Prostate imaging: Contribution of PET PSMA and MRI

Prostate cancer is the most common malignant tumour and represents the third cause of cancer-mortality in men. The management of prostate cancer has dramatically changed over the last decades, mainly due to improvement of diagnostic modalities and development of new therapeutic strategies. Imaging plays a key role in all the steps of prostate cancer management. In recent years, magnetic resonance imaging (MRI) and positron-emission tomography (PET) – computed tomography (CT) have emerged as two major tools for the detection of prostate cancer, tumour staging and treatment choice. Both MRI and PET-CT – using choline or prostate-specific membrane antigen (PSMA) as radiotracer – have become mandatory. This article presents the contribution of the latest advances in these two imaging techniques of prostate cancer and their future developments.     

History of Diabetes,Clinical Features of Prostate Cancer,and Prostate Cancer Recurrence-Data from CaPSURE<Superscript>TM</Superscript> (United States)

Objectives: There is a growing epidemiologic literature suggesting an inverse association between history of diabetes and risk of incident prostate cancer. To our knowledge, the relationship between diabetes and tumor features and risk of recurrence among men with prostate cancer has not been examined previously. We hypothesized that men with diabetes would present with more favorable prostate cancer and experience lower risk of recurrence. Methods: We identified 691 men with diabetes at the time of prostate cancer diagnosis, among 6722 men diagnosed with prostate cancer in 1989 to 2002 within CaPSURE^TM, a community-based prostate cancer registry study. We compared clinical and socio-demographic variables by diabetes status, using χ² tests, t-tests, and multinomial logistic regression. We examined recurrence rates for prostate cancer among patients with and without diabetes using Kaplan–Meier log-rank tests and Cox proportional hazard models. Results: In multivariate analyses, history of diabetes was not associated with any diagnostic clinical parameter, and treatment-specific recurrence rates for prostate cancer generally did not differ by diabetes history. Among men with low-prognostic risk or who were younger at prostate cancer diagnosis, being diabetic (versus not) was associated with an elevated risk of recurrence after radiation therapy, in multivariate analyses. Conclusions: Contrary to data suggesting that diabetes may be modestly protective against risk of incident prostate cancer, we did not observe any evidence of an inverse association between history of diabetes and aggressiveness at diagnosis or risk of recurrence, in this population of men with prostate cancer.     

Discussing the predictive,prognostic, and therapeutic value of germline DNA-repair gene mutations in metastatic prostate cancer patients

Recent trends in cancer therapy have begun emphasizing the use of precision medicine, especially genetic tools, in the evaluation of malignancies and decision-making. Prostate cancer is a malignancy where the benefits and utility of screening and early treatment are still heavily controversial. A recent paper in the New England Journal of Medicine found that patients with metastatic prostate cancer presented germline mutations in DNA-repair genes at a significantly higher incidence than those with localized prostate cancer. These findings indicate the need for further research in this field as genetic differences between metastatic and localized prostate cancer could have great clinical value.     

The current and potential role of cryoablation as a primary therapy for localized prostate cancer

Targeted cryoablation of the prostate has evolved significantly since its reintroduction in the early 1990s. This evolution stems from engineering advancements, procedural refinement, introduction of temperature monitoring, and greater understanding of cryobiology. Recent publications demonstrate durable efficacy for cryoablation, equivalent to other therapies for low-risk disease and possibly superior for moderate- and high-risk prostate cancer. Morbidity following the procedure is mild in comparison with other therapies, with the exception of sexual function impairment. However, longer-term quality-of-life studies show that a significant number of patients return to having intercourse, and late-onset morbidities are not observed. These results contrast with those for radiotherapy—specifically brachytherapy—for which several recent studies document a decline in sexual function, protracted morbidity, and the emergence of late-onset morbidity. Cryoablation is an effective therapy with acceptable morbidity that should be offered as a treatment option to all patients with localized prostate cancer. Furthermore, cryoablation has the potential ability to be tailored to an individual patient’s disease. As diagnostic tools and methods continue to advance, it may become possible to target the less aggressive forms of prostate cancer. Focal cryoablation may prove to be an ideal treatment modality in this setting.     

Imaging for prostate cancer

The increased incidence and awareness of prostate cancer, together with developments in treatment, has generated a significant need for appropriate imaging to detect and stage the tumour initially, guide radiotherapy delivery and monitor disease on follow-up. Transrectal ultrasound is usually the first imaging investigation, and its role is primarily to guide prostate needle biopsy. It also has an established role in imaging-guided treatments, such as brachytherapy. Magnetic resonance imaging has developed considerably in recent years, and is now the principal staging investigation before treatment. Innovations in functional and biological imaging of the prostate will, in the future, contribute valuable information to support parallel developments in radiotherapy techniques for prostate cancer. The ultimate goal is a coordinated diagnostic and therapeutic approach to individualise and optimise the treatment plan for patients with prostate cancer.     

The novel tumor‐suppressor Mel‐18 in prostate cancer: Its functional polymorphism,expression and clinical significance

Mel‐18 is a member of the polycomb group (PcG) proteins, which are chromatin regulatory factors and play important roles in development and oncogenesis. This study was designed to investigate the clinical and prognostic significance of Mel‐18 in patients with prostate cancer. A total of 539 native Japanese subjects consisting of 393 prostate cancer patients and 146 controls were enrolled in this study. Mel‐18 genotyping was analyzed using a PCR‐RFLP method and an automated sequencer using the GENESCAN software. Immunohistochemistry revealed that Mel‐18 expression was diminished in high grade and high stage prostate cancers. Moreover, patients with positive Mel‐18 expression had significantly longer PSA recurrence‐free survival than patients negative for Mel‐18 expression (p = 0.038). A Mel‐18 1805A/G SNP was located in the 3' untranslated region and was predicted to alter the secondary structure of the mRNA. Mel‐18 mRNA expression of the 1805A allele was clearly higher than expression of the 1805G allele by allele specific quantitative RT‐PCR. In multivariate analysis, a homozygous G allele genotype and negative Mel‐