High-grade Prostate Cancer Patients Research Articles

External validation of the Memorial Sloan Kettering Cancer Center preoperative nomogram predicting lymph node invasion in a cohort of high-grade prostate cancer patients.

Commonly used preoperative nomograms predicting clinical and pathological outcomes in prostate cancer (PCa) patients have not been yet validated in high-grade only PCapatients. Our objective is to perform an external validation of the Memorial Sloan Kettering Cancer Center (MSKCC) preoperative nomogram as a predictor of lymph node invasion (LNI) in a cohort of high-grade PCa patients. We included patients with high-grade PCa (Gleason ≥8) treated at our institution between 2011 and 2020 with radical prostatectomy and pelvic lymph node dissection without receiving neoadjuvant or adjuvant therapy. The area under the curve (AUC) of the receiver operator characteristic (ROC) was used to quantify the accuracy of the model to predict LNI. A calibration plot was used to evaluate the model's precision, and a decision curve analysiswas computed to evaluate the net benefit associated with its use. This study was approved by our institution's ethics board. A total of 242 patients with a median age of 66 (60-71) years were included. LNI was observed in 70 (29%) patients with a mean of 16 (median = 15; range = 2-42) resected nodes. The MSKCC nomogram discriminative accuracy, as evaluated by the AUC-ROC was 79.0% (CI: [0.727-0.853]). The MSKCC preoperative nomogram is a good predictor of LNI and a useful tool associated with net clinical benefit in this patient population.

Abstract 1396: Targeting immune suppressive myeloid cells in prostate cancer recurrence and metastasis

Abstract Metastatic prostate cancer is a leading cause of cancer-related deaths worldwide and therefore an urgent inadequately addressed clinical problem. We have approached this problem primarily by studying immune cells within the tumor microenvironment rather than the tumor cells themselves. One critical cell subset that seems to be contributing to the aggressive behavior of clinically significant prostate cancers is the immune suppressive myeloid cells (MDSC) within the tumor microenvironment. MDSC have been shown to promote tumor metastases by participating in the formation of pre-metastatic niche, promoting angiogenesis, tumor cell invasion, and mediating immune suppression. Understanding the heterogeneity and function of these myeloid cells is an essential step toward developing effective therapeutic strategies to target them and enhance anti-tumor immune responses that have thus far been so elusive. We utilized previously generated scRNAseq data and combined it with publicly available prostate cancer scRNAseq datasets. The analysis included a total of 96 samples at different disease stages, including healthy prostate tissue, adjacent-normal tissue, low-grade tumors, high-grade tumors, as well as local and bone metastatic tumors. In addition, GeoMx spatial profiling was performed on 24 high-grade prostate cancer patients to assess immune cell spatial infiltration. This meta-analysis provided comprehensive insights into the molecular characteristics of prostate cancer. We characterized multiple MDSC subpopulations and revealed the dynamics of tumor associated macrophages (TAMs) during tumor progression and metastasis. We found that a specific type of TAM, known as APOE+ SPP1+TAM, is significantly enriched in metastatic tumors. They are transcriptionally similar to the TAMs found in the bone metastasis niche of prostate cancer. Moreover, we found APOE+ SPP1+TAMs within primary/localized tumors tumors alone could predict prostate cancer recurrence despite curative-intent local therapy. We validated the accumulation of APOE+ SPP1+TAMs in a prostate cancer mice model. We are currently studying the role of the specific subset of TAMs in tumor metastases by focused analysis of the communication between these TAMs, T cells, and tumors. Additionally, we are exploring the therapeutic potential of blocking APOE+ SPP1+TAMs in a mice model of prostate cancer. Our analyses provide a comprehensive picture of myeloid cell linage across different prostate cancer stages, highlighting the potential for therapeutic targets that disrupt the metastatic process via their effects on tumor associated macrophages. Citation Format: Shenglin Mei, Hanyu Zhang, Taghreed Hirz, Nathan Elias Jeffries, Shulin Wu, Chin Lee Wu, Douglas M. Dahl, Philip J. Saylor, David B. Sykes. Targeting immune suppressive myeloid cells in prostate cancer recurrence and metastasis [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 1396.

Circulating levels of PCSK9, ANGPTL3, and other lipid-related factors in men with high-grade prostate cancer.

e17001 Background: Cancer cells rely on abundant lipid supplies for growth and metastasis. Previous studies have shown that lipid-lowering drugs provide a protective effect against cancer progression, including prostate cancer. However, the role of hyperlipidemic factors has not yet been extensively studied. Here, we aimed to measure circulating levels of hyperlipidemic factors, such as PCSK9 and ANGPTL3, in a small cohort of men diagnosed with high-grade prostate cancer compared to men without cancer. Methods: Plasma samples and data were obtained from 70 consenting men treated at CHU de Québec-Université Laval. Thirty-five patients with high-grade prostate cancer (cases) were age and BMI-matched to 35 patients without cancer (controls). The circulating levels of various lipids, Apo B and Lp(a) were obtained with a Roche Modular analytical platform, whereas levels of PCSK9, ANGPTL3 and leptin were measured by ELISA. We performed group comparisons and correlations using R version 4.2.1. Results: As expected, Prostate-specific antigen (PSA) levels were significantly higher in the cancer group. The lipid profile as well as Lp(a) and leptin levels did not differ between groups. ANGPTL3 level tended to be lower in patients with prostate cancer without reaching statistical significance (mean 32.2 vs 36.3 ng/mL, p = 0.051). ANGPTL3 level also inversely correlated with leptin among the cases (rho = -0.44, p = 0.008). PCSK9 level was similar in both groups, but inversely correlated with PSA in the cancer group (rho = -0.39, p = 0.022). PSA level correlated with triglycerides, total cholesterol, Apo B, non-HDL-cholesterol and LDL in the control group (p < 0.05). Conclusions: None of the hyperlipidemic factors measured here was significantly different between high-grade prostate cancer patients and controls. However, the trend for lower ANGPTL3 levels in cancer, as well as the inverse correlations between PCSK9 and PSA and between ANGPTL3 and leptin levels in cancer patients, warrant further investigation in larger cohorts.

Diagnosis of high-grade prostate cancer in patients with unexpectedly low prostate specific antigen levels: a rare case series

Link of Video Abstract: https://youtu.be/PfhZ7H4kszQ Background: Prostate cancer is regarded as one of the most common leading causes of male cancer-related death worldwide. Clinicians agree that prostate specific antigen (PSA) is the best prostate cancer predictor. High PSA levels increase prostate cancer risk in most men. However, other research suggests that prostate cancer with low PSA levels is aggressive. In this uncommon case series, we present three high-grade prostate cancer patients with low PSA. Case Description: Between 2018 and 2019, three patients were referred for further therapeutic management after initial evaluation and treatment from secondary hospitals. All patients underwent complete diagnostic procedures including Laboratory examination, Pathological examination, and Radiologic imaging. PSA levels were 0.67 ng/mL, 4.0 ng/ml, and 4.93 ng/mL in the first, second, and third patients, respectively. The first two of three patients had a Gleason score (GS) of 9 (5+4), and one patient presented with GS of 8 (5+3). Distant metastatic disease was not found in our series. All of the patients underwent hormonal therapy, and none of them underwent radical prostatectomy. Follow-ups were completed in all patients, with the survival of 3 months, 4 months, and 12 months respectively. Conclusion: High-grade prostate cancer in patients with low PSA levels emphasizes the need for rigorous history taking and physical examination and quick investigation of new biomarkers and criteria for prostate cancer detection. These patients' prognosis and optimal therapy are unknown. These patients have a worse prognosis than those with high PSA values, according to multiple studies.

Comparative evaluation of hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate and high risk prostate cancer.

The purpose of this study was to comparatively evaluate an efficacy and toxicity profile of hypofractionated radiotherapy (67.5 Gy in 25 fractions) to conventionally fractionated radiotherapy (78 Gy in 39 fractions) in prostate cancer patients with intermediate and high-risk disease. From January 2015 to December 2018, 168 patients were randomized to hypofractionated radiation treatment and conventional fractionated radiation treatment schedules of volumetric modulated arc therapy (VMAT) to the prostate and seminal vesicles. All the patients also received androgen deprivation therapy (ADT) and radiation therapy started after ADT. The median (range) follow-up was 51 (31-63) and 53 (33-64) months in the hypofractionated and conventionally fractionated regimes, respectively. The 3-year biochemical no evidence of disease (bNED) rates were 86.9% and 73.8% in the hypofractionated and conventionally fractionated groups, respectively (p = 0.032, significant). The 3-year bNED rates in patients at a high risk [i.e., pretreatment prostate-specific antigen (PSA) > 20 ng/mL, Gleason score ≥ 8, or T ≥ 2 c], were 87.9% and 73.5% (p = 0.007, significant) in the hypofractionated and conventionally fractionated radiotherapy groups, respectively. No statistically significant difference was found for late toxicity between the two groups, with 3-year grade 2 gastrointestinal toxicity rates of 19% and 16.7% and 3-year grade 2 genitourinary toxicity rates of 15.5% and 11.9% in the hypofractionated and conventionally fractionated radiotherapy groups, respectively. Hypofractionated schedule is superior to the conventional fractionation schedule of radiation treatment in terms of bNED in intermediate and high grade prostate cancer patients. Also, the late toxicity is found to be equivalent between the two treatment groups.

Cyc-DEP: Cyclic immunofluorescence profiling of particles collected using dielectrophoresis.

Cancer is a highly heterogenous disease that requires precise detection tools and active surveillance methods. Liquid biopsy assays provide an agnostic way to follow the complex trajectory of cancer, providing better patient stratification tools for optimized treatment. Here, we present the development of a low-volume liquid biopsy assay called cyc-DEP (cyclic immunofluorescent imaging on dielectrophoretic chip) to profile biomarkers collected on a dielectrophoretic microfluidic chip platform. To enable on-chip cyclic imaging, we optimized a fluorophore quenching method and sequential rounds of on-chip staining with fluorescently conjugated primary antibodies. cyc-DEP allows for the quantification of a multiplex array of proteins using 25µl of a patient plasma sample. We utilized nanoparticles from a prostate adenocarcinoma (LNCaP) cell line and a panel of six target proteins to develop our proof-of-concept technique. We then used cyc-DEP to quantify blood plasma levels of target proteins from healthy individuals, low-grade and high-grade prostate cancer patients (n=3 each) in order to demonstrate that our platform is suitable for liquid biopsy analysis in its present form. To ensure accurate quantification of signal intensities and comparisons between different samples, we incorporated a signal intensity normalization method (fluorescent beads) and a custom signal intensity quantification algorithm that account for the distribution of signal across hundreds of collection regions on each chip. Our technique enabled a threefold improvement in multiplicity for detecting proteins associated with fluid samples, opening doors for early detection, and active surveillance through quantification of a multiplex array of biomarkers from low-volume liquid biopsies.

A preliminary study of micro-RNAs as minimally invasive biomarkers for the diagnosis of prostate cancer patients

