genes via miR-378: A Potential Therapy in Prostate Cancer.

Simple SummaryCastration resistant prostate cancer (CRPC) is one of the most pestilent form of prostate cancer (PCa), accounting for approximately 10–20% of all PCas, which carry poor mortality and morbidity rates. The focus in this study is on EPA, a natural supplement commonly found in fish oils. EPA induces the expression of PGC-1β gene and co-expresses miR-378 in cells, a nucleic acid sequence that inhibits PCa cell proliferation. This significance is highlighted in this study as a potential adjunctive therapy for all stages of PCa including CRPC.It is known that miRNA-378a-3p (miR-378) could be induced by eicosapentaenoic acid (EPA), an omega-3 fatty acid. Herein, we first demonstrated how miR-378 exerts anti-prostate cancer (PCa) actions by influencing multiple target genes, including KLK2, KLK4, KLK6, and KLK14, which are implicated in PCa development, cell proliferation, and cell survival. Furthermore, these genes also correlate with androgen and mTOR signaling transduction, and are considered pivotal pathways for the onset and progression of PCa. In total, four PCa cell lines and eight pairing tissues (tumor vs. normal) from clinical PCa patients were included in the current study. The results showed high significance after EPA induced tumor cells containing higher expression levels of miR-378, and led the PCa cells having low cell viabilities, and they progressed to apoptosis when compared with normal prostate cells (p < 0.001). The findings indicated that EPA might become a potential therapy for PCa, especially because it is derived from the components of natural fish oil; it may prove to be a great help for solving the problem of castration-resistant prostate cancer (CRPC).

Genomic landscape and homologous recombination repair (HRR) genes analysis in Chinese prostate cancer (PCa) patients.

e17020 Background: HRR gene mutations have been proven to be effective biomarkers for PARP inhibitor (PARPi) therapy in metastatic castration resistant PCa. The epidemiological data of genomic variation and the characteristic of HRR gene alterations in Chinese population is still insufficient. Methods: Tumor tissue samples (including surgical and biopsy samples) and blood samples from 250 pathologically confirmed PCa patients were collected and analyzed using next generation sequencing (733-gene panel). Tumor mutation burden (TMB) was defined as total number of somatic non-synonymous mutations in coding region. Homologous recombination deficiency (HRD) was evaluated by the sum of the loss of heterozygosity, telomeric allelic imbalance and large-scale state transition. Somatic or germline alterations (including copy number reduction, CNV-loss) of HRR pathway genes were classified as HRR-altered positive. Results: In total, the top three alteration frequency somatic genes were FOXA1 (24.9%), TP53 (15.2%) and MYC (13.6%) while the top three alteration frequency germline genes were DPYD (17.1%), UGT1A1 (13.2%) and SLX4 (4.3%). In HRR pathway genes, the top three alteration frequency somatic genes were CDK12 (9.7%), ATM (4.7%) and BRCA2 (3.9%) while the top three alteration frequency germline genes were BRCA2 (3.1%), PALB2 (1.9%) and BRCA1 (1.6%). 25.6% (64/250) cases carried HRR gene alterations. Among HRR-altered positive cases with HRD score, only 8.9% (4/45) carried more than one HRR gene alteration and most carried a single HRR gene alteration (40.0% [18/45] in CDK12, 17.8% [8/45] in ATM or BRCA2, 11.1% [5/45] in BRCA1 and 2.2% [1/45] in PALB2 or FANCA). 61 HRR gene alterations were detected in these 45 cases and the commonly alteration types of HRR genes were single base substitution (47.5%, 29/61). The alteration type of CNV-loss (14.8%, 9/61) was only detected in somatic samples. The HRD score of HRR-altered group was significantly higher than wild group (median HRD socre, altered-type vs. wild-type = 23.5 vs. 19.0, P= 0.0097). And there was no significant difference in HRD score between CNV-loss and other alteration types. Moveover, the TMB level of HRR-altered group tended to be higher than wild group (median TMB, altered-type vs. wild-type = 4.5 vs. 2.8 Muts/Mb, P= 0.5). Conclusions: The results illustrated the molecular characteristics of HRR gene in Chinese PCa and indicated that HRR gene alterations (including CNV-loss) were associated with higher HRD score. These data provide further evidence for the clinical management of PARPi personalized therapy.

