Prognosis Of Castration-resistant Prostate Cancer Research Articles

Retinoblastoma-associated protein is important for TRIM24-mediated activation of the mTOR signaling pathway through DUSP2 action in prostate cancer.

RB transcriptional corepressor 1 (RB) deletion is the most important genomic factor associated with the prognosis of castration-resistant prostate cancer (CRPC) patients receiving androgen receptor (AR) signaling inhibitor therapy. Loss of RB could support prostate cancer cell growth in a hormone-independent manner, but the underlying mechanism by which RB regulates tumor progression extends far beyond the cell cycle pathway. A previous study indicated that RB inactivates AKT signaling but has no effect on mTOR signaling in cancer cells. Here, we found that the S249/T252 site in RB is key to regulating the transcriptional activity of the tumor-promoting factor TRIM24 in CRPC, as identified through FXXXV mapping. The RB/TRIM24 complex functions through DUSP2, which serves as an intermediate bridge, to activate the mTOR pathway and promote prostate cancer progression. Accordingly, we designed RB-linker-proteolysis-targeting chimera (PROTAC) molecules, which decreased TRIM24 protein levels and inactivated the mTOR signaling pathway, thereby inhibiting prostate cancer. Therefore, this study not only elucidates the novel function of RB but also provides a theoretical basis for the development of new drugs for treating prostate cancer.

Role of HIKESHI on Hyperthermia for Castration-Resistant Prostate Cancer and Application of a Novel Magnetic Nanoparticle with Carbon Nanohorn for Magnetic Hyperthermia.

The prognosis of castration-resistant prostate cancer (CRPC) is technically scarce; therefore, a novel treatment for CRPC remains warranted. To this end, hyperthermia (HT) was investigated as an alternative therapy. In this study, the analysis focused on the association between CRPC and heat shock protein nuclear import factor "hikeshi (HIKESHI)", a factor of heat tolerance. Silencing the HIKESHI expression of 22Rv1 cells (human CRPC cell line) treated with siRNAs inhibited the translocation of heat shock protein 70 from the cytoplasm to the nucleus under heat shock and enhanced the effect of hyperthermia. Moreover, a novel magnetic nanoparticle was developed via binding carbon nanohorn (CNH) and iron oxide nanoparticle (IONP) with 3-aminopropylsilyl (APS). Tumor-bearing model mice implanted with 22 Rv1 cells were examined to determine the effect of magnetic HT (mHT). We locally injected CNH-APS-IONP into the tumor, which was set under an alternative magnetic field and showed that tumor growth in the treatment group was significantly suppressed compared with other groups. This study suggests that HIKESHI silencing enhances the sensitivity of 22Rv1 cells to HT, and CNH-APTES-IONP deserves consideration for mHT.

Molecular Mechanisms of Noncoding RNA in the Occurrence of Castration-Resistant Prostate Cancer.

Although several therapeutic options have been shown to improve survival of most patients with prostate cancer, progression to castration-refractory state continues to present challenges in clinics and scientific research. As a highly heterogeneous disease entity, the mechanisms of castration-resistant prostate cancer (CRPC) are complicated and arise from multiple factors. Among them, noncoding RNAs (ncRNAs), the untranslated part of the human transcriptome, are closely related to almost all biological regulation, including tumor metabolisms, epigenetic modifications and immune escape, which has encouraged scientists to investigate their role in CRPC. In clinical practice, ncRNAs, especially miRNAs and lncRNAs, may function as potential biomarkers for diagnosis and prognosis of CRPC. Therefore, understanding the molecular biology of CRPC will help boost a shift in the treatment of CRPC patients. In this review, we summarize the recent findings of miRNAs and lncRNAs, discuss their potential functional mechanisms and highlight their clinical application prospects in CRPC.

Identification and Validation of Three Hub Genes Involved in Cell Proliferation and Prognosis of Castration-Resistant Prostate Cancer.