BackgroundA prostate cancer diagnosis is based on biopsy sampling that is an invasive, expensive procedure, and doesn’t accurately represent multifocal disease.MethodsTo establish a model using plasma miRs to distinguish Prostate cancer patients from non-cancer controls, we enrolled 600 patients histologically diagnosed as having or not prostate cancer at biopsy. Two hundred ninety patients were eligible for the analysis. Samples were randomly divided into discovery and validation cohorts.ResultsNGS-miR-expression profiling revealed a miRs signature able to distinguish prostate cancer from non-cancer plasma samples. Of 51 miRs selected in the discovery cohort, we successfully validated 5 miRs (4732-3p, 98-5p, let-7a-5p, 26b-5p, and 21-5p) deregulated in prostate cancer samples compared to controls (p ≤ 0.05). Multivariate and ROC analyses show miR-26b-5p as a strong predictor of PCa, with an AUC of 0.89 (CI = 0.83–0.95;p < 0.001). Combining miRs 26b-5p and 98-5p, we developed a model that has the best predictive power in discriminating prostate cancer from non-cancer (AUC = 0.94; CI: 0,835-0,954).To distinguish between low and high-grade prostate cancer, we found that miR-4732-3p levels were significantly higher; instead, miR-26b-5p and miR-98-5p levels were lower in low-grade compared to the high-grade group (p ≤ 0.05).Combining miR-26b-5p and miR-4732-3p we have the highest diagnostic accuracy for high-grade prostate cancer patients, (AUC = 0.80; CI 0,69-0,873).ConclusionsNoninvasive diagnostic tests may reduce the number of unnecessary prostate biopsies.The 2-miRs-diagnostic model (miR-26b-5p and miR-98-5p) and the 2-miRs-grade model (miR-26b-5p and miR-4732-3p) are promising minimally invasive tools in prostate cancer clinical management.

Targeted Metabolomics Analyses Reveal Specific Metabolic Alterations in High-Grade Prostate Cancer Patients.

Prostate cancer (PCa) is a hormone-dependent tumor characterized by an extremely heterogeneous prognosis. Despite recent advances in partially uncovering some of the biological processes involved in its progression, there is still an urgent need for identifying more accurate and specific prognostic procedures to differentiate between disease stages. In this context, targeted approaches, focused on mapping dysregulated metabolic pathways, could play a critical role in identifying the mechanisms driving tumorigenesis and metastasis. In this study, a targeted analysis of the nuclear magnetic resonance-based metabolomic profile of PCa patients with different tumor grades, guided by transcriptomics profiles associated with their stages, was performed. Serum and urine samples were collected from 73 PCa patients. Samples were classified according to their Gleason score (GS) into low-GS (GS < 7) and high-GS PCa (GS ≥ 7) groups. A total of 36 metabolic pathways were found to be dysregulated in the comparison between different PCa grades. Particularly, the levels of glucose, glycine and 1-methlynicotinamide, metabolites involved in energy metabolism and nucleotide synthesis were significantly altered between both groups of patients. These results underscore the potential of targeted metabolomic profiling to characterize relevant metabolic changes involved in the progression of this neoplastic process.

Highlights of This Issue

The heterogeneity of glioma is thought to underlie their limited response to therapy and poor prognosis. The transcriptional heterogeneity was found to be driven by metabolic reprogramming and microenvironmental influences. In particular, creatine maintained a reduction of reactive oxygen species (ROS) within the tumor leading to an inhibition of HIF-signaling. These effects shifted the transcriptional pattern toward a proneural subtype and reduced the rate of tumor migration and invasion in vitro. Combined, this study uncovers a regulatory function of the tumor microenvironment (TME) by metabolic-driven, transcriptional reprogramming in infiltrating glioma cells.The initiation and progression of cancer is often a complex process due to genetic and epigenetic alterations. Recently, a family of transcription factors known as bromodomain and extraterminal (BET) domain proteins have been shown to be important regulators of cancer progression and have been targeted in many cancers. The current Rapid Impact article, by Andrieu and Denis, manipulates individual BET proteins to reveal independent transcriptional programs in the context of epithelial-to-mesenchymal transition (EMT) in breast cancer model systems. Importantly, these results suggest that epigenetic plasticity invoked by various BET proteins should be considered when designing targeted epigenetic therapies.Long non-coding RNAs (lncRNAs) are increasingly demonstrated to be important regulators in cancer, serve as biomarkers of prognosis, and become potential therapeutic targets. However, the molecular functions of most lncRNAs remain poorly understood. Here, Tracy and colleagues functionally characterize a novel lncRNA, MANCR, which is upregulated in aggressive breast cancer. Knockdown studies reveal essential roles for MANCR in supporting cell cycle, cell viability, and genomic integrity. Importantly, the greater frequencies of defective cytokinesis and cell death observed upon MANCR depletion indicate MANCR as a potential target in breast cancer therapy.Prostate cancer is the second leading cause of male cancer-related death in the U.S. Here, the miR-888 cluster (composed of seven human miRNAs) is identified as a novel non-coding RNA network elevated in expressed prostatic secretion (EPS) urine from high-grade prostate cancer patients. Assessment using in vitro approaches revealed that the miR-888 cluster modulates prostate cancer progression, i.e. proliferation, migration, invasion, colony formation. miR-888 and miR-891a were validated as oncogenes and accelerated tumor growth in mice. This work provides new insight into molecular mechanisms for aggressive prostate cancer and indicates cluster members as promising diagnostic and therapeutic tools. Moreover, dysregulation of cluster members in other cancers suggests wider clinical implications.

The Effect of Neoadjuvant Androgen Deprivation Therapy on Tumor Hypoxia in High-Grade Prostate Cancer: An 18F-MISO PET-MRI Study

Tumor hypoxia is associated with radioresistance and poor prognosis after radiation therapy for prostate cancer (PCa). In this prospective pilot study, we assessed the ability of 18F-misonidazole (18F-MISO) positron emission tomography (PET)-magnetic resonance imaging (MRI) to detect hypoxia in high-grade PCa patients who were candidates for curative radiation therapy, and we evaluated 18F-MISO PET-MRI modulation after 3months of neoadjuvant androgen deprivation therapy (nADT). Eleven PCa patients with a Gleason score (GS) ≥ 8 underwent 18F-fluorocholine (18F-FCH) PET-computed tomography at diagnosis and an18F-MISO hybrid PET-MRI examination before nADT; a second 18F-MISO PET-MRI examination was acquired after 3 months of nADT for all patients but one who dropped out because of noncompliance with nADT.Immunohistochemistry for tissue hypoxia- and proliferation-related biomarkers (glucose transporter 1, carbonic anhydrase IX, vascular endothelial growth factor A, Ki-67, hypoxia-inducible factor 1 alpha, and epidermal growth factor receptor) was performed in lesions bearing the highest GS.We used nonparametric tests to assess (1) the presence of 18F-MISO-positive regions (tumor-to-background ratio [TBR]≥1.4) at baseline; (2) the correlation between imaging parameters (PET tracer uptake, Prostate Imaging Reporting and Data System [PIRADS] scores, and dynamic contrast enhancement perfusion markers) at baseline; (3) the difference in immunohistochemistry staining between 18F-MISO-positive and -negative lesions; and (4) the changes in 18F-MISO PET-MRI after nADT. Uptake of 18F-MISO was significant in 7 patients, being coincidental with the highest GS region in 5 of them. A significant correlation was found at baseline between GS and 18F-MISO TBR, between 18F-MISO TBR and MRI perfusion markers, between GS and 18F-FCH maximum standardized uptake value, between GS and PIRADS score, and between 18F-FCH maximum standardized uptake value and PIRADS score.No difference was found between 18F-MISO-positive and -negative biopsy specimens with respect to tissue biomarkers. The TBR of 18F-MISO diminished significantly after nADT only in high-grade lesions and in regions with a significant uptake at baseline. PET imaging with 18F-MISO showed variable uptake in PCa, associated with a higher GS, lowering significantly after 3months of nADT in high-grade lesions. These results suggest the existence of a hypoxic microenvironment in PCa and a reoxygenation effect of nADT.

Use of prostate health index in diagnosing prostate cancer in Chinese men

Objective: To investigate the value of prostate health index (PHI) in the diagnosis of prostate cancer in patients with total prostate specific antigen (tPSA) <20 μg/L. Methods: Totally 1 135 patients with tPSA<20 μg/L and prostate biopsy indications at Department of Urology, Fudan University Shanghai Cancer Center from March 2013 to April 2016 were enrolled in this study. They were tested for serum tPSA, free prostate specific antigen and prostate specific antigen isoform 2, from which PHI was calculated. Diagnostic efficacy of PHI and tPSA were evaluated using receiver operating characteristic (ROC) curve analysis. The detection rates of prostate cancer were calculated in different ranges of PHI. Subgroup analysis of 716 patients, who were aged 50 or above with tPSA in the range of 4 to 10 μg/L and digital rectal examination negative, was performed. Results: In the biopsied objects with tPSA<20 μg/L, PHI was significantly higher in prostate cancer patients than that in non-cancer patients (48.4(37.4) vs. 26.5(16.9), U=52 674.00, P=0.000), PHI was also significantly higher in high-grade prostate cancer patients than that of low-grade prostate cancer patients (44.5(30.8) vs. 56.4(42.5), U=23 314.00, P=0.000). The area under the curve (AUC) of PHI for diagnosing prostate cancer was significantly higher than that of tPSA (0.771 vs. 0.627, P=0.000). When PHI was in the range of <27, 27 to <36, 36 to <55 and ≥55, the probability of prostate cancer was 9.4% (95%CI: 7.0% to 12.2%), 16.3% (95%CI: 12.2% to 20.8%), 31.0% (95%CI: 25.9% to 37.3%) and 66.4% (95%CI: 58.9% to 74.2%), respectively. Subgroup analysis showed that the AUC of PHI in diagnosing prostate cancer was significantly higher than that of tPSA (0.764 vs. 0.569, P=0.000). When PHI was in the range of <27, 27 to <36, 36 to <55 and ≥55, the probability of prostate cancer was 8.1% (95%CI: 5.4% to 11.3%), 14.0% (95%CI: 9.1% to 19.9%), 30.8% (95%CI: 23.6% to 38.7%) and 78.8% (95%CI: 66.7% to 88.9%), respectively. Conclusion: PHI is superior to tPSA in the diagnosis of prostate cancer in Chinese men with tPSA<20 μg/L.

Abstract 2229: CD117 expression and activation in prostate cancer progression

Abstract We have demonstrated that CD117/c-kit expression on circulating tumor cells and in primary tumors correlates with advanced disease in prostate cancer patients. In addition, the ligand for CD117, stem cell factor (SCF) is increased in high-grade prostate cancer patients. To examine the effects of CD117 activation and expression on prostate cancer progression, we sorted CD117 positive and negative RM1 murine prostate cancer cells and LNCaP-C4-2 human prostate cancer cells. Sorted cells were then examined for tumorigenicity, proliferation, cell signaling, cell migration, angiogenesis and epithelial-mesenchymal transition. A xenograft model demonstrated that CD117 positive LNCaP-C4-2 tumors generate larger tumors characterized by increased vascularization and proliferation. In vitro, SCF induced CD117 activation results in altered cell signaling, migration and epithelial-to-mesenchymal transition. In addition, in vivo imaging of tumor growth demonstrated changes in tumor cell organization between CD117 positive and negative cell populations. In summary, CD117 expression and activation enhances prostate cancer progression. Citation Format: Bethany Kerr. CD117 expression and activation in prostate cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2229. doi:10.1158/1538-7445.AM2015-2229

Elevated serum microRNA levels associate with absence of high-grade prostate cancer in a retrospective cohort.

To reduce treatment of indolent prostate cancer (PCa), biomarkers are needed to improve identification of patients with a low-risk of having aggressive disease. Over-treatment of these patients occurs because of uncertainty in the aggressiveness of the entire tumor based on the biopsies, which do not accurately sample multifocal tumors. Circulating microRNAs (miRNAs) are stable serum markers and differential miRNA levels occur in men with PCa. The goal of this study was to identify circulating miRNAs that were associated with aggressive or indolent PCa. We measured circulating miRNAs in 150 patients prior to surgery and compared the miRNA levels to the pathology of the entire radical prostatectomy specimen. For this study we used an exceptionally well-characterized cohort of patients who had benign prostatic hyperplasia (BPH), low-grade or high-grade PCa. Low-grade was defined as patients with 100% Gleason grade 3 tumor as determined by step-wise sectioning. High-grade PCa patients had 30-90% Gleason grade 4+5 in the tumor. BPH patients had at least two biopsies negative for PCa. Twenty one miRNAs were selected for analysis. The miRNAs were quantified by RT-qPCR and analyzed by logistic regression. High levels of 14 miRNAs were exclusively present in the serum from patients with low-grade PCa or BPH, compared to men with high-grade PCa who had consistently low levels. The expression levels of the 14 miRNAs were combined into a “miR Score” which had a negative predictive value (NPV) of 0.939 to predict absence of high-grade PCa among PCa and BPH patients. Biochemical recurrence (BCR) was known for the PCa patients and a combined “miR Risk Score” accurately classified a subset of patients with low risk of BCR (NPV 0.941). In summary, measurement of serum miRNAs may have pre-surgical utility in combination with clinical risk calculators to identify patients with low risk of harboring aggressive PCa.

Roles of Serine Protease Inhibitor Kazal type 1 (SPINK1) in Prostate Cancer

Altered genes that play a driving role in cancer development can often serve as specific diagnostic markers, criteria of molecular classification and therefore potential therapeutic targets. Serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor or tumor-associated trypsin inhibitor, encodes a 56 amino acid secreted peptide, and its normal function is thought to be the inhibition of serine proteases such as trypsin. Recent studies have indicated marked overexpression of SPINK1 defines an aggressive molecular subtype of ETS (erythroblastosis virus E26 transformation-specific) fusion-negative prostate cancer ((PCa) patients. SPINK1 may act as an autocrine growth factor and promotes PCa growth and invasion. Most recently, we suggested that SPINK1 induces epithelial-mesenchymal transition (EMT) through EGFR signaling pathway in PCa. The association between SPINK1 overexpression and poor prognosis in PCa has been reported. Notably, SPINK1 might be a novel extracellular therapeutic target in a subset of high-grade PCa patients. In this review, we will summarize the current understanding of SPINK1 involving its role in PCa biology, association with prognosis as well as perspective in therapy from the pathologist's point of view.

Radical prostatectomy is the most cost-effective primary treatment modality for men diagnosed with high-risk prostate cancer

Radical prostatectomy is the most cost-effective primary treatment modality for men diagnosed with high-risk prostate cancer

1057 Delayed versus immediate radical prostatectomy in intermediate and high grade prostate cancer patients – postoperative (functional) outcomes

1057 Delayed versus immediate radical prostatectomy in intermediate and high grade prostate cancer patients – postoperative (functional) outcomes

The Effect of Obesity and Diabetes on Intermediate to High Grade Prostate Cancer Patients Treated with Radical Prostatectomy

Aims: The relationships between obesity, diabetes and prostate cancer are unclear. A retrospective study was performed to determine the effects of body mass index (BMI) and diabetes on patients with intermediate to high grade prostate cancer treated with radical prostatectomy. Methods: We reviewed 582 patients with Gleason score ≥ 7 non-metastatic prostate cancer treated with radical prostatectomy. Patients were stratified by BMI. End points were biochemical failure free survival (BFFS), overall survival (OS), and cancer specific survival (CSS). Results: Mean pre-treatment PSA decreased with increasing BMI (12.5, 7.6, 7.8 and 5.3 ng/mL with BMI 35, respectively; p 35, respectively. However, for overall mortality the adjusted hazard ratio was 0.39 (0.18, 0.82; p = 0.01) for overweight patients (BMI 25 - 30) compared to patients with a BMI in the normal range. Patients with a BMI of 30 - 35 and > 35 had increased rates of positive margins than those with a BMI of 25 - 30 or 35 2.04) on multivariate analysis, margin positivity alone was not a significant factor. Conclusions: Patients with increasing BMI tend to have a lower PSA at diagnosis but are more likely to have biochemical failure after radical prostatectomy. In our cohort, this was not due to the increased incidence of positive margins. Having diabetes had no effect.

Influencia de la demora quirúrgica en los hallazgos patológicos y el pronóstico de los pacientes con cáncer de próstata

Purpose To determine if a delay between prostate biopsy (PB) and radical prostatectomy (RP) has an impact on pathological findings and prognosis of prostate cancer patients (PCa). Material and methods Patients (n = 232) who underwent RP, with at least two postoperative PSA readings. Design: retrospective observational cohort study. Period: May 2000 – March 2007. Delay was defined as time in months between PB and RP. Statistical analysis: delay was analysed as a continuous variable or else categorised according to the median (6 months). A multivariate logistic regression analysis was performed to define variables associated with extracapsular disease. Biochemical recurrence-free survival (BRFS) was studied using the Kaplan-Meier method and multivariate Cox proportional hazards analysis. Results Differences between delay groups ≤ and > 6 months were significant only with regards to age (p = 0.041), considering both groups as comparable. Differences between groups related to pathological variables were not observed in any case. Mean followup was not significantly different between both groups (p = 0.112). The probability of extracapsular disease varied significantly depending on PSA, biopsy Gleason score and the percentage of positive cores, while multivariate analysis found no relationship with delay. Biochemical relapse was detected in 39 cases (16.81%). BRFS in delay ≤ 6 months group was 86.1%, 78.4%, 78.4% and 78.4% at 1, 2, 5 and 7 years, while BRFS in delay > 6 months group was 88.9%, 82.8%, 77.4%, 77.4% and 77.4% at 1, 2, 5 and 7 years (p = 0.632). Delay was not associated with BRFS in multivariate analysis; only the percentage of positive cores independently predicted BRFS. In patients with high-grade PCa, percentage of positive cores was the only independent variable to predict extracapsular disease and BRFS. Delay was not associated with extracapsular disease or BRFS. Conclusions Reasonable surgical delay does not cause a significant negative impact on pathological findings of RP specimens, nor in the BRFS of patients with localized PCa.

Lack of prostate cancer radiosensitization by androgen deprivation

Purpose: The majority of clinical trials have shown that high-grade prostate cancer patients treated with androgen deprivation (AD) plus radiation (RT) have a survival advantage over those treated with RT alone. One possible mechanism for such a favorable interaction is that AD sensitizes cells to radiation. Animal model studies have provided suggestive evidence that AD sensitizes cells to radiation, but this mechanism is difficult to confirm conclusively in vivo. This question was investigated in LNCaP cells grown in vitro.Methods and Materials: LNCaP cells were cultured in vitro in Dulbecco’s modified Eagle’s medium (DMEM)-F12 medium, containing 10% fetal bovine serum (complete medium [CM]). AD was achieved by culture in charcoal-stripped serum (SS)-containing medium. Replacement of androgen was done by adding the synthetic androgen R1881 at 1 × 10−10 M to SS. Apoptosis was measured with a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Clonogenic survival was used to determine overall cell death, and the results were corrected for differences in plating efficiency from the various growth conditions.Results: LNCaP cells were grown in CM, SS, or SS + R1881 medium, and cell counts obtained at 3, 4, and 5 days. Cell number increased exponentially in CM, whereas no increase in cell number was observed in SS medium. Cell counts from growth in SS + R1881 were intermediate between these extremes. Apoptosis was measured to determine if the combination of AD + RT in vitro resulted in supra-additive cell death, as has been previously described in an in vivo model system. The cells were cultured for 3 days before RT and apoptosis quantified 24 h after RT. There was a consistent supra-additive increase in apoptosis in cells exposed to AD + RT (2 or 8 Gy), as compared to either treatment given individually. In contrast, significant radiosensitization by AD was not observed by clonogenic survival even when the conditions of AD were varied. No radiosensitization was observed upon incubation in SS medium for 3, 4, or 5 days before RT, or extending AD after RT for 6 h before plating or 24 h after plating.Conclusion: The results show that in LNCaP prostate tumor cells supra-additive apoptosis does not translate into radiosensitization by clonogenic survival. Because clonogenic survival is a measure of overall cell death, either the level of apoptosis is too small a component of overall cell death or the increases in apoptosis occurred in a subpopulation that would have been killed by other mechanisms. Although the findings indicate that AD does not act by sensitizing prostate cancer cells to RT, the additive cell death and growth inhibitory effects of AD + RT are clinically meaningful.