Clinical Prostate Cancer Research Articles

Abstract B002: Lactate metabolism regulates chromatin accessibility and prostate luminal differentiation

Abstract Lineage transitions are a central feature of prostate development, tumorigenesis and treatment resistance. While epigenetic changes drive prostate lineage transitions, whether upstream metabolic signaling modulates prostate lineage identity remains unclear. Investigations into prostate metabolism are focused primarily on targeting energy metabolism without considering how altering metabolism may influence epigenetic state or cellular differentiation. To understand the relationship between metabolism and prostate lineage identity, we developed an approach to perform metabolic profiling and nutrient tracing on primary prostate epithelial cells and demonstrated that basal and luminal cells exhibit distinct metabolic features. Furthermore, we show that basal to luminal differentiation in vivo and in three-dimensional ex vivo culture is accompanied by metabolic changes consistent with increased glucose oxidation. Using genetic and pharmacological approaches, we identify the mitochondrial pyruvate carrier (MPC) as a regulator of prostate luminal identity in benign and prostate cancer cells. Low MPC expression is inversely correlated with luminal differentiation and associated with poor response to androgen receptor inhibition in clinical prostate cancer. Mechanistically, our results suggest that MPC inhibition likely impairs luminal differentiation through accumulation of intracellular lactate. Increasing intracellular lactate levels is sufficient to alter chromatin accessibility at lineage-specific genes and impair luminal differentiation in prostate epithelial cells. These findings indicate that upstream metabolism is a regulator of chromatin accessibility and prostate lineage differentiation, suggesting that alterations in tumor metabolism may contribute to lineage plasticity and resistance to androgen receptor blockade in prostate cancer. Citation Format: Andrew S. Goldstein, Jenna M. Giafaglione, Preston D. Crowell. Lactate metabolism regulates chromatin accessibility and prostate luminal differentiation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B002.

Concomitant Introduction of New Robotic Systems (Hugo RAS and Versius) at a Single Center: Analysis of First Clinical Cases of Radical Prostatectomy by a Single Surgeon

Abstract Introduction: Radical prostatectomy is a standard option for clinically localized prostate cancer. The first robot-assisted radical prostatectomy (RARP) was performed in 2001 with the DaVinci surgical system (Intuitive Surgical Inc., Sunnyvale, CA); after 2 decades from the first procedure and the expiry of the patents, new systems are entering the market to improve the existing technology and increase the whole accessibility to robotic surgery. Currently, a face-to-face comparison of systems is still unavailable. The aim of the study was to report the first case of concomitant introduction of new systems—Hugo robot-assisted surgery (RAS) and Versius surgical system—at a single center already equipped with a Da Vinci. Methods: This is a prospective study that analyzes the first cases performed with the Hugo RAS and Cambridge Medical Robotics Versius for RARP at a single center. Three patients with clinical organ-confined prostate cancer were selected to receive a Hugo RAS, a CMR Versius, or a DaVinci—as standard reference—radical prostatectomy. All procedures were recorded, and videos were reviewed by internal and external reviewers. RARP was evaluated according to the definition of metric errors and critical errors (Mottrie et al, BJU 2020) (See Supplemental Data, http://links.lww.com/JU9/A20). The primary end point is to evaluate the safety of novel systems; outcome measure is the absence of critical errors or intraoperative adverse events. Results: Surgical procedures were fully completed with all robotic systems. No intraoperative adverse events occurred, nor surgical errors classified as “critical” according to the European Association of Urology Robotic Urology Section metric system. None of the metric error nor technological issues were clinically significant to invoke a change in surgical strategy. Conclusions: This is the first analysis of concomitant introduction of new robotic systems at a single institution. Even if the shift from one model to another is expected to pose some challenges for surgeons, RARP is feasible with HugoRAS and Versius systems by an already experienced surgeon with the Da Vinci. A proper structured training is mandatory; the impact of prior console expertise is unknown and still unmeasured, but is expected to have significance. The current clinical experience supports the feasibility of the implementation of a new surgical system into surgical practice; however, further studies are required to evaluate outcomes in an unselected cohort.