The circSPON2/miR-331-3p axis regulates PRMT5, an epigenetic regulator of CAMK2N1 transcription and prostate cancer progression

BackgroundProstate cancer (PCa) is the most frequently diagnosed malignancy in men, and its mechanism remains poorly understood. Therefore, it is urgent to discover potential novel diagnostic biomarkers and therapeutic targets that can potentially facilitate the development of efficient anticancer strategies.MethodsA series of functional in vitro and in vivo experiments were conducted to evaluate the biological behaviors of PCa cells. RNA pulldown, Western blot, luciferase reporter, immunohistochemistry and chromatin immunoprecipitation assays were applied to dissect the detailed underlying mechanisms. High-throughput sequencing was performed to screen for differentially expressed circRNAs in PCa and adjacent normal tissues.ResultsUpregulation of protein arginine methyltransferase 5 (PRMT5) is associated with poor progression-free survival and the activation of multiple signaling pathways in PCa. PRMT5 inhibits the transcription of CAMK2N1 by depositing the repressive histone marks H4R3me2s and H3R8me2s on the proximal promoter region of CAMK2N1, and results in malignant progression of PCa both in vitro and in vivo. Moreover, the expression of circSPON2, a candidate circRNA in PCa tissues identified by RNA-seq, was found to be associated with poor clinical outcomes in PCa patients. Further results showed that circSPON2 induced PCa cell proliferation and migration, and that the circSPON2-induced effects were counteracted by miR-331-3p. Particularly, circSPON2 acted as a competitive endogenous RNA (ceRNA) of miR-331-3p to attenuate the repressive effects of miR-331-3p on its downstream target PRMT5.ConclusionsOur findings showed that the epigenetic regulator PRMT5 aggravates PCa progression by inhibiting the transcription of CAMK2N1 and is modulated by the circSPON2/miR-331-3p axis, which may serve as a potential therapeutic target for patients with aggressive PCa.

Identification of ISG15 and ZFP36 as novel hypoxia- and immune-related gene signatures contributing to a new perspective for the treatment of prostate cancer by bioinformatics and experimental verification

BackgroundProstatic cancer (PCa) is one of the most common malignant tumors in men worldwide. Emerging evidence indicates significance of hypoxia and immunity in PCa invasion and metastasis. This study aimed to develop a hypoxia- and immune-related gene risk signature and explore the molecular mechanisms to formulate a better prognostic tool for PCa patients.MethodsThe hypoxia and immune scores of all PCa patients in The Cancer Genome Atlas (TCGA) dataset were calculated via the maximally selected rank statistics method and the ESTIMATE algorithm. From common genes identified overlapping hypoxia- and immune-related differentially expressed genes (DE-HRGs and DE-IRGs), a hypoxia- and immune-related gene risk signature was developed utilizing univariate and multivariate Cox regression analyses, and validated in the Memorial Sloan Kettering Cancer Centre (MSKCC) database. The immune cell infiltration level of PCa samples were evaluated with ssGSEA algorithm. Differential expression of prognostic genes was evidenced by immunohistochemistry and western blot (WB) in paired PCa samples. Expression levels of these genes and their variations under regular and hypoxic conditions were examined in cell lines. The functional effects of the prognostic gene on PCa cells were examined by wound healing and transwell assays.ResultsA hypoxia- and immune-related gene risk signature constructed by ISG15 and ZFP36 displays significant predictive potency, with higher risk score representing worse survival. A nomogram based on independent prognostic factors including the risk score and Gleason score exhibited excellent clinical value in the survival prediction of PCa. Infiltration levels of eosinophils, neutrophils, Tcm, Tem, TFH, Th1 cells, and Th17 cells were significantly lower in the high-risk group. Conversely, aDC, pDC, T helper cells, and Tregs were significantly higher. Additionally, the two prognostic genes were closely correlated with the tumor-infiltrating immune cell subset in PCa progression. RT-qPCR and WB presented higher and lower expression of ISG15 and ZFP36 in PCa cells, respectively. They were correspondingly increased and decreased in PCa cells under hypoxic conditions. Wound healing and transwell assays showed that over-expression of ISG15 promoted the migration and invasion of PCa cells.ConclusionOur study identified a novel hypoxia- and immune-related gene signature, contributing a new perspective to the treatment of PCa

