Differentiated Prostate Cancer Research Articles

Abstract 554: Determining the role of PROX1 in prostate cancer neuroendocrine trans-differentiation

Abstract Nonbiased mutational screening to identify essential genes and pathways in cancer is a powerful approach for understanding underlying biology as well as the identification of potential therapeutic targets. Epigenetic (EPI) and transcriptional factors (TF) play an important role in the change of phenotype and lineage plasticity from adenocarcinoma to castration resistant prostate cancer (CRPC), double negative (DN) or treatment-induced neuroendocrine prostate cancer (NEPC). When RB1 loss occurs in combination with TP53 alterations, stemness and lineage plasticity increase with one consequence being differentiation to a neuroendocrine (NE) lineage. Here, we are identifying and testing the functional role of epigenetic and transcription factors required for the viability of CRPC, DN and NEPC relative to a matrix of genotypic and phenotypic characteristics. We applied CRISPR-CAS9 dropout screens in prostate organoids and cell lines to identify gene/s associated with CRPC, DN and NEPC viability. We successfully CRISPR-engineered LNCaP clones of single (LNCaP-TP53-SKO, LNCaP-RB1-SKO) and double (LNCaP-TP53-RB1-DKO) gene knockouts, which were subsequently characterized for immuno-phenotype and transcriptome. Our dropout screens, targeting all TFs and EPIs, identified 117 TF and 40 EPI genes responsible for the viability of DN, NEPC and LNCaP models. We found known genes such as FOXA1 and ASCL1, as well as novel genes including PROX1 and KLF3, which were validated through guide RNA competition assays. Our results showed PROX1 is essential for cell viability in a DN organoid model, and its expression is associated with increased aggressiveness, indicating PROX1 has role in stemness/lineage plasticity in treatment resistant adenocarcinoma. RNA-seq analysis following overexpression of PROX1 in the LNCaP-TP53-RB1 null adenocarcinoma model, with and without enzalutamide, identified pathways enriched for cell proliferation, differentiation, neuronal development, and prostate gland development. In summary, our study has suggested an important role for PROX1 in the growth and differentiation of poorly differentiated prostate cancer, which may lead to the identification of potential therapeutic targets. Citation Format: Sonam Raj, Brian Capaldo, Joel Bowman, Margaret White, Xavier Moore, Berkley Gryder, Aian N. Alilin, David Takeda, Kathleen Kelly. Determining the role of PROX1 in prostate cancer neuroendocrine trans-differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 554.

Assessment the Ability of Free/Total Ratio of Serum PSA in Diagnosing Prostate Cancer and Benign Prostatic Hyperplasia

Background: The Prostate gland is the male secondary sexual organ most commonly affected by benign or malignant neoplasm. Prostate cancer (Ca-P) is one of the most commonly diagnosed cancers in men and is now the third commonest cause of cancer death in western countries.The aim of the study was to evaluate the use of serum prostate-specific antigen levels in differentiating prostate cancer from benign prostatic hyperplasia. Methods:The present study is a cross-sectional observational study.The study was conducted at the outpatient department and indoor patients at the department of Urology, Rajshahi Medical College Hospital (RMCH), Rajshahi, and different private clinic in Rajshahi City during the period from July 2019 to June 2020.The study population included male patients above 50 years of age, who attended in the department of Urology, Rajshahi Medical College Hospital (RMCH), Rajshahi, and different private clinic in Rajshahi City complaining of irritative or obstructive lower urinary tract symptoms (LUTS) suspected as clinically prostate cancer or benign prostatic hyperplasia (BPHStatistical analysis of the results was obtained by using window-based computer software devised with Statistical Packages for Social Sciences (SPSS-24). Results: The age distribution of the prostatic carcinoma and BPH patients. Prostatic carcinoma was observed to be significantly higher from 80 years onwards, while BPH was common between 60 - 80 years (p = 0.00001). Table 10shows the validity or accuracy of the free/total ratio of serum PSA as a diagnostic test in differentiating prostatic carcinoma from BPH in patientswith total PSA levels between 4-10ng/ml. The percentage of false positives was significantly higher when total PSA ratio was used to diagnose the disease compared to when free to total PSA was used as a diagnostic tool (p<0.000001). The overall accuracy of total PSA was also significantly lower (61.45%) than that of free/total PSA (91.67%) (p< 0.011526). Conclusion: Free and total prostate specific antigen (PSA) is increased significantly in carcinoma prostate than benign prostatic hyperplasia but free/total ratio of serum prostate- specific antigen level significantly decreases in prostatic carcinoma than benign prostatic hyperplasia. TAJ 2023; 36: No-2: 215-230