Background The acquisition of castration resistance is lethal and inevitable in most prostate cancer patients under hormone therapy. However, effective biomarkers and therapeutic targets for castration-resistant prostate cancer remain to be defined. Methods Comprehensive bioinformatics tools were used to screen hub genes in castration-resistant prostate cancer and were verified in androgen-dependent prostate cancer and castration-resistant prostate cancer in TCGA and the SU2C/PCF Dream Team database, respectively. Gene set enrichment analysis and in vitro experiments were performed to determine the potential functions of hub genes involved in castration-resistant prostate cancer progression. Results Three hub genes were screened out by bioinformatics analysis: MCM4, CENPI, and KNTC1. These hub genes were upregulated in castration-resistant prostate cancer and showed high diagnostic and prognostic value. Moreover, the expression levels of the hub genes were positively correlated with neuroendocrine prostate cancer scores, which represent the degree of castration-resistant prostate cancer aggression. Meanwhile, in vitro experiments confirmed that hub gene expression was increased in castration-resistant prostate cancer cell lines and that inhibition of hub genes hindered cell cycle transition, resulting in suppression of castration-resistant prostate cancer cell proliferation, which confirmed the gene set enrichment analysis results. Conclusions MCM4, CENPI, and KNTC1 could serve as candidate diagnostic and prognostic biomarkers of castration-resistant prostate cancer and may provide potential preventive and therapeutic targets.

Squalene Epoxidase Metabolic Dependency Is a Targetable Vulnerability in Castration-Resistant Prostate Cancer.

This study reveals PTEN and p53 deficiency confers a dependence on SQLE-mediated cholesterol metabolism, providing insights for new therapeutic strategies for treating castration-resistant prostate cancer.

PD35-10 PROGNOSTIC SIGNIFICANCE OF RISK STRATIFICATION IN CHAARTED AND LATITUDE STUDIES AMONG JAPANESE MEN WITH CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022PD35-10 PROGNOSTIC SIGNIFICANCE OF RISK STRATIFICATION IN CHAARTED AND LATITUDE STUDIES AMONG JAPANESE MEN WITH CASTRATION-RESISTANT PROSTATE CANCER Masaki Shiota, Sotaro Chikamatsu, Leandro Blas, Takashi Matsumoto, Eiji Kashiwagi, Junichi Inokuchi, Ken-ichiro Shiga, Akira Yokomizo, and Masatoshi Eto Masaki ShiotaMasaki Shiota More articles by this author , Sotaro ChikamatsuSotaro Chikamatsu More articles by this author , Leandro BlasLeandro Blas More articles by this author , Takashi MatsumotoTakashi Matsumoto More articles by this author , Eiji KashiwagiEiji Kashiwagi More articles by this author , Junichi InokuchiJunichi Inokuchi More articles by this author , Ken-ichiro ShigaKen-ichiro Shiga More articles by this author , Akira YokomizoAkira Yokomizo More articles by this author , and Masatoshi EtoMasatoshi Eto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002593.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The CHAARTED and LATITUDE trials demonstrated a survival benefit of docetaxel and abiraterone for hormone-sensitive prostate cancer. In this study, we examined the impact of the risk stratification criteria used in the CHAARTED and LATITUDE trials on the prognosis of castration-resistant prostate cancer (CRPC). We also tested whether these risk stratification criteria could help in selecting effective initial treatment for CRPC. METHODS: Japanese patients with CRPC who were treated with docetaxel or androgen receptor pathway inhibitors such as abiraterone acetate or enzalutamide between 2014 and 2018 were included in this study. Clinicopathological factors, progression-free survival, and overall survival were investigated. RESULTS: Of 215 patients, 110 men (51.2%) and 93 men (43.3%) were grouped as high volume by CHAARTED criteria and high risk by LATITUDE criteria, respectively. Median progression-free survival was 10.3/4.5 months (P <0.0001) for low/high volume (CHAARTED criteria) and 9.9/4.8 months (P=0.0032) for low/high risk (LATITUDE criteria). The median overall survival was 44.8/17.4 months (P <0.0001) for low/high volume (CHAARTED criteria) and 37.4/17.4 months (P=0.0011) for low/high risk (LATITUDE criteria). The prognostic impact of CHAARTED and LATITUDE criteria was comparable between androgen receptor pathway inhibitors and docetaxel as first-line treatment for CRPC. CONCLUSIONS: The CHAARTED and LATITUDE criteria were prognostic, but not predictive factors for CRPC. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e631 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Masaki Shiota More articles by this author Sotaro Chikamatsu More articles by this author Leandro Blas More articles by this author Takashi Matsumoto More articles by this author Eiji Kashiwagi More articles by this author Junichi Inokuchi More articles by this author Ken-ichiro Shiga More articles by this author Akira Yokomizo More articles by this author Masatoshi Eto More articles by this author Expand All Advertisement PDF DownloadLoading ...