Scutellaria barbata D.Don (SBD) extracts suppressed tumor growth, metastasis and angiogenesis in Prostate cancer via PI3K/Akt pathway

BackgroundScutellaria barbata D.Don (SBD) is derived from the dried whole plant of Labiate which has been widely used to treat patients with multiple cancer. It was previously reported that the ethanol extract of SBD is able to promote apoptosis, and inhibit cell proliferation and angiogenesis in cancer.Materials and methodsCCK8, Edu assays and colony formation assay were performed to assess the effect of SBD on PCa cell growth. Effect of SBD on apoptosis and cell cycle was detected by flow cytometry. Transwell and wounding healing assay were conducted to detect the invasion and migration activities of PCa cells. Western blot was employed to detect the protein expression. 2RRV1 mouse xenograft model was established to detect the effect of SBD on prostate cancer. Angiogenesis was analysed by coculturing PCa cell lines and HUVECs.ResultsThe results showed that SBD induced a significant decrease in cell viability and clonogenic growth in a dose-dependent manner. SBD induced cell apoptosis and cell cycle G2/M phase arrest by inactivating PI3K/AKT signalling pathway. Treatment with SBD also significantly decreased the cell migration and invasion via phenotypic inversion of EMT that was characterized by the increased expression of E-cadherin and Vimentin, and decreased expression of N-cadherin, which could be partially attributed to inhibiting PI3K/AKT signalling pathway. Subsequently, using AKT inhibitor MK2206, we concluded that PI3K/AKT are also involved in cell apoptosis and metastasis of PCa cells stimulated by SBD. Apart from its direct effects on PCa cells, SBD also exhibited anti-angiogenic properties. SBD alone or conditioned media from SBD-treated PCa cells reduced HUVEC tube formation on Matrigel without affecting HUVEC viability. Furthermore, 22RV1 xenograft C57BL/6 mice treated with SBD in vivo showed a significant inhibitory in tumour size and tumour weight without toxicity. In addition, administration with medium- or high-dose of SBD significantly inhibited the cell proliferation and enhanced the damage to tumour tissues.ConclusionsCollectively, our in vitro and in vivo findings suggest that SBD has the potential to develop into a safe and potent alternative therapy for PCa patients.

The Long Non-Coding BC200 Is a Novel Circulating Biomarker of Parathyroid Carcinoma

Long non-coding RNAs (lncRNAs) are an important class of epigenetic regulators involved in both physiological processes and cancer development. Preliminary evidence suggested that lncRNAs could act as accurate prognostic and diagnostic biomarkers. Parathyroid cancer is a rare endocrine neoplasia, whose management represents a clinical challenge due to the lack of accurate molecular biomarkers. Our previous findings showed that human parathyroid tumors are characterized by a different lncRNAs signature, suggesting heterogeneity through the different histotypes. Particularly, we found that the lncRNA BC200/BCYRN1 could represent a candidate biomarker for parathyroid carcinomas (PCas). Here we aimed to extend our preliminary data evaluating whether BC200 could be an accurate non-invasive biomarker of PCas to support the clinical management of patients affected by parathyroid tumors at diagnosis, prognosis and follow-up. To provide a non-invasive point-of-care for parathyroid carcinoma diagnosis and follow-up, we analyzed BC200 expression in patients’ serum through digital PCR. Our results show that BC200 counts are higher in serum from patients harboring PCa (n=4) compared to patients with parathyroid adenoma (PAd; n=27). Further, in PAd patients circulating BC200 levels are positively correlated with serum total calcium. Then, we found that BC200 is overexpressed in metastatic PCas (n=4) compared to non-metastatic ones (n=9). Finally, the lncRNA expression in PCa patients’ serum drops are reduced after parathyroidectomy, suggesting its possible use in the post-operative setting for patients follow-up. Overall, these findings extend the knowledge on BC200 in parathyroid tumors, supporting its role as a useful biomarker for management of PCa.