An artificial intelligence model based on transrectal ultrasound images of biopsy needle tract tissues to differentiate prostate cancer.

We aimed to develop an artificial intelligence (AI) model based on transrectal ultrasonography (TRUS) images of biopsy needle tract (BNT) tissues for predicting prostate cancer (PCa) and to compare the PCa diagnostic performance of the radiologist model and clinical model. A total of 1696 2D prostate TRUS images were involved from 142 patients between July 2021 and May 2022. The ResNet50 network model was utilized to train classification models with different input methods: original image (Whole model), BNT (Needle model), and combined image [Feature Pyramid Networks (FPN) model]. The training set, validation set, and test set were randomly assigned, then randomized 5-fold cross-validation between the training set and validation set was performed. The diagnostic effectiveness of AI models and image combination was accessed by an independent testing set. Then, the optimal AI model and image combination were selected to compare the diagnostic efficacy with that of senior radiologists and the clinical model. In the test set, the area under the curve, specificity, and sensitivity of the FPN model were 0.934, 0.966, and 0.829, respectively; the diagnostic efficacy was improved compared with the Whole and Needle models, with statistically significant differences (P < 0.05), and was better than that of senior radiologists (area under the curve: 0.667). The FPN model detected more PCa compared with senior physicians (82.9% vs. 55.8%), with a 61.3% decrease in the false-positive rate and a 23.2% increase in overall accuracy (0.887 vs. 0.655). The proposed FPN model can offer a new method for prostate tissue classification, improve the diagnostic performance, and may be a helpful tool to guide prostate biopsy.

Prostate cancer genetic risk and associated aggressive disease in men of African ancestry

African ancestry is a significant risk factor for prostate cancer and advanced disease. Yet, genetic studies have largely been conducted outside the context of Sub-Saharan Africa, identifying 278 common risk variants contributing to a multiethnic polygenic risk score, with rare variants focused on a panel of roughly 20 pathogenic genes. Based on this knowledge, we are unable to determine polygenic risk or differentiate prostate cancer status interrogating whole genome data for 113 Black South African men. To further assess for potentially functional common and rare variant associations, here we interrogate 247,780 exomic variants for 798 Black South African men using a case versus control or aggressive versus non-aggressive study design. Notable genes of interest include HCP5, RFX6 and H3C1 for risk, and MKI67 and KLF5 for aggressive disease. Our study highlights the need for further inclusion across the African diaspora to establish African-relevant risk models aimed at reducing prostate cancer health disparities.

Cancer of unknown primary eventually diagnosed as poorly differentiated prostate cancer: a case report

BackgroundProstate cancer has been well known to have a high prevalence among middle-aged and older men, with high incidence of metastases to the bone—the main metastatic site. However, prostate cancer among those less than 50 years of age is extremely rare, and neck swelling is seldom the initial symptom.Case presentationWe herein report case of a 47-year-old Japanese male with poorly differentiated prostate cancer that had been initially diagnosed as a cancer of unknown primary with multiple lymph node and bone metastases before reaching a definitive diagnosis. The patient has been started on endocrine therapy and is currently alive without progression.Discussion and conclusionWhen locating the primary lesion in men with cancer of unknown primary, it is important to consider the possibility of prostate cancer, confirm serum prostate-specific antigen levels, and perform local prostate evaluation.