Asymmetric rotaxanes as dual-modality supramolecular imaging agents for targeting cancer biomarkers

Dual-modality imaging agents featuring both a radioactive complex for positron emission tomography (PET) and a fluorophore for optical fluorescence imaging (OFI) are crucial tools for reinforcing clinical diagnosis and intraoperative surgeries. We report the synthesis and characterisation of bimodal mechanically interlocked rotaxane-based imaging agents, constructed via the cucurbit[6]uril CB[6]-mediated alkyne-azide ‘click’ reaction. Two synthetic routes involving four- or six-component reactions are developed to access asymmetric rotaxanes. Furthermore, by using this rapid and versatile approach, a peptide-based rotaxane targeted toward the clinical prostate cancer biomarker, prostate-specific membrane antigen (PSMA), and bearing a 68Ga-radiometal ion complex for positron emission tomography and fluorescein as an optically active imaging agent, was synthesised. The chemical and radiochemical stability, and the cellular uptake profile of the radiolabelled and fluorescent rotaxane was evaluated in vitro where the experimental data demonstrate the viability of using an asymmetric rotaxane platform to produce dual-modality imaging agents that specifically target prostate cancer cells.

Circulating chromatin conformation signatures to enhance PSA positive predictive value and overall accuracy for prostate cancer detection.

e17016 Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. Methods: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. Results: PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.93 and NPV of 0.95 when tested on the independent prospective cohort. Conclusions: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing, with further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence as the next step for PSE adoption in PCa screening.

Updates in urologic oncology guidelines: prostate cancer: A review

The emergence of new drug therapy regimens and the completion of several large randomized trials led to significant changes in the clinical guidelines of the Ministry of Health of Russia and the practical guidelines of the Russian Society of Clinical Oncology (RUSSCO) for the treatment of urologic oncology diseases. However, different interpretations of some studies by expert panels and requirements for these documents led to a divergence of some statements in these publications. The article presents executive summaries of the updated clinical and practical prostate cancer treatment guidelines.

Qingdai Decoction suppresses prostate cancer growth in lethal-stage prostate cancer models.

Contemporary therapy for advanced castration-resistant prostate cancer (CRPC) employs reagents such as enzalutamide and abiraterone acetate targeting the androgen receptor (AR) transcription axis only provide a temporary response and rapidly develop resistance. Additionally, neuroendocrine prostate cancer (NEPC) is an AR pathway-independent and lethal-stage prostate cancer with no standard therapy. Qingdai Decoction (QDT), a traditional Chinese medicine formula, has various pharmacological activities and was widely used for the treatment of different diseases including prostatitis which may contribute to prostate cancer development. This study aims to explore the anti-tumor role and potential mechanism of QDT on prostate cancer. CRPC prostate cancer cell models and xenograft mice models were established for research. The effect of TCMs on cancer growth and metastasis were determined by CCK-8, wound-healing assays and the PC3-xenografted mice model. The toxicity of QDT in the major organs was investigated by H&E staining. The compound-target network was analyzed with network pharmacology. The correlation of QDT targets with prostate cancer patient's prognosis was analyzed with multiple prostate cancer patient cohorts. The expression of related proteins and mRNA were detected by western blot and real-time PCR. The gene knockdown was achieved with CRISPR-Cas13 technology. By integrating functional screening, network pharmacology analysis, CRISPR-Cas13 directed RNA targeting, and molecular biology validation in different prostate cancer models and clinical prostate cancer cohorts, we found that Qingdai Decoction (QDT), a Traditional Chinese Medicine, can repress cancer growth in advanced prostate cancer models in vitro and in vivo in an AR independent manner by targeting NOS3, TGFB1, and NCOA2. This study not only identified QDT as a novel drug for lethal-stage prostate cancer treatment but also provided an extensive Integrative research paradigm for investigating the roles and mechanisms of TCMs for the treatment of other diseases.