Comparison of the clinicopathologic features of prostate cancer in US and Chinese populations

BackgroundProstate cancer (PCa) is the most common malignant tumor found among men in the United States. Incidence rates of PCa have recently grown in Asian countries, partially due to the comprehensive implementation of early detection systems. Interestingly, a prospective cohort study showed that adopting a westernized dietary pattern was associated with a higher risk of being diagnosed with PCa among Korean and Japanese men. However, a comparison of current clinicopathological features of PCa between American and Chinese men is lacking. In this study, we report the current clinicopathological features of PCa in Chinese men and compare them to those of patients in the USA. Materials and methodsCase cohorts included, in total, 871 PCa cases with prostatectomy sequentially treated since 2017, including 299 cases from USA and 572 cases from two different academic hospitals in China. The parameters, including patient’s age, preoperative Prostate-Specific Antigen (PSA) level, Gleason score, Grade Group, stage and tumor focality, were collected, analyzed and compared using two sample t-test, Wilcoxon rank sum test, Pearson’s Chi-squared test and Fisher’s exact test. ResultsSignificant differences were demonstrated in the mean age of patients, preoperative PSA levels, extra-prostatic extension, Gleason scores, and Grade Groups (p < 0.05). PCa patients in the Chinese group were older than patients in the USA group (67.81 vs. 63.53, p < 0.01). The preoperative PSA levels in the Chinese group were higher than those in the USA group (11.69 v.s 6.30, p < 0.01). A higher percentage of high Grade Groups (Groups 4 and 5) was observed in the Chinese group (25.7%) compared to the USA cohort (17.11%), while Grade Group 2 was more common in the USA group than in the Chinese group (51.68% vs. 32.52%, p < 0.01). ConclusionsAll these data suggest that the clinicopathologic features of PCa are different between the USA and Chinese populations, which may be influenced by treatment strategies (including surgical case selection criteria).

MP53-13 TRANSITION OF PROSTATE CANCER PRIMARY DIAGNOSTICS: TAKEOVER OF MRI-GUIDED TARGETED- VERSUS SYSTEMATIC BIOPSY

You have accessJournal of UrologyCME1 May 2022MP53-13 TRANSITION OF PROSTATE CANCER PRIMARY DIAGNOSTICS: TAKEOVER OF MRI-GUIDED TARGETED- VERSUS SYSTEMATIC BIOPSY Mykyta Kachanov, Sami-Ramzi Leyh-Bannurah, Christoph Würnschimmel, Dirk Beyersdorff, Fabian Falkenbach, Tobias Maurer, Hendrik Isbarn, Thomas Steuber, Markus Graefen, and Lars Budäus Mykyta KachanovMykyta Kachanov More articles by this author , Sami-Ramzi Leyh-BannurahSami-Ramzi Leyh-Bannurah More articles by this author , Christoph WürnschimmelChristoph Würnschimmel More articles by this author , Dirk BeyersdorffDirk Beyersdorff More articles by this author , Fabian FalkenbachFabian Falkenbach More articles by this author , Tobias MaurerTobias Maurer More articles by this author , Hendrik IsbarnHendrik Isbarn More articles by this author , Thomas SteuberThomas Steuber More articles by this author , Markus GraefenMarkus Graefen More articles by this author , and Lars BudäusLars Budäus More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002628.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To explore stage migration patterns of primary diagnostic tools of prostate cancer, namely systematic biopsy (SBx) and the dawn of MRI-targeted biopsy (TBx) combined with SBx. METHODS: Within our institutional database, we identified 7,470 SBx and 1,717 TBx+SBx patients, who received respective primary diagnostics between 2005-2020 and 2016-2020. The estimated annual percentage changes (EAPC) for Gleason Grade Groups (GGG) and for proportion strata of PCa yield, within overall biopsy tissue was calculated by a log linear regression methodology. For TBx+SBx, adjustment according to PIRADS strata 3,4 and 5 was performed. RESULTS: At SBx, the incidence of GGG 1 (EAPC -3.45) and GGG 3 (EAPC -3.51) significantly decreased, accompanied by an increase of GGG 5 (EAPC +10; p=0.003). Similarly, proportion of biopsy tissue PCa yield >20% also significantly increased (EAPC: +3.71; p=0.002). After TBx+SBx was introduced at our institution 2016, the percentage of TBx+SBx for purpose of primary PCa diagnostics (as opposed to repeat Bx) increased from 12% to 52% until 2020. There were no significant EAPCs of TBx+SBx GGGs within this period. During the period 2016-2020, clinically significant GGG ≥2 was detected at a significantly higher rate of 58% at TBx+SBx compared to 46% at SBx, respectively. CONCLUSIONS: Increased high-risk GGG 5 proportions at SBx strongly suggest that previously observed inverse stage migration pattern of unfavorable PCa characteristics at first diagnosis are still present in contemporary PCa patients. However, the greater comparable yield of clinically significant PCa at TBx+SBX also indicates that the inverse stage migration of SBx might systematically underestimate truly aggressive PCa burden due to poorer diagnostic performance. This must be taken into account when considering a primary biopsy examination, supporting the existing recommendations regarding primary MRI and TBx based diagnostics. Source of Funding: none © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e900 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mykyta Kachanov More articles by this author Sami-Ramzi Leyh-Bannurah More articles by this author Christoph Würnschimmel More articles by this author Dirk Beyersdorff More articles by this author Fabian Falkenbach More articles by this author Tobias Maurer More articles by this author Hendrik Isbarn More articles by this author Thomas Steuber More articles by this author Markus Graefen More articles by this author Lars Budäus More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP48-17 ONCOLOGICAL OUTCOMES IN PATIENTS WITH RECURRENT PROSTATE CANCER STAGED WITH PSMA PET/CT: RESULTS FROM 3 EUROPEAN TERTIARY CENTERS