13 C NMR quantification of polyamine syntheses in rat prostate.

Currently, many prostate cancer patients, detected through the prostate specific antigen test, harbor organ-confined indolent disease that cannot be differentiated from aggressive cancer according to clinically and pathologically known measures. Spermine has been considered as an endogenous inhibitor for prostate-confined cancer growth and its expression has shown correlation with prostate cancer growth rates. If established clinically, measurements of spermine bio-synthesis rates in prostates may predict prostate cancer growth and patient outcomes. Using rat models, we tested the feasibility of quantifying spermine bio-synthesis rates with 13 C NMR. Male Copenhagen rats (10weeks, n = 6) were injected with uniformly 13 C-labeled L-ornithine HCl, and were sacrificed in pairs at 10, 30, and 60 min after injection. Another two rats were injected with saline and sacrificed at 30 min as controls. Prostates were harvested and extracted with perchloric acid and the neutralized solutions were examined by 13 C NMR at 600 MHz. 13 C NMR revealed measurable ornithine, as well as putrescine-spermidine-spermine syntheses in rat prostates, allowing polyamine bio-synthetic and ornithine bio-catabolic rates to be calculated. Our study demonstrated the feasibility of 13 C NMR for measuring bio-synthesis rates of ornithine to spermine enzymatic reactions in rat prostates. The current study established a foundation upon which future investigations of protocols that differentiate prostate cancer growth rates according to the measure of ornithine to spermine bio-synthetic rates may be developed.

A novel prostate cancer subtyping classifier based on luminal and basal phenotypes.

Prostate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression-based subtyping model based on prostate-specific biological processes was sought. Unsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n=32,000; evaluation, n=68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts. Clustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01-0.71; n=855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n=108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09-0.51). With the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features. Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors-the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management.

Abstract 1446: The elevated expression of INSM1 is correlated with EZH2 in neuroendocrine prostate cancer

Abstract Background: Neuroendocrine prostate cancer (NEPCa) is the most aggressive and non-targetable prostate cancer (PCa). It is well accepted that NEPCa arises from prostate adenocarcinoma (AdPCa) via trans-differentiation. NEPCa tumors exhibit a similar mutation burden but a different transcriptome profile from AdPCa. This suggests that the acquisition of the NE phenotype is driven by epigenetic, transcriptional reprogramming but not genetic alterations. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, is an epigenetic regulator and upregulated in NEPCa. The upregulation of EZH2 in PCa has been considered to be correlated with therapy-induced plasticity and NE differentiation. Insulinoma-associated 1 (INSM1), is a zinc-finger transcription factor, which is predominantly expressed in neuroendocrine (NE) cells and important for the NE developmental pathways. INSM1 has been considered as a biomarker for multiple types of NE tumors, like pancreatic, lung, and prostate. Also, the increase level of INSM1 is associated with NE differentiation in PCa. Analysis of PCa transcriptomic profiles suggests that EZH2 and INSM1 have positive correlation in PCa and function together in NEPCa. Methods: To study the expression of INSM1 and EZH2, we did immunofluorescence (IF), immunohistochemistry (IHC), Western blot and RT-qPCR in prostate cancer cell lines, mouse tissues, and human patients samples. The bioinformatics analysis was done using the publicly available RNA-Seq data obtained from the cBioportal, the Cancer Genome Atlas (TCGA), and the Cancer Cell Line Encyclopedia websites (CCLE). Results and Conclusion: Our IHC results confirmed that INSM1 is highly expressed in NEPCa rather that AdPCa in both human and mouse tissues. By IF, we further found that INSM1 also expresses in PCa amphicrine cells. Additionally, we found that the expression of INSM1 is positively associated with EZH2 expression in PCa. These data indicates that INSM1 may act as a marker for not only NE cells but also amphicrine cells in PCa. Also the correlation between INSM1 and EZH2 further indicates the importance of INSM1 in NEPCa. Our further study will focus on how INSM1 functions and whether there’s a direct regulation between INSM1 and EZH2. Acknowledgement: This work was supported by NIH R01 CA226285, and the Feist-Weiller Cancer Center (FWCC). Citation Format: Lin Li, Siyuan Cheng, Xiuping Yu. The elevated expression of INSM1 is correlated with EZH2 in neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1446.

Sub-differentiation of PI-RADS 3 lesions in TZ by advanced diffusion-weighted imaging to aid the biopsy decision process.