Definitive local therapy for T4 prostate cancer associated with improved local control and survival.

To evaluate patients with clinical (c)T4 prostate cancer (PCa), which represent both a heterogenous and understudied population, who often present with locally advanced disease and obstructive symptoms causing significant morbidity and mortality. We analysed whether receiving definitive local therapy influenced symptomatic and oncological outcomes. Retrospective analysis of 154 patients with cT4 PCa treated at a single institution in 1996-2020. Systemic therapy with or without local treatment (surgery, radiotherapy [RT], or both). Uni- and multivariate analyses of associations between clinicopathological features (including obstructive symptoms) and receipt of local therapy on overall survival (OS) and disease control were done with Cox regression. The median follow-up time was 5.9 years. Most patients had adenocarcinoma (88%), Gleason score 9-10 (77%), and median baseline prostate-specific antigen (PSA) of 20 ng/mL; most (54%) had metastatic cT4N0-1M1 disease; 24% regionally advanced cT4N1M0, and 22% localised cT4N0M0. Local therapies were RT (n = 44), surgery (n = 28), or both (n = nine). Local therapy was associated with improved OS (hazard ratio [HR] 0.3, P < 0.001), longer freedom from local recurrence (HR 0.39, P = 0.002), less local progression (HR 0.41, P = 0.02), fewer obstructive symptoms with progression (HR 0.31, P = 0.01), and less death from local disease (HR 0.25, P = 0.002). On multivariate, local therapy was associated with improved survival (HR 0.58, P = 0.02), and metastatic disease (HR 2.93, P < 0.001) or high-risk pathology (HR 2.05, P = 0.03) was associated with worse survival. Definitive local therapy for cT4 PCa was associated with improved symptomatic outcomes and survival even among men with metastatic disease. Pending prospective evaluation, these findings support definitive treatment with local therapy for cT4 disease in select cases.

Abstract 3070: Leveraging oxysterol sulfation by SULT2B1b sulfotransferase and liver X receptor inactivation to suppress advanced prostate cancer

Abstract Advanced prostate cancer is a heterogeneous disease driven by diverse genetic alterations, with metastasis and lethal progression as the inevitable outcome. We observed that a subset of clinical primary prostate cancer is markedly reduced for SULT2B1b (SULT2B) sulfotransferase, which is an oxysterol-sulfating enzyme. Metastasized castration-resistant prostate cancer (CRPC) uniformly lacks SULT2B. Oxysterols are oxidized cholesterol metabolites and in agonist function, they activate liver X receptors (LXRα/β), which are members of the nuclear receptor family and regulators of lipogenesis, cholesterol homeostasis and immune functions. LXR signaling is enzymatically inhibited by SULT2B activity since sulfated oxysterols are LXR-inert. We previously reported that genetic silencing of SULT2B led to escalated CRPC proliferation; enhanced xenograft tumor growth; increased cell migration, invasion; reduced stiffness, adhesiveness; and EMT activation. SULT2B-depleted CRPC cells showed robust upregulation of AKR1C3 aldo-keto reductase and AKR1C3-dependent activation of the ERK1/2 survival signal. AKR1C3 regulates intratumoral androgen biosynthesis, and it is known to be elevated in advanced prostate cancer. In the current study, we validate our previous result by showing that ectopic expression of SULT2B caused AKR1C3 reduction in CRPC cells. Mechanistically, we observed that enhanced AKR1C3 expression in SULT2B-depleted cells was prevented upon genetic or pharmacologic inactivation of LXR. In addition, ERRα, another non-steroid nuclear receptor, was reduced in LXR-inactivated cells and notably, AKR1C3 was reduced in CRPC cells upon ERRα degradation by an ERRα-selective PROTAC. The LXR dependence of ERRα and AKR1C3 expression was observed in both androgen receptor expressing and non-expressing CRPC cells. Conclusion &amp; Translational Significance: Above results reveal a novel LXR-ERRα-AKR1C3-ERK axis which is activated in SULT2B-deficient CRPC cells irrespective of the androgen receptor status of these cells. Notably, elevated ERRα portends poor prognosis for prostate cancer and cholesterol is an ERRα agonist. Considering that statin can diminish ERRα activity (PMID 26777690) and AKR1C3 inhibitors are in clinical trials, this novel axis revealed from our study may be actionable for the clinical interception of the progression in SULT2B-low advanced prostate cancer. Citation Format: Bobae Park, Katarzyna Knapczyk-Stwora, Yaguang Liu, Chung S. Song, Bandana Chatterjee. Leveraging oxysterol sulfation by SULT2B1b sulfotransferase and liver X receptor inactivation to suppress advanced 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 3070.