MP48-17 ONCOLOGICAL OUTCOMES IN PATIENTS WITH RECURRENT PROSTATE CANCER STAGED WITH PSMA PET/CT: RESULTS FROM 3 EUROPEAN TERTIARY CENTERS

Sex steroid hormones in urinary exosomes as biomarkers for the prediction of prostate cancer

BackgroundAlthough they are involved in the progression of PCa, the use of sex steroid hormones in urinary exosomes as biomarkers for PCa remains obscure. Here, the potential use of sex steroid hormones in urinary exosomes as biomarkers was investigated for the prediction of early-stage PCa to assist in clinical diagnosis. MethodsTwo hundred and eighty-six participants were randomly recruited, 231 patients with PCa and 55 healthy controls. According to their Gleason scores (GSs), the patients with PCa were divided into two groups, mild PCa (GS6) (n = 116) and severe (≥GS7) group (n = 115). The concentrations of 8 sex steroid hormones in urinary exosomes were quantitated using liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization (LC-APCI–MS/MS). ResultsThe results showed that the levels of 7 out of 8 sex steroids including dehydroepiandrosterone (DHEA), dehydroepiandrosteronesulfate (DHEAS), androstenedione (A4), testosterone (T), progesterone (P), dihydrotestosterone (DHT), and estrone (E1), but not estradiol (E2) in urinary exosomes, were not only distinguished the PCa patients from healthy controls, can also differentiate between patients with mild and severe PCa. Of the 8 selected urinary exosomal biomarkers, DHEA, DHEAS, T, and DHT were finally screened further to build the regression model, and the detection method of the 4 biomarkers-combined achieved an area under the ROC curve (AUC) of 0.854 and predictive accuracy of 78.2%. ConclusionOur data showed the use of exosomal sex steroids in urine could be as biomarkers for predicting PCa for the first time. This finding would supply a novel insight for PCa diagnosis.