Performing biopsy for intermediate lesions with PI-RADS 3 has always been controversial. Moreover, it is difficult to differentiate prostate cancer (PCa) and benign prostatic hyperplasia (BPH) nodules in PI-RADS 3 lesions by conventional scans, especially for transition zone (TZ) lesions. The purpose of this study is sub-differentiation of transition zone (TZ) PI-RADS 3 lesions using intravoxel incoherent motion (IVIM), stretched exponential model, and diffusion kurtosis imaging (DKI) to aid the biopsy decision process. A total of 198 TZ PI-RADS 3 lesions were included. 149 lesions were BPH, while 49 lesions were PCa, including 37 non-clinical significant PCa (non-csPCa) lesions and 12 clinical significant PCa (csPCa) lesions. Binary logistic regression analysis was used to examine which parameters could predict PCa in TZ PI-RADS 3 lesions. The ROC curve was used to test diagnostic efficiency in distinguishing PCa from TZ PI-RADS 3 lesions, while one-way ANOVA analysis was used to examine which parameters were statistically significant among BPH, non-csPCa and csPCa. The logistic model was statistically significant (χ2 = 181.410, p<0.001) and could correctly classify 89.39% of the subjects. Parameters of fractional anisotropy (FA) (p=0.004), mean diffusion (MD) (p=0.005), mean kurtosis (MK) (p=0.015), diffusion coefficient (D) (p=0.001), and distribute diffusion coefficient (DDC) (p=0.038) were statistically significant in the model. ROC analysis showed that AUC was 0.9197 (CI 95%: 0.8736-0.9659). Sensitivity, specificity, positive predictive value and negative predictive value were 92.1%, 80.4%, 93.9% and 75.5%, respectively. FA and MK of csPCa were higher than those of non-csPCa (all p<0.05), while MD, ADC, D, and DDC of csPCa were lower than those of non-csPCa (all p<0.05). FA, MD, MK, D, and DDC can predict PCa in TZ PI-RADS 3 lesions and inform the decision-making process of whether or not to perform a biopsy. Moreover, FA, MD, MK, D, DDC, and ADC may have ability to identify csPCa and non-csPCa in TZ PI-RADS 3 lesions.

Accurate prostate cancer detection based on enrichment and characterization of prostate cancer specific circulating tumor cells.

The low specificity of serum PSA resulting in the inability to effectively differentiate prostate cancer from benign prostate conditions is a persistent clinical challenge. The low sensitivity of serum PSA results in false negatives and can miss high-grade prostate cancers. We describe a non-invasive test for detection of prostate cancer based on functional enrichment of prostate adenocarcinoma associated circulating tumor cells (PrAD-CTCs) from blood samples followed by their identification by immunostaining for pan-cytokeratins (PanCK), prostate specific membrane antigen (PSMA), alpha methyl-acyl coenzyme-A racemase (AMACR), epithelial cell adhesion molecule (EpCAM), and common leucocyte antigen (CD45). Analytical validation studies were performed to establish the performance characteristics of the test using VCaP prostate cancer cells spiked into healthy donor blood (HDB). The clinical performance characteristics of the test were evaluated in a case-control study with 160 known prostate cancer cases and 800 healthy males, followed by a prospective clinical study of 210 suspected cases of prostate cancer. Analytical validation established analyte stability as well as acceptable performance characteristics. The test showed 100% specificity and 100% sensitivity to differentiate prostate cancer cases from healthy individuals in the case control study and 91.2% sensitivity and 100% specificity to differentiate prostate cancers from benign prostate conditions in the prospective clinical study. The test accurately detects PrAD-CTCs with high sensitivity and specificity irrespective of stage, serum PSA or Gleason score, which translates into low risks of false negatives or overdiagnosis. The high accuracy of the test could offer advantages over PSA based prostate cancer detection.

METCAM Is a Potential Biomarker for Predicting the Malignant Propensity of and as a Therapeutic Target for Prostate Cancer.