Abstract 1157: Uncovering a novel role of peroxisomal β-oxidation in advanced, treatment-resistant prostate cancer

Abstract Background and Aims: Prostate cancer (PCa) is highly reliant on lipids for energy, hence targeting fatty acid oxidation (FAO) is a highly promising approach to the treatment of PCa. Recent work by our group and others have shown that FAO is critical for cell viability and survival, and is one of the key drivers of treatment resistance. Although FAO occurs in both the mitochondria and peroxisomes, the functional relevance and therapeutic exploitability of peroxisomal FAO (perFAO) in PCa has not been extensively explored compared to the mitochondria. Herein, we aim to investigate the therapeutic efficacy of targeting perFAO in clinical prostate tumors and PCa cells, and explore its role in PCa progression. Methods and Results: Pharmacological inhibition of perFAO using the clinical agent, thioridazine, significantly suppressed proliferation, migration, and colony formation of a range of advanced and treatment-resistant PCa cells. Further, we evaluated the therapeutic efficacy of thioridazine in a more clinically relevant setting using patient-derived tissues and showed a significant inhibition of cell proliferation (n = 11, p &amp;lt; 0.05). Next, we performed a bioinformatics analysis of clinical RNAseq datasets composed of primary and metastatic PCa tissues and identified DECR2, the auxiliary enzyme of perFAO, as a key target of perFAO in PCa. DECR2 is overexpressed in metastatic castrate-resistant PCa (CRPC) tissues compared to primary PCa and benign tissues, and is significantly associated with shorter relapse-free survival (p &amp;lt; 0.01). DECR2 knockdown significantly suppressed proliferation and migration of CRPC and enzalutamide-resistant PCa cells, and markedly reduced LNCaP tumor growth in vivo. In contrast, overexpression of DECR2 in LNCaP cells significantly increased tumor growth in vivo. Interestingly, analysis of a published proteomics dataset of PCa cells that are either androgen-dependent or resistant to androgen receptor (AR) inhibitors revealed a significant correlation of peroxisomal genes (MSigDB) with acquired resistance to AR inhibition. Notably, DECR2 overexpression was significantly associated with shorter overall survival (p &amp;lt; 0.05) in a metastatic CRPC cohort treated with AR inhibitors. We further showed that DECR2 overexpression in LNCaP cells significantly reduced sensitivity to AR inhibitor treatments and androgen-deprivation, suggesting a role for perFAO in promoting survival and treatment resistance. Conclusion: Our study has revealed a novel role for perFAO in PCa progression and treatment resistance. Importantly, this study also identified DECR2 as a key regulator of tumor cell proliferation and lipid metabolism, representing a potential novel therapeutic target for advanced, treatment-resistant PCa that currently lacks effective targeted therapies. Citation Format: Chui Yan Mah, An D. Nguyen, Takuto Niijima, Madison Helm, Jonas Dehairs, Feargal J. Ryan, Natalie Ryan, Ian G. Mills, Johannes V. Swinnen, David J. Lynn, Zeyad D. Nassar, Lisa M. Butler. Uncovering a novel role of peroxisomal β-oxidation in advanced, treatment-resistant 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 1157.