Single center analysis of an advisable control interval for follow-up of patients with PI-RADS category 3 in multiparametric MRI of the prostate

To evaluate if follow-up mpMRI scans of patients in PI-RADS category 3 are safe enough to omit or delay prostate biopsy in the future and to determine an optimal control interval. This retrospective single center study includes consecutive PI-RADS category 3 patients with one or more follow-up mpMRI (T2WI, DWI, DCE) and subsequent MRI-targeted and systematic TRUS-guided biopsy between 2012 and 2018. Primary study objective was the verification of a significant PI-RADS category upgrade in follow-up mpMRI in patients with subsequent PCA positive biopsy versus patients with negative biopsy. Further objectives were development of the PI-RADS category and clinical parameters between initial and follow-up mpMRI in the context of histopathologic results and time interval. Eighty-nine patients (median PSA 6.6 ng/ml; PSAD 0.13 ng/ml/ml) were finally included (follow-up period 31 ± 18 months). 19 cases had PCA (median PSA 7.8 ng/ml; PSAD 0.14 ng/ml/ml). 4 cases had csPCA (median PSA 5.4 ng/ml; PSAD 0.13 ng/ml/ml) for which there was a significant PI-RADS upgrade after 12–24 months (mean 3.75; p = 0.01) compared to patients without PCA (mean 2.74). Without PCA the mean PI-RADS category decreased after 25–36 months (mean 2.74; p = 0.02). Clinical parameters did not change significantly except a PSAD increase for PCA patients after 24 months. Patients within PI-RADS category 3 may not need prompt biopsy since those with PCA reliably demonstrate a PI-RADS category upgrade in follow-up mpMRI after 12–24 months. PI-RADS 3 patients with negative biopsy do not benefit from follow-up mpMRI earlier than 24 months.

Expression status and prognostic value of autophagy-related lncRNAs in prostate cancer

ABSTRACT LncRNAs involve in the autophagy to regulate prostate cancer (PCA) initiation and progression. Therefore, it urges to explore more significant AR-lncRNAs in PCa. mRNA data and clinical information of PCa were achieved from TCGA database, and ARGs were obtained from the HADb. AR-lncRNAs were identified by correlation analysis of DE ARGs and lncRNAs. Univariate Cox regression, LASSO regression, and multivariate Cox regression were used to identify the prognostic AR-lncRNA signature and constructed a risk model. GESA was used to biological function analysis between high- and low-risk score group. A nomogram was constructed and used to predicate the survival of PCa patients. A calibration curve was used to determine the accuracy of the predication model. AR-related ceRNA network was constructed by correlation analysis. Expression of six AR-related lncRNAs were detected by qRT-PCR. 222 ARGs and 385 AR-lncRNAs were screened from PCa and normal tissues, and 17 AR-lncRNAs were identified as prognostic signature for PCa. Based on the expression of prognostic signature, a risk score was calculated, and PCa samples were distributed into high- and low-risk score groups. The biological function and predicated value of the prognostic signature were also examined. Finally, based on the correlation between each ARG and its prognostic signature, three modules of AR-lncRNA-miRNA-mRNA regulatory networks were constructed based on 6 AR-lncRNAs, 17 miRNAs, and 12 ARGs. And we found that AC012085.2, UBXN10-AS1, LINC00261 downregulated, whereas AP004608.1, AC104667.2, AC008610.1 upregulated in PCa compared with BPH tissues. Our finding supplied the potential AR-lncRNAs prognostic signature for PCa.

Amide Proton Transfer Could Provide More Accurate Lesion Characterization in the Transition Zone of the Prostate.

There is an overlap comparing transition zone prostate cancer (TZ PCa) and benign prostatic hyperplasia (BPH) on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI), creating additional challenges for assessment of TZ tumors on MRI. To evaluate whether amide proton transfer-weighted (APTw) imaging provides new diagnostic ideas for TZ PCa. Prospective. A total of 51 TZ PCa patients (age, 49-89), 44 stromal BPH (age, 57-92), and 45 glandular BPH patients (age, 56-92). A 3 T; T2WI turbo spin echo (TSE), quantitative T2*-weighted imaging, DWI echo planar imaging, 3D APTw TSE. Differences in APTw, apparent diffusion coefficient (ADC), and T2* among three lesions were compared by one-way analysis of variance (ANOVA). Regions of interest were drawn by two radiologists (X.Q.Z. and X.Y.Q., with 21 and 15 years of experience, respectively). Multivariable logistic regression analyses; ANOVA with post hoc testing; receiver operator characteristic curve analysis; Delong test. Significance level: P < 0.05. APTw among TZ PCa, stromal BPH, and glandular BPH (3.48% ± 0.83% vs. 2.76% ± 0.49% vs. 2.72% ± 0.45%, respectively) were significantly different except between stromal BPH and glandular BPH (P >0.99). Significant differences were found in ADC (TZ PCa 0.76 ± 0.16 × 10-3 mm2 /sec vs. stromal BPH 0.91 ± 0.14 × 10-3 mm2 /sec vs. glandular BPH 1.08 ± 0.18 × 10-3 mm2 /sec) among three lesions. APTw (OR=12.18, 11.80, respectively) and 1/ADC (OR=703.87, 181.11, respectively) were independent predictors of TZ PCa from BPH and stromal BPH. The combination of APTw and ADC had better diagnostic performance in the identification of TZ PCa from BPH and stromal BPH. APTw imaging has the potential to be of added value to ADC in differentiating TZ PCa from BPH and stromal BPH. 2 TECHNICAL EFFICACY: Stage 2.

Application of Proteogenomics to Urine Analysis towards the Identification of Novel Biomarkers of Prostate Cancer: An Exploratory Study

Simple SummaryProstate cancer (PCa) is one of the most common cancers. Due to the limited and invasive approaches for PCa diagnosis, it is crucial to identify more accurate and non-invasive biomarkers for its detection. The aim of our study was to non-invasively uncover new protein targets for detecting PCa using a proteomics and proteogenomics approach. This work identified several dysregulated mutant protein isoforms in urine from PCa patients, some of them predicted to have a protective or an adverse role in these patients. These results are promising given urine’s non-invasive nature and offers an auspicious opportunity for research and development of PCa biomarkers.To identify new protein targets for PCa detection, first, a shotgun discovery experiment was performed to characterize the urinary proteome of PCa patients. This revealed 18 differentially abundant urinary proteins in PCa patients. Second, selected targets were clinically tested by immunoblot, and the soluble E-cadherin fragment was detected for the first time in the urine of PCa patients. Third, the proteogenome landscape of these PCa patients was characterized, revealing 1665 mutant protein isoforms. Statistical analysis revealed 6 differentially abundant mutant protein isoforms in PCa patients. Analysis of the likely effects of mutations on protein function and PPIs involving the dysregulated mutant protein isoforms suggests a protective role of mutations HSPG2*Q1062H and VASN*R161Q and an adverse role of AMBP*A286G and CD55*S162L in PCa patients. This work originally characterized the urinary proteome, focusing on the proteogenome profile of PCa patients, which is usually overlooked in the analysis of PCa and body fluids. Combined analysis of mass spectrometry data using two different software packages was performed for the first time in the context of PCa, which increased the robustness of the data analysis. The application of proteogenomics to urine proteomic analysis can be very enriching in mutation-related diseases such as cancer.

Quantitative imaging parameters to predict the local staging of prostate cancer in intermediate- to high-risk patients

ObjectivesPSMA PET/MRI showed the potential to increase the sensitivity for extraprostatic disease (EPD) assessment over mpMRI; however, the interreader variability for EPD is still high. Therefore, we aimed to assess whether quantitative PSMA and mpMRI imaging parameters could yield a more robust EPD prediction.MethodsWe retrospectively evaluated PCa patients who underwent staging mpMRI and [68Ga]PSMA-PET, followed by radical prostatectomy at our institution between 01.02.2016 and 31.07.2019. Fifty-eight cases with PET/MRI and 15 cases with PET/CT were identified. EPD was determined on histopathology and correlated with quantitative PSMA and mpMRI parameters assessed by two readers: ADC (mm2/1000 s), longest capsular contact (LCC, mm), tumor volume (cm3), PSMA-SUVmax and volume-based parameters using a fixed threshold at SUV > 4 to delineate PSMAtotal (g/ml) and PSMAvol (cm3). The t test was used to compare means, Pearson’s test for categorical correlation, and ROC curve to determine the best cutoff. Interclass correlation (ICC) was performed for interreader agreement (95% CI).ResultsSeventy-three patients were included (64.5 ± 6.0 years; PSA 14.4 ± 17.1 ng/ml), and 31 had EPD (42.5%). From mpMRI, only LCC reached significance (p = 0.005), while both volume-based PET parameters PSMAtotal and PSMAvol were significantly associated with EPD (p = 0.008 and p = 0.004, respectively). On ROC analysis, LCC, PSMAtotal, and PSMAvol reached an AUC of 0.712 (p = 0.002), 0.709 (p = 0.002), and 0.718 (p = 0.002), respectively. ICC was moderate–good for LCC 0.727 (0.565–0.828) and excellent for PSMAtotal and PSMAvol with 0.944 (0.990–0.996) and 0.985 (0.976–0.991), respectively.ConclusionsQuantitative PSMA parameters have a similar potential as mpMRI LCC to predict EPD of PCa, with a significantly higher interreader agreement.

Synthesis, preclinical evaluation, and first-in-human study of Al18F-PSMA-Q for prostate cancer imaging.

To investigate the potential of a novel Al18F-labeled PSMA-targeted radiotracer for PCa diagnosis through both preclinical and pilot clinical studies. Al18F-PSMA-Q was prepared automatically. The binding affinity to PSMA was evaluated in vitro using the 22Rv1 (PSMA +) and PC-3 (PSMA -) cell lines. Pharmacokinetics evaluation, biodistribution study, Micro-PET imaging of Al18F-PSMA-Q in normal mice and tumor-bearing mice, and a comparison with 18F-DCFPyL were performed. PET/CT imaging was performed on 8 healthy volunteers and 20 newly diagnosed PCa patients at 1h post-injection (p.i.). The biodistribution in human and preliminary diagnostic efficacy of Al18F-PSMA-Q were evaluated, and the radiation dosimetry was estimated using OLINDA/EXM 2.0 software. Qualified Al18F-PSMA-Q was efficiently prepared with a non-decay-corrected radiochemical yield (RCY) of 22.0-28.3%, a specific activity (SA) of > 50GBq/μmol. The hydrophilicity was comparably high with a log P value of - 3.69 ± 0.39. Al18F-PSMA-Q was found to bind to PSMA specifically with a Ki value of 17.05 ± 1.14nM. The distribution and elimination half-lives of Al18F-PSMA-Q were 3.93min and 14.22min, respectively, which were shorter than those of 18F-DCFPyL. Micro-PET imaging of Al18F-PSMA-Q can clearly differentiate 22Rv1 tumors from PC-3 tumors and background with a high SUVmax of 2.17 ± 0.42 and a tumor-to-muscle ratio of 84.37 ± 31.62, which were higher than those of 18F-DCFPyL (1.79 ± 0.39 and 13.25 ± 1.65). The uptake of Al18F-PSMA-Q in 22Rv1 cells and tumors can be substantially blocked by 2-PMPA. High level accumulation of Al18F-PSMA-Q was observed in organs physiologically expressing PSMA. Twenty-six tumor lesions were detected in 20 PCa patients, and the mean SUVmax values of primary tumors, lymph node metastasis, bone metastases, and tumor-muscle ratios were 19.71 ± 16.52, 5.11, 31.30 ± 29.85, and 44.77 ± 22.29, respectively. The mean SUVmax of tumors in patients with PSA > 10ng/mL was significantly higher than that in patients with PSA ≤ 10ng/mL (25.97 ± 18.64 vs. 10.33 ± 3.74). Meanwhile, the mean SUVmax of tumors in patients with a Gleason score ≥ 8 was significantly higher than that in patients with a Gleason score < 8 (31.85 ± 22.09 vs. 13.18 ± 11.58). The kidneys received the highest estimated dose of 0.098 ± 0.006mGy/MBq, and the effective dose was calculated as 0.0128 ± 0.007mGy/MBq. The novel qualified PSMA-targeted radiotracer Al18F-PSMA-Q was conveniently prepared with favorable yield and SA. The results of preclinical and pilot clinical studies exhibited a high specific uptake in PCa lesions and an excellent tumor-to-background ratio with a reasonable radiation exposure, which indicated the great potential of Al18F-PSMA-Q for PCa imaging. Chinese Clinical trial registry ChiCTR2100053507, Registered 23 November 2021, retrospectively registered.