Prostate cancer is the second leading cause of cancer-related death worldwide. This is because it is still unknown why indolent prostate cancer becomes an aggressive one, though many risk factors for this type of cancer have been suggested. Currently, many diagnostic markers have been suggested for predicting malignant prostatic carcinoma cancer; however, only a few, such as PSA (prostate-specific antigen), Prostate Health Index (PHI), and PCA3, have been approved by the FDA. However, each biomarker has its merits as well as shortcomings. The serum PSA test is incapable of differentiating prostate cancer from BPH and also has an about 25% false-positive prediction rate for the malignant status of cancer. The PHI test has the potential to replace the PSA test for the discrimination of BPH from prostate cancer and for the prediction of high-grade cancer avoiding unnecessary biopsies; however, the free form of PSA is unstable and expensive. PCA3 is not associated with locally advanced disease and is limited in terms of its prediction of aggressive cancer. Currently, several urine biomarkers have shown high potential in terms of being used to replace circulating biomarkers, which require a more invasive method of sample collection, such as via serum. Currently, the combined multiple tumor biomarkers may turn out to be a major trend in the diagnosis and assessment of the treatment effectiveness of prostate cancer. Thus, there is still a need to search for more novel biomarkers to develop a perfect cocktail, which consists of multiple biomarkers, in order to predict malignant prostate cancer and follow the efficacy of the treatment. We have discovered that METCAM, a cell adhesion molecule in the Ig-like superfamily, has great potential regarding its use as a biomarker for differentiating prostate cancer from BPH, predicting the malignant propensity of prostate cancer at the early premalignant stage, and differentiating indolent prostate cancers from aggressive cancers. Since METCAM has also been shown to be able to initiate the spread of prostate cancer cell lines to multiple organs, we suggest that it may be used as a therapeutic target for the clinical treatment of patients with malignant prostate cancer.

Human Kallikrein-2 and Free Prostate Specific Antigen as Biomarkers for Early Detection of Prostate Cancer, Sudan: A Case-Control Study

Background: Prostate cancer (PCa) is considered one of the major health threats facing males in Sudan. Prostate-specific antigen (PSA) test is the most important laboratory test used in the diagnosis of prostate cancer, the main disadvantage of PSA is its limited specificity, which triggered a lot of interest in development, more research on other markers such as serum human kallikrein-2 (KLK-2) and free prostate specific antigen (fPSA). Objectives: To evaluate the validity of serum kallikrein-2 (KLK-2) and free prostate specific antigen (fPSA) in the early detection of prostate cancer among Sudanese patients. Method: In this study seventy men were considered as a case subject, who were diagnosed as cancer prostate at Gezira Hospital for Renal Disease and Surgery (GHRDS), Sudan during the period February 2018 to July 2019. Randomly selected sixty patients of BPH patients and forty-five apparently healthy men as control subject. KLK-2, fPSA and PSA estimations were performed from serum samples using the principle of Enzyme Linked Immunosorbent Assay (ELISA). Results: The results revealed a highly significant difference between the serum levels individual biomarkers (KLK-2, fPSA, PSA) and multiple biomarkers (fPSA/PSA, KLK-2/fPSA, KLK-2/PSA) for patients with prostate cancer when compared with the control groups. Furthermore, the fPSA/PSA ratio was lower in the patients with prostate cancer (P value = 0.00) than in the control group, the fPSA/PSA ratio showed that best accuracy to differentiate prostate cancer from control group, fPSA cut-off value was found to be more than (18 ng/ml), with sensitivity (93%), specificity (80%), and odds ratio (55). Conclusions: The use of multiple biomarkers rather than individual biomarkers especially fPSA/PSA ratio improves the specificity as well as maintenance of higher sensitivity for early diagnosis of the prostate cancer.

Machine learning approach for classification of prostate cancer based on clinical biomarkers

In this study, it is aimed to classify cancer based on machine learning (ML) and to determine the most important risk factors by using risk factors for prostate cancer patients. Clinical data of 100 patients with prostate cancer were used. A prediction model was created with the random forest (RF) algorithm to classify prostate cancer. The performance of the model was obtained by Monte-Carlo cross validation (MCCV) using balanced subsampling. In each MCCV, two-thirds (2/3) of the samples were used to assess the significance of the feature. In order to evaluate the performance of the model, graph, accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1-score and Area under the ROC Curve (AUC) criteria including prediction class probabilities and confusion matrix were calculated. When the results were examined, the sensitivity, specificity, positive predictive value, negative predictive value, accuracy, F1-score, and AUC values obtained from the RF model were 0.89, 0.84, 0.77, 0.93, 0.86, 0.83, and 0.88, respectively. Area, perimeter, and texture were the three most important risk factors for differentiating prostate cancer. In conclusion, when the RF algorithm can be successfully predicted prostate cancer. The important risk factors determined by the RF model may contribute to diagnosis, follow-up and treatment researches in prostate cancer patients.

Diagnostic role of plasma ORM2 in differentiating prostate cancer from benign prostatic hyperplasia.

Markers are needed to increase the diagnostic accuracy of prostate-specific antigen (PSA) in prostate cancer (PCa) screening. Mounting evidence has shown that plasma proteins can be hopeful biomarkers for cancer diagnosis. Tandem mass tag (TMT)-based proteomics and parallel reaction monitoring (PRM) analysis were used to screen the differential proteins and further validated in other independent studies (n = 539). Receiver-operating characteristic (ROC), decision curves and nomograms were applied to assess the diagnostic accuracy of biomarkers. Three candidate proteins (DBP, LCAT and ORM2) were preliminarily screened. Subsequent validation studies revealed significant upregulation of ORM2 in PCa patients across other independent cohorts. ORM2 yielded excellent discriminative power for PCa from benign prostatic hyperplasia (BPH) patients (AUC = 0.861 and 0.814 in validation phases 2a and 2b, respectively). Importantly, the combination of ORM2 and PSA gave better predictive accuracy than PSA alone. We incorporated age, PSA and ORM2 into a nomogram, which yielded C-index of 0.883 in validation phase 2a. A similar C-index of 0.879 was obtained in external validation phase 2b. In summary, our study suggests that ORM2 could be treated as a complementary biomarker for PSA in distinguishing PCa from BPH.

Specific classification and new therapeutic targets for neuroendocrine prostate cancer: A patient-based, diagnostic study.

Objective: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer (PC) that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. In our investigation, there appeared to be a strong correlation between neuroendocrine differentiation prostate cancer (NEDPC) and NEPC. The objectives of this study included exploring whether NEDPC is an intermediate stage in the progression of high-risk prostate cancer (HRPC) to NEPC and identifying risk factors and new targets associated with survival in the treatment of NEPC. Methods: The selected prostate cancer patients were progressed to high-risk and characterized by neuroendocrine. We collected the clinical data and characteristics of patients with three types of cancer: the incidence of metastasis, site and time of metastasis, recurrence rate, related treatment methods, etc. The similarity and differences of the three groups were compared through experiment and database. Results: By analyzing the clinical data and immunohistochemical results, we found that there seems to be a clinical feature of neuroendocrine differentiation (NED) status in between when patients progress from PC to NEPC. Finding novel treatment targets would therefore be beneficial by taking into account NEDPC as the stage of PC progression prior to NEPC. The metastasis-free survival curve and the immunohistochemical results are informing us that NEDPC can be a pre-state for diagnosing NEPC. Conclusion: NEPC is a late PC symptom that is frequently disregarded and has a bad prognosis. Finding novel treatment targets would therefore be beneficial by taking into account NEDPC as the stage of PC progression prior to NEPC.

Serum levels of chromogranin are not predictive of poorly differentiated prostate cancer: Results from a multicenter radical prostatectomy cohort.