Review of Active Surveillance in Underrepresented and High-Risk Populations: Feasibility and Safety.

The purpose of this review is to investigate the current use and effectiveness of active surveillance (AS) for clinical low-risk prostate cancer (PCa) in men considered to be "high-risk" based on the factors of race, genetics, healthcare access, and socioeconomic status. Advances in molecular biomarkers and imaging have improved the detection, risk stratification, and treatment of PCa. Still, overdiagnosis and overtreatment of indolent disease remain a concern. AS is therefore the preferred option for clinical low-risk disease. Yet, because of the variability in PCa presentation based on the aforementioned environmental and genetic factors, the question remains: Is active surveillance a safe option for everyone? Provider hesitancy should not necessarily exclude high-risk men from participating in AS. Rather, clinicians should employ shared decision-making, sound clinical judgment, and stringent follow-up in order to effectively counsel AS candidates and optimize AS-related outcomes in "high-risk" individuals.

The association of genitourinary cancer among Saudi patients with gastrointestinal stromal tumors and a systematic literature review

The gastrointestinal tract's most commonly occurring primary mesenchymal tumor is the gastrointestinal stromal tumor (GIST). However, few cases worldwide were reported associated with renal cell carcinoma (RCC). Therefore, we aimed to identify the association of genitourinary tumors in patients with GIST in our tertiary care hospital in Saudi Arabia and compare it to the literature. We identified all patients in the pathology department database with the diagnosis of GIST. We excluded duplicate and recurrent cases. We examined patients’ files for the presence of RCC, adrenal tumors, or other genitourinary cancer. A systematic review of the association was conducted. From 2003 to 2020, 170 patients had a histopathologic diagnosis of primary GIST, 100 men and 70 women, median age of 57 (range 9–91) years at the time of diagnosis. The site of primary GIST was gastric 103, small bowel 43, mesenteric 5, omentum/peritoneum 7, abdomen 4, isolated adrenal 1, and other 7. Six patients had associated primary genitourinary cancer. Three patients had RCC (two clear cell RCC and one radiologic diagnosis only), and three had adrenal tumors (one adrenal carcinoma, one an isolated adrenal GIST, and one pheochromocytoma). In addition, two patients had a tumor invading the urinary bladder. Although the cohort included 63 men aged 60 or above (median 71 ± 8.7 years, range 60–94), none demonstrated clinical prostatic carcinoma. Data was compared to 69 systematic review articles. We report the rare association between GIST tumors and primary genitourinary cancer, mainly RCC and adrenal tumors. Also, we identified a secondary invasion of the urinary bladder. Unlike the reported series, none of the older male patients had clinical prostate cancer.

Epiregulin expression and secretion is increased in castration-resistant prostate cancer.

In prostate cancer, long-term treatment directed against androgens often leads to the development of metastatic castration-resistant prostate cancer, which is more aggressive and not curatively treatable. Androgen deprivation results in elevated epiregulin expression in LNCaP cells which is a ligand of EGFR. This study aims to reveal the expression and regulation of epiregulin in different prostate cancer stages enabling a more specific molecular characterization of different prostate carcinoma types. Five different prostate carcinoma cell lines were used to characterize the epiregulin expression on the RNA and protein levels. Epiregulin expression and its correlation with different patient conditions were further analyzed using clinical prostate cancer tissue samples. Additionally, the regulation of epiregulin biosynthesis was examined at transcriptional, post-transcriptional and release level. An increased epiregulin secretion is detected in castration-resistant prostate cancer cell lines and prostate cancer tissue samples indicating a correlation of epiregulin expression with tumor recurrence, metastasis and increased grading. Analysis regarding the activity of different transcription factors suggests the involvement of SMAD2/3 in the regulation of epiregulin expression. In addition, miR-19a, -19b, and -20b are involved in post-transcriptional epiregulin regulation. The release of mature epiregulin occurs via proteolytic cleavage by ADAM17, MMP2, and MMP9 which are increased in castration-resistant prostate cancer cells. The results demonstrate epiregulin regulation by different mechanism and suggest a potential role as a diagnostic tool to detect molecular alterations in prostate cancer progression. Additionally, although EGFR inhibitors false in prostate cancer, epiregulin could be a therapeutic target for patients with castration-resistant prostate cancer.