Prognostic significance of risk stratification in CHAARTED and LATITUDE studies among Japanese men with castration-resistant prostate cancer.

BackgroundThe CHAARTED and LATITUDE trials demonstrated a survival benefit of docetaxel and abiraterone for hormone-sensitive prostate cancer. In this study, we examined the impact of the risk stratification criteria used in the CHAARTED and LATITUDE trials on the prognosis of castration-resistant prostate cancer (CRPC). We also tested whether these risk stratification criteria could help in selecting effective initial treatment for CRPC.MethodJapanese patients with CRPC who were treated with docetaxel or androgen receptor pathway inhibitors such as abiraterone acetate or enzalutamide between 2014 and 2018 were included in this study. Clinicopathological factors, progression-free survival, and overall survival were investigated.ResultsOf 215 patients, 110 men (51.2%) and 93 men (43.3%) were grouped as high volume by CHAARTED criteria and high risk by LATITUDE criteria, respectively. Median progression-free survival was 10.3/4.5 months (P < 0.0001) for low/high volume (CHAARTED criteria) and 9.9/4.8 months (P = 0.0032) for low/high risk (LATITUDE criteria). The median overall survival was 44.8/17.4 months (P < 0.0001) for low/high volume (CHAARTED criteria) and 37.4/17.4 months (P = 0.0011) for low/high risk (LATITUDE criteria). The prognostic impact of CHAARTED and LATITUDE criteria was comparable between androgen receptor pathway inhibitors and docetaxel as first-line treatment for CRPC.ConclusionThe CHAARTED and LATITUDE criteria were prognostic, but not useful to discriminate the therapeutic outcome between androgen receptor pathway inhibitors and docetaxel for CRPC.

Prognostic impact of prior local therapy in castration-resistant prostate cancer

This study aimed to reveal the prognostic values of prior local therapy in first-line therapy using androgen receptor-axis targeting agents (abiraterone or enzalutamide) or docetaxel for castration-resistant prostate cancer (CRPC). The study included 303 patients treated with first-line therapy for non-metastatic and metastatic CRPC. The association between prior local therapy and therapeutic outcome including progression-free survival and overall survival was investigated by univariate and multivariate analyses as well as propensity score-matched analysis. In univariate analysis, local prior therapy was associated with a lower risk of all-cause mortality (hazard ratio, 0.56, 95% confidence interval, 0.40-0.79; P=0.0009). Overall survival, but not progression-free survival, was better among patients with prior local therapy compared with patients without prior local therapy even after multivariate analysis and propensity score-matched analysis. This study robustly indicated that prior local treatment was prognostic for overall survival among patients with CRPC. This finding is useful to predict patient prognosis in CRPC.

Novel nanococktail of a dual PI3K/mTOR inhibitor and cabazitaxel for castration-resistant prostate cancer.

Prognosis of castration-resistant prostate cancer (CRPC) carries is poor, and no effective therapeutic regimen is yet known. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway played a predominant role and may be a promising molecular target for CRPC. However, the toxicity of the dual PI3K inhibitors in clinical trials limits their clinical efficacy for CRPC. To solve this problem, we employed a highly integrated precision nanomedicine strategy to molecularly and physically target CRPC through synergistic effects, enhanced targeted drug delivery efficiency, and reduced unwanted side-effects. Gedatolisib (Ge), a potent inhibitor of PI3K/mTOR, was formulated into our disulfied-crosslinked micelle plateform (NanoGe), which exhibits excellent water solubility, small size (23.25±2 nm), excellent stability with redox stimulus-responsive disintegration, and preferential uptake at tumor sites. NanoGe improved the anti-neoplastic effect of free Ge by 53 times in PC-3M cells and 13 times in C4-2B cells though its enhanced uptake via caveolae- and clathrin-mediated endocytic pathways and the subsequent inhibition of the PI3K/mTOR pathway, resulting in Bax/Bcl-2 dependent apoptosis. In an animal xenograft model, NanoGe showed superior efficacy than free Ge, and synergized with nanoformulated cabazitaxel (NanoCa) as a nanococktail format to achieve a cure rate of 83%. Taken together, our results demonstrate the potency of NanoGe in combination with NanoCa is potent against prostate cancer.

Identification of PTPRR and JAG1 as key genes in castration-resistant prostate cancer by integrated bioinformatics methods.

To identify novel genes in castration-resistant prostate cancer (CRPC), we downloaded three microarray datasets containing CRPC and primary prostate cancer in Gene Expression Omnibus (GEO). R packages affy and limma were performed to identify differentially expressed genes (DEGs) between primary prostate cancer and CRPC. After that, we performed functional enrichment analysis including gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway. In addition, protein-protein interaction (PPI) analysis was used to search for hub genes. Finally, to validate the significance of these genes, we performed survival analysis. As a result, we identified 53 upregulated genes and 58 downregulated genes that changed in at least two datasets. Functional enrichment analysis showed significant changes in the positive regulation of osteoblast differentiation pathway and aldosterone-regulated sodium reabsorption pathway. PPI network identified hub genes like cortactin-binding protein 2 (CTTNBP2), Rho family guanosine triphosphatase (GTPase) 3 (RND3), protein tyrosine phosphatase receptor-type R (PTPRR), Jagged1 (JAG1), and lumican (LUM). Based on PPI network analysis and functional enrichment analysis, we identified two genes (PTPRR and JAG1) as key genes. Further survival analysis indicated a relationship between high expression of the two genes and poor prognosis of prostate cancer. In conclusion, PTPRR and JAG1 are key genes in the CRPC, which may serve as promising biomarkers of diagnosis and prognosis of CRPC.

Abstract A197: Synthesis and in vitro anti-prostate cancer activities of androgen receptor ligand-isothiocyanate hybrid drug

Abstract Prostate cancer (PCa) is the most common male malignancy in U.S.. In contrast to the localized early-stage disease, prognosis of castration-resistant prostate cancer (CRPC), i.e., the relapsed/metastatic advanced disease phenotype, is extremely poor. Because the sustained androgen receptor (AR) signaling remains one of the central driving forces of CRPC, new-generation nonsteroid AR antagonist has been developed in recent years, exemplified by the approval of enzalutamide (Enz) in 2012 for post-chemo and in 2014 for chemotherapy-naïve CRPC. However, drug resistance inevitably develops and survival benefits of Enz in CRPC patients are short-lived. Isothiocyanates (ITCs), e.g., sulforaphane (SFN) and phenethyl isothiocyanate (PEITC), are active metabolites of dietary glucosinolate from cruciferous vegetables with broad anti-PCa activities, such as suppressing AR expression, downregulating antiapoptotic proteins, inducing cell cycle arrest and apoptosis, and inhibiting PCa stem-like cells, etc. SFN-rich extract was recently tested in recurrent PCa patients and notably prolonged PSA doubling time without severe adverse events. By modifying Enz structure, we designed and synthesized AR ligand-ITC hybrid drug, aimed at antagonizing androgen-stimulated AR transcriptional activity and meanwhile downregulating AR expression and inducing other anticancer effects in PCa cells. To increase water solubility, ITCs were further reacted with N-acetyl cysteine (NAC) to obtain NAC conjugates. A representative hybrid drug NAC conjugate 2-63 was selected for in vitro study. In PBS buffer (pH 7.4), 2-63 gradually decomposes and releases free ITC with a half-life of about 3.4h. Measured using MTT assay, 2-63 was more tolerable in noncancerous RWPE-1 cell, significant differences were observed between RWPE-1 and PCa LNCaP cells, suggesting NAC conjugate could be a water-soluble carrier of AR ligand-ITC hybrid drug. The slower release of ITC constrains the concentration of electrophilic ITC within limit that is tolerated in healthy tissue. The newly designed hybrid drug chemical scaffold retains AR antagonist activity, evidenced by the inhibition of ARE-regulated luciferase activity in kb2 cell and the suppression of DHT-stimulated proliferation of LNCaP cell. 2-63 also dose- and time-dependently inhibited growth of CRPC VCaP cell and disrupted mitochondrial membrane potential, more effectively than SFN and Enz. Analyzed using Western blot, 2-63 downregulated the expression of full-length AR (fAR) and AR splice variants 7 (AR-V7). The AR downregulating properties were also observed in LNCaP and in 22Rv1 cells carrying different AR mutants. Since AR-V expression is one of the mechanisms causing clinical resistance to Enz treatment, targeting both fAR and AR-Vs using the newly discovered AR ligand-ITC hybrids may provide a new modality to improve the prognosis in CRPC patients. Citation Format: Siyu Ou, Liping Xu, Zhihui Qin. Synthesis and in vitro anti-prostate cancer activities of androgen receptor ligand-isothiocyanate hybrid drug [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A197.

Prognostic and Therapeutic Implications of Circulating Androgen Receptor Gene Copy Number in Prostate Cancer Patients Using Droplet Digital Polymerase Chain Reaction.

Resistance mechanisms in the androgen receptor (AR) signaling pathway remain key drivers in the progression to castration-resistant prostate cancer (CRPC) and relapse under antihormonal therapy. We evaluated the circulating AR gene copy number (CN) gain using droplet digital polymerase chain reaction in 21 control and 91 prostate cancer serum samples and its prognostic and therapeutic implications in prostate cancer. In CRPC, AR CN gain was associated with faster progression to CRPC (P= .026), a greater number of previous treatments (P = .045), and previous chemotherapy (P= .016). Comparing patients with and without CN gain, the median progression-free survival (PFS) in the abiraterone subgroup was 1.7 months versus not reached (P= .004), and the median overall survival (OS) was 7 months versus 20.9 months (P= .020). In the enzalutamide subgroup, PFS was 1.7 versus 10.8 months (P= .006), and OS was 6.1 versus 16.5 months (P= .042). In the taxane subgroup, PFS was 3.2 versus 6.5 months (P= .093), and OS was 3.9 months versus not reached (P= .026). The presence of more AR copies correlated with shorter androgen deprivation (P= .002), abiraterone (P= .022), enzalutamide (P= .008), and taxane (P= .039) therapy. Circulating AR CN gain predicts for a poor prognosis in CRPC. It is a promising biomarker predetermining rapid CRPC progression and predicting worse abiraterone and enzalutamide outcomes. Furthermore, it is associated with multiple previous treatments and previous chemotherapy.

A distinct plasma lipid signature associated with poor prognosis in castration-resistant prostate cancer.

Lipids are known to influence tumour growth, inflammation and chemoresistance. However, the association of circulating lipids with the clinical outcome of metastatic castration-resistant prostate cancer (CRPC) is unknown. We investigated associations between the plasma lipidome and clinical outcome in CRPC. Lipidomic profiling by liquid chromatography-tandem mass spectrometry was performed on plasma samples from a Phase 1 discovery cohort of 96 CRPC patients. Results were validated in an independent Phase 2 cohort of 63 CRPC patients. Unsupervised analysis of lipidomic profiles (323 lipid species) classified the Phase 1 cohort into two patient subgroups with significant survival differences (HR 2.31, 95% CI 1.44-3.68, p = 0.0005). The levels of 46 lipids were individually prognostic and were predominantly sphingolipids with higher levels associated with poor prognosis. A prognostic three-lipid signature was derived (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0) and was also associated with shorter survival in the Phase 2 cohort (HR 4.8, 95% CI 2.06-11.1, p = 0.0003). The signature was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics. The association of plasma lipids with CRPC prognosis suggests a possible role of these lipids in disease progression. Further research is required to determine if therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.

Therapies for castration-resistant prostate cancer in a new era: The indication of vintage hormonal therapy, chemotherapy and the new medicines.

When advanced prostate cancer recurred during hormonal therapy and became the castration-resistant prostate cancer, "vintage hormonal therapy," such as antiandrogen alternating therapy or estrogen-related hormonal therapy, was widely carried out in Japan until 2013. This vintage hormonal therapy controlled the progression of castration-resistant prostate cancer. When castration-resistant prostate cancer relapses during these therapies, chemotherapy using docetaxel has been carried out subsequently. Since new hormonal therapies using abiraterone acetate and enzalutamide, which improve the prognosis of castration-resistant prostate cancer, became available in Japan from 2014, therapeutic options for castration-resistant prostate cancer have increased. Furthermore, the improvement of the further prognosis is promising by using cabazitaxel for docetaxel-resistant castration-resistant prostate cancer and radium-223 for castration-resistant prostate cancer with bone metastasis. An increase in therapeutic options gives rise to many questions, including best timing to use them and the indication. Furthermore, physicians have to consider the treatment for the recurrence after having carried out chemotherapy. We want to argue the difference in hormonal therapy between Japan and Western countries, and problems when carrying out new treatments, and the importance of imaging in the present review article.

Is chemical/surgical castration necessary during docetaxel chemotherapy for castration-resistant prostate cancer?

e16530 Background: Docetaxel is the standard treatment for castration-resistant prostate cancer (CRPC). However, the role of chemical/surgical castration during docetaxel chemotherapy is unclear. The purpose of this study was to analyze the impact of castration during docetaxel chemotherapy. Methods: Data from 43 patients diagnosed with CRPC and treated at our institute with docetaxel chemotherapy, from January 2007 to September 2016, were analyzed retrospectively. They were divided into two groups according to the continuation of chemical castration during docetaxel chemotherapy: a continuation group and a discontinued group. Patients’ background data (age and serum prostate-specific antigen [PSA] level), PSA decline, progression-free survival, and overall survival were compared between the two groups. Results: The continuation group included 19 patients, and the discontinued group included 24 patients. Castration included surgical castration (15.8%), use of a luteinizing hormone-releasing hormone (LH-RH) agonist (68.4%), and use of an LH-RH antagonist (15.8%). There were no significant differences in patient age (73.5 years vs. 73.5 years; p = 0.878) and baseline serum PSA levels (14.25 ng/ml vs. 31.1 ng/ml, p = 0.745) between the two groups at the start of chemotherapy. PSA declines of ≥50% were observed in 7/14 patients and in 9/20 patients, respectively. There were no significant differences between the two groups with respect to the median progression-free survival (5.7 months vs. 9.9 months, p = 0.406) and overall survival. (52.1 months vs. 44.1 months, p = 0.776). Conclusions: Continuing chemical/surgical castration during docetaxel chemotherapy did not affect progression and prognosis of CRPC. Our results might suggest that chemical castration is not necessary during docetaxel chemotherapy.

Bone scan index at baseline as a tool for predicting hematologic toxicity in metastatic castration-resistant prostate cancer patients eligible for radium-223 treatment.

e16513 Background: The prognosis of castration-resistant prostate cancer with skeletal metastasis (CRPCSM) is poor. The ALSYMPCA trial led to the approval of radium-223 (Ra223) in such patients. Factors that could predict hematologic toxicities associated with Ra223 remain poorly defined. We analyzed the utility of bone scan index (BSI) at baseline (BSI-B) as a predictive marker for such toxicities. Methods: This is a retrospective study of CRPCSM patients without visceral metastasis who received Ra223 at Roswell Park Cancer Institute from 2013 to 2015. BSI was defined utilizing the estimation of a numerical index (max, 70.8% for diffuse skeletal involvement) that expresses the fractional involvement of each bone by tumor. BSI-B values were classified into &lt; first quartile ( &lt; Q1), between first and third quartile (Q1-Q3), and &gt; third quartile ( &gt; Q3). The associations between BSI-B and different hematologic parameters [hemoglobin (Hgb), platelets (Plt), absolute neutrophil count (ANC)] over the Ra223 treatment duration were evaluated using linear mixed models. Results: A total of 79 patients were included in this analysis. The median Gleason score was 8 (range: 4-10) and the median age at first Ra223 was 71 years. Seventy percent of patients received 5 or more doses of Ra223. There was a significant association between BSI-B and Hgb (p = 0.005) and Plt (p = 0.011) levels at baseline and at all time points. The &gt; Q3 BSI-B was associated with a greater drop in Plt from an elevated baseline with subsequent treatments of Ra223 [drop from a mean of 293.5±21.3 x109/L (n = 19) to 132.2±48.8 x109/L (n = 9) after sixth Ra223]; while such a decline was not observed for lower BSI-B (p &lt; 0.001). The ANC decreased with each Ra223 in patients with &gt; Q3 BSI-B but not in the ones with lower BSI-B (p = 0.003). Conclusions: Our work demonstrates that hematologic parameters at baseline and during Ra223 treatment are associated with higher BSI-B values, raising the possibility of BSI-B as a valuable tool for predicting the risk of cytopenias before initiating Ra223 in CRPCSM patients. Prospective validation is needed to confirm the utility of our findings.

Prognostic value of pre-chemotherapy serum cystatin C in patients with castration-resistant prostate cancer

Objective To explore the prognostic value of pre-chemotherapy serum cystatin C (Cys C) in patients with castration-resistant prostate cancer (CRPC). Methods The medical records of 48 patients with CRPC were reviewed. These patients were diagnosed and underwent docetaxel-based chemotherapy in Xinjiang Military Command General Hospital between January 2009 and January 2015. Statistical analysis was performed to identify the clinical and prognosis value of Cys C. Results Of 48 patients with CRPC, the expre-ssion of serum Cys C before chemotherapy was related with Gleason score (χ2=4.218, P=0.040) and distant metastasis(χ2=4.090, P=0.043). 23 patients was in high group (Cys C>1.61 mg/L), 25 in low (Cys C≤1.61 mg/L). The median survival time of high group and low group were 15.6 and 25.3 months, respectively (χ2=13.876, P<0.001). Univariate analysis showed that TNM stage (χ2=6.934, P=0.018), Gleason score (χ2=7.933, P=0.005), baseline prostate specific antigen (PSA) (χ2=9.038, P=0.003), number of chemotherapy cycles (χ2=5.024, P=0.028), distant metastases (χ2=6.963, P=0.013) and serum Cys C before chemotherapy (χ2=6.976, P=0.012) were associated with overall survival of patients with CRPC. COX multivariate analysis showed that baseline PSA at diagnosis (χ2=4.257, P=0.039), number of chemotherapy cycles (χ2=6.245, P=0.017), distant metastases (χ2=5.122, P=0.028) and serum Cys C before chemotherapy (χ2=8.172, P=0.004) were independent risk factors of overall survival of patients with CRPC, especially serum Cys C before chemotherapy (HR=2.394). Conclusion The patients with high Cys C level have poor prognosis, and the pre-chemotherapy Cys C is an independent risk factor for prognosis of CRPC patients treated with docetaxel-based chemotherapy which can be used as an effective indicator to assess the prognosis of CRPC. Key words: Prostatic neoplasms; Prognosis; Drug therapy; Cystatin C

Identification of novel SNPs associated with risk and prognosis in patients with castration-resistant prostate cancer.

Metabolism and transport play major roles in life-long exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in absorption, distribution, metabolism and elimination genes and the risk and prognosis of castration-resistant prostate cancer (CRPC). A total of 634 genotypes were tested in 74 patients using the Affymetrix DMETv1.0 platform. No relation to risk was found. Three SNPs were associated with CRPC prognosis in Caucasians: ABCB11 rs7602171G>A (p = 0.003; n = 30; hazard ratio [HR]: 0.307), GSTP1 rs1799811C>T (p = 0.001; n = 38; HR: 0.254) and SLC5A6 rs1395 (p = 0.004; n = 35; HR: 3.15). Two other polymorphisms among Caucasians were associated with interesting trends: ABCB4 rs2302387C>T (p = 0.039) and ABCC5 rs939339A>G (p = 0.018). This exploratory study is the first to show that polymorphisms in several absorption, distribution, metabolism and elimination genes may be associated with CRPC prognosis.

A Phase 2 Randomized Controlled Trial of Personalized Peptide Vaccine Immunotherapy with Low-dose Dexamethasone Versus Dexamethasone Alone in Chemotherapy-naive Castration-resistant Prostate Cancer

BackgroundIt is well known that the prognosis of castration-resistant prostate cancer (CRPC) is poor, and several immunotherapeutic strategies have been applied to the clinical trials. Research on immunotherapy has been of special interest for the treatment of CRPC for years. ObjectiveTo evaluate the safety of personalized peptide vaccine (PPV) immunotherapy and its clinical outcomes. Design, setting, and participantsA phase 2 randomized controlled trial of PPV immunotherapy with low-dose dexamethasone versus dexamethasone alone for chemotherapy-naive CRPC began in 2008. Eligible patients (prostate-specific antigen [PSA] <10 ng/ml) were human leukocyte antigen (HLA) A02, A24, or A03 superfamily positive and had asymptomatic or minimally symptomatic CRPC. Patients were allocated (1:1) to PPV plus dexamethasone (1mg/d) or to dexamethasone (1mg/d) alone. A maximum of four HLA-matched peptides (each 3mg) was selected based on the preexisting immunoglobulin G responses against the 24 warehouse peptides and administered every 2 wk. Outcome measurements and statistical analysisPSA, progression-free survival (PFS), time to initiation of chemotherapy, and overall survival (OS) were analyzed using the Kaplan-Meier method, a log-rank test, and proportional hazard analysis. Results and limitationsOverall, 37 patients received peptide vaccinations and 35 received dexamethasone alone. The primary end point was PSA PFS, which was significantly longer in the vaccination group than in the dexamethasone group (22.0 vs 7.0 mo; p=0.0076). Median OS was also significantly longer in the vaccination group (73.9 vs 34.9 mo; p=0.00084). The relatively small number of patients enrolled is the major limitation of the study. ConclusionsPPV immunotherapy was well tolerated and associated with longer PSA PFS and OS in men with chemotherapy-naive CRPC. A larger phase 3 study is needed to confirm our findings. Patient summaryWe compared clinical outcomes of the treatment with personalized peptide vaccine plus dexamethasone versus dexamethasone alone. Our data provide promising evidence of clinical benefit for peptide vaccines. Trial registrationUMIN-CTR: 000000959.

The association of JAK2 polymorphisms with prognosis in castration-resistant prostate cancer (CRPC).

313 Background: We evaluated variation in candidate genes implicated in either initiation or progression of prostate cancer with survival in CRPC stage. Methods: Germline DNA was extracted from peripheral blood mononuclear cells of CRPC patients enrolled in a clinically annotated registry. Fourteen candidate genes were tagged using single nucleotide polymorphisms (SNPs) from HapMap with minor allele frequency of &gt; 5%. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. Principal component analysis was used for gene levels tests of significance. For SNP level results the per allele hazard ratios (HR) and 95% confidence intervals (CI) under the additive allele model using Cox regression adjusted for age at CRCP and Gleason score (GS) were used. Results: Two hundred and forty five CRPC patients who met the criteria of having adequate DNA were genotyped (14 genes, 84 SNPs). The median age of the cohort was 69 years (range 43-93). The GS distribution was 55% with GS≥8, 32% with GS = 7 and 13% with GS &lt; 7 or unknown. Median time from castration resistance to death for the cohort was 2.67 years (IQ range: 1.6-4.07, 144 deaths). At the gene level JAK2 was detected to be associated with OS. Six of 18 JAK2 SNPs were associated with OS after adjustment for age and GS as well as pruning of SNPs in high linkage disequilibrium with each other (see table). In our multivariate model including age, GS, rs2149556, and rs4372063, the adjusted HRs for rs2149556 and rs4372063 were 0.67 (95% CI 0.38-1.18) and 2.17 (95% CI 1.25-3.76), respectively. The protective effect of rs2149556 appears after adjusting for the presence of minor alleles for rs4372063 in this dataset. Conclusions: Germline variation in the JAK2gene is associated with survival in CRPC stage and warrants further validation as a potential prognostic biomarker. [Table: see text]