Recently a possible link between elevated Chromogranin A (CgA) levels and poorly differentiated prostate cancer has been proposed. The aim of our study was to explore the association of CgA levels and the risk of poorly differentiated prostate cancer (PCa) in men undergoing radical retropubic prostatectomy (RRP). From 2012 onwards, 335 consecutive men undergoing RRP for PCa at three centers in Italy were enrolled into a prospective database. Body mass index (BMI) was calculated before RRP. Blood samples were collected and tested for total prostate-specific antigen (PSA) levels and chromogranin A (CgA). We evaluated the association between serum levels of CgA and upstaging and upgrading using logistic regression analyses. Median age and preoperative PSA levels were 65 years (interquartile range [IQR]: 60-69) and 7.2 ng/ml (IQR: 5.3-10.4), respectively. Median BMI was 26.1 kg/m2 (IQR: 24-29) with 56 (16%) obese (BMI ≥ 30 kg/m2 ). Median CgA levels were 51 (39/71). Overall, 129/335 (38,5%) presented an upstaging, and 99/335 (30%) presented an upgrading. CgA was not a predictor of upstaging or upgrading on RP. In our multicenter cohort of patients, CgA is not a predictor of poorly differentiated PCa on radical prostatectomy. According to our experience, CgA should not be considered a reliable marker to predict poorly differentiated or advanced prostate cancer.

Metabolic Syndrome and Prostate Cancer Risk: A Population Case-control Study

Metabolic syndrome (MS) with mixed dyslipidemia and prostate cancer (PC) are relevant health problems among Mexican men. However, there is no information regarding the association between MS and PC for this population. To evaluate this association in a population case-control study in Mexico City. We analyzed the information from 394 incident PC-cases and 793 population age-matched (± 5 years) controls, identified in Mexico City (2011-2014). For cases, Gleason score at diagnosis was available. We defined MS history based on the self-report of hypertension, hypercholesterolemia, hypertriglyceridemia, and diabetes; obesity was evaluated using weight-change trajectories throughout life. In addition, the four MS-typologies described for Mexican population were used. The association between MS with PC and histological PC differentiation was evaluated using independent multivariate logistic regression models. MS history was associated with a high PC probability (OR 1.94; 95% CI 1.37-2.75). Lipid alterations, arterial hypertension, and a marked weight increase throughout life were associated with increased PC probability; however, only the marked weight increase was associated with more poorly differentiated PC (Gleason ≥8) (OR 2.79; 95% CI 1.50-5.17). Like other populations, in this Mexican study, MS and some of its components were identified as potential PC risk factors. MS-lipid alteration typology seems to be relevant; however, the novelty of this approach together with the retrospective nature of this study, indicate that a prospective evaluation of the MS typologies and PC association must be performed.

Ribonuclease 4 is associated with aggressiveness and progression of prostate cancer

Prostate specific antigen screening has resulted in a decrease in prostate cancer-related deaths. However, it also has led to over-treatment affecting the quality of life of many patients. New biomarkers are needed to distinguish prostate cancer from benign prostate hyperplasia (BPH) and to predict aggressiveness of the disease. Here, we report that ribonuclease 4 (RNASE4) serves as such a biomarker as well as a therapeutic target. RNASE4 protein level in the plasma is elevated in prostate cancer patients and is positively correlated with disease stage, grade, and Gleason score. Plasma RNASE4 level can be used to predict biopsy outcome and to enhance diagnosis accuracy. RNASE4 protein in prostate cancer tissues is enhanced and can differentiate prostate cancer and BPH. RNASE4 stimulates prostate cancer cell proliferation, induces tumor angiogenesis, and activates receptor tyrosine kinase AXL as well as AKT and S6K. An RNASE4-specific monoclonal antibody inhibits the growth of xenograft human prostate cancer cell tumors in athymic mice.

Multiple metastases of androgen indifferent prostate cancer in the urinary tract: two case reports and a literature review

BackgroundProstate cancer (PC) is mainly known to metastasize to bone, lung and liver, but isolated metastases of prostate cancer, including ductal carcinoma, in the urinary tract are very rare. We describe two patients with nodular masses in the urinary tract (the anterior urethra or the urinary bladder) that were found on cystoscopy during treatment of castration-resistant prostate cancer.Case presentationIn both cases, the pathological diagnosis from transurethral tumor resection showed that they were androgen indifferent prostate cancer (AIPC), including aggressive variant prostate cancer (AVPC) in Case 1 and treatment-induced neuroendocrine differentiation prostate cancer (NEPC) in Case 2. In Case 1, Loss of genetic heterozygosity (LOH) of BRCA2 and gene amplification of KRAS was identified from the urethra polyps. In Case 2, homozygous deletion was observed in PTEN, and LOH without mutation was observed in RB1.ConclusionThese are the first reports of two cases of urinary tract metastasis of AIPC.

PD27-03 FEASIBILITY OF NONLINEAR MICROSCOPY TECHNIQUE FOR EVALUATING PROSTATECTOMY MARGINS IN REAL TIME

You have accessJournal of UrologyCME1 May 2022PD27-03 FEASIBILITY OF NONLINEAR MICROSCOPY TECHNIQUE FOR EVALUATING PROSTATECTOMY MARGINS IN REAL TIME May Jean Counsilman, Yuchen Liu, Yue Sun, Seymour Rosen, Lucas Cahill, Tadayuki Yoshitake, James Fujimoto, Yubo Wu, Allison Kleeman, Jeffrey Sun, Timothy Weber, Sagar Doshi, Peter Chang, and Andrew Wagner May Jean CounsilmanMay Jean Counsilman More articles by this author , Yuchen LiuYuchen Liu More articles by this author , Yue SunYue Sun More articles by this author , Seymour RosenSeymour Rosen More articles by this author , Lucas CahillLucas Cahill More articles by this author , Tadayuki YoshitakeTadayuki Yoshitake More articles by this author , James FujimotoJames Fujimoto More articles by this author , Yubo WuYubo Wu More articles by this author , Allison KleemanAllison Kleeman More articles by this author , Jeffrey SunJeffrey Sun More articles by this author , Timothy WeberTimothy Weber More articles by this author , Sagar DoshiSagar Doshi More articles by this author , Peter ChangPeter Chang More articles by this author , and Andrew WagnerAndrew Wagner More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002575.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Nonlinear microscopy (NLM) is a novel technology that can quickly image fresh surgical specimens at adjustable depths and produce digital images resembling standard hematoxylin and eosin (H&E) histology. We have previously demonstrated the ability to accurately differentiate prostate cancer from benign glands using NLM (Cahill et al 2020). Intraoperative margin evaluation using frozen section during radical prostatectomy (RP) has been shown to improve nerve-sparing (NS) rates and decrease positive surgical margins (Schlomm et al 2012) but is time and resource-intensive and has not been widely adopted. We describe a new method to evaluate RP margins using NLM, present preliminary data on feasibility and compare NLM with paraffin embedded H&E staining. METHODS: NS-RP or non NS-RP was performed per standard of care. The neurovascular bundle, if present on the prostate, was dissected off ex vivo to simulate nerve-sparing and this margin inked separately. The specimen was inked and grossed into standard whole mount slices. Pathology staff were previously trained in NLM slide preparation and cancer identification. Margins were evaluated using NLM, and the tissue subsequently processed for standard paraffin embedded H&E (see Figure 1). After an initial trial period of 3 patients, the timing of the NLM process was recorded to assess intraoperative feasibility. RESULTS: 23 participants were included in the analysis. NLM evaluation correctly identified 7 cases with positive margins and 10 with negative margins. In 5 cases, tumors closely approached the margin and were cautiously deemed equivocal by NLM. All of these cases were ultimately negative on paraffin-embedded H&E. 1 case was falsely negative by NLM, but focally positive on H&E. The average time for NLM processing (inking, grossing, and evaluation) was 36 minutes. Transportation from the operating room to the NLM unit required an additional 6 minutes. CONCLUSIONS: This study suggests the feasibility of RP margin evaluation using NLM without compromising final H&E margin status. A clinical workflow has been developed for prospective evaluation of prostate margins during RP using NLM. Source of Funding: NIH R01 CA249151 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e494 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information May Jean Counsilman More articles by this author Yuchen Liu More articles by this author Yue Sun More articles by this author Seymour Rosen More articles by this author Lucas Cahill More articles by this author Tadayuki Yoshitake More articles by this author James Fujimoto More articles by this author Yubo Wu More articles by this author Allison Kleeman More articles by this author Jeffrey Sun More articles by this author Timothy Weber More articles by this author Sagar Doshi More articles by this author Peter Chang More articles by this author Andrew Wagner More articles by this author Expand All Advertisement PDF DownloadLoading ...