MiR-124-3p inhibits tumor progression in prostate cancer by targeting EZH2

Prostate cancer (PCa) is widespread cancer with significant morbidity and mortality rates. MicroRNAs (miRNAs) have been identified as important post-transcriptional modulators in various malignancies. This study investigated the miR-124-3p effect on PCa cell proliferation, infiltration, and apoptosis. EZH2 and miR-124-3p expression levels were measured in PCa tissues. PCa cell lines DU145 and PC3 were transfected with miR-124-3p inhibitors or analogs. EZH2 and miR-124-3p linkage was validated by conducting the luciferase enzyme reporter test. The cell viability and apoptosis were assessed by flow cytometry and MTT test. Cell movement was noted during infiltration using transwell assays. EZH2, AKT, and mTOR contents were assessed using qRT-PCR and western blotting. In clinical PCa specimens, miR-124-3p and EZH2 contents were inversely correlated. Further research has demonstrated that EZH2 is the miR-124-3p direct target. Furthermore, miR-124-3p overexpression reduced EZH2 levels and lowered cell viability, infiltration, and promoted cell death, whereas miR-124-3p silencing had the opposite effect. Overexpression of miR-124-3p decreased the phosphorylation level of AKT and mTOR, whereas miR-124-3p downregulation produced the opposite result. Our findings depict that miR-124-3p prevents PCa proliferative and invasive processes while promoting apoptosis by targeting EZH2.

TEAD3 inhibits the proliferation and metastasis of prostate cancer via suppressing ADRBK2

TEAD3 acts as a transcription factor in many tumors to promote tumor occurrence and development. But in prostate cancer (PCa), it appears as a tumor suppressor gene. Recent studies have shown that this may be related to subcellular localization and posttranslational modification.We found that TEAD3 was down-expressed in PCa. Immunohistochemistry of clinical PCa specimens confirmed that TEAD3 expression was the highest in benign prostatic hyperplasia (BPH) tissues, followed by primary PCa tissues, and the lowest in metastatic PCa tissues, and its expression level was positively correlated with overall survival. MTT assay, clone formation assay, and scratch assay confirmed that overexpression of TEAD3 could significantly inhibit the proliferation and migration of PCa cells. Next-generation sequencing results indicated that Hedgehog (Hh) signaling pathway was significantly inhibited after overexpression of TEAD3. Rescue assays suggested that ADRBK2 could reverse the proliferation and migration ability caused by overexpression of TEAD3.TEAD3 is downregulated in PCa and associated with poor patient prognosis. Overexpression of TEAD3 inhibits the proliferation and migration ability of PCa cells via restraining the mRNA level of ADRBK2.These results indicate that TEAD3 was down-expressed in PCa patients and was positively correlated with a high Gleason score and poor prognosis. Mechanistically, we found that the upregulation of TEAD3 inhibits the proliferation and metastasis of prostate cancer by inhibiting the expression of ADRBK2.

Pelvic clinical node-positive prostate cancer: Impact of radiotherapy and nodal disease burden.

338 Background: The optimal management of pelvic clinical node-positive (cN1) prostate cancer remains controversial and randomized evidence for local therapy is lacking. Recent data suggests that common iliac nodal metastases (CIM), while technically constituting M1a disease, are more common than previously recognized and might carry a prognosis similar to that of cN1 disease when treated radically. In this context, we reviewed the experience at our center of treating cN1 prostate cancer, with or without CIM, focusing on the role of radiotherapy (RT) and measures of nodal disease burden. Methods: The study population consisted of men diagnosed between 2002 and 2018 with prostate cancer with cN1 disease and/or CIM and treated with androgen deprivation therapy and/or definitive local therapy. Outcomes of interest included overall survival (OS) and castration resistance-free survival (CRFS), which were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression were used to identify factors associated with OS and CRFS. In the subgroup of patients treated with RT, the association between a number of RT characteristics – including biologically effective dose (BED) to the prostate, use of elective pelvic nodal RT, and escalated dose (RT boost) to positive nodes – and OS was studied. Results: A total of 87 patients were included, of whom 14 had CIM and 68 received RT. Median follow-up was 110 months. On univariate analysis, RT was associated with improved OS (hazard ratio [HR] 0.28, 95% CI 0.14-0.55, p&lt;0.0005) and CRFS (HR 0.22, 95% CI 0.12-0.41, p&lt;0.0005). Median OS in patients receiving RT was 134.9 months versus 63.1 months in those not receiving RT. Receipt of RT remained significantly associated with OS on multivariate analysis (HR 0.12, 95% CI 0.05-0.31, p&lt;0.001). Biopsy Gleason score 10 and presence of &gt;2 positive lymph nodes were associated with worse OS while presence of CIM was not associated with OS. In patients treated with RT, increasing BED to the prostate was associated with improved OS (HR 0.73 per 10 Gy increase, 95% CI 0.54-0.97, p=0.03) while use of elective pelvic nodal RT and use of an RT boost to positive nodes were not associated with OS. Conclusions: This is the first cohort to evaluate the impact of RT in pelvic clinical node-positive prostate cancer that includes CIM. Receipt of RT was associated with improved oncologic outcomes. The number of positive pelvic nodes, but not their common iliac location, was prognostic and warrants further investigation in a larger dataset.

Impact of Maximal Transurethral Resection on Pathological Outcomes at Cystectomy in a Large, Multi-institutional Cohort.

While the presence of residual disease at the time of radical cystectomy for bladder cancer is an established prognostic indicator, controversy remains regarding the importance of maximal transurethral resection prior to neoadjuvant chemotherapy. We characterized the influence of maximal transurethral resection on pathological and survival outcomes using a large, multi-institutional cohort. We identified 785 patients from a multi-institutional cohort undergoing radical cystectomy for muscle-invasive bladder cancer after neoadjuvant chemotherapy. We employed bivariate comparisons and stratified multivariable models to quantify the effect of maximal transurethral resection on pathological findings at cystectomy and survival. Of 785 patients, 579 (74%) underwent maximal transurethral resection. Incomplete transurethral resection was more frequent in patients with more advanced clinical tumor (cT) and nodal (cN) stage (P < .001 and P < .01, respectively), with more advanced ypT stage at cystectomy and higher rates of positive surgical margins (P < .01 and P < .05, respectively). In multivariable models, maximal transurethral resection was associated with downstaging at cystectomy (adjusted odds ratio 1.6, 95% CI 1.1-2.5). In Cox proportional hazards analysis, maximal transurethral resection was not associated with overall survival (adjusted HR 0.8, 95% CI 0.6-1.1). In patients undergoing transurethral resection for muscle-invasive bladder cancer prior to neoadjuvant chemotherapy, maximal resection may improve pathological response at cystectomy. However, the ultimate effects on long-term survival and oncologic outcomes warrant further investigation.

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.

Survival after radical prostatectomy vs. radiation therapy in clinical node positive prostate cancer patients: A multicentric study

Survival after radical prostatectomy vs. radiation therapy in clinical node positive prostate cancer patients: A multicentric study

Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection.

Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch® PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.92 and NPV of 0.94 when tested on the independent prospective cohort. Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing. Further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence would be the recommended step for PSE adoption in PCa screening.

Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer

BackgroundCurrent diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC.MethodsIntegrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins were further validated by targeted 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models.ResultsThree potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolomic evaluation of exosomes, a series of differentially expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa. Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis.ConclusionIntegration of proteomics and metabolomics data generated proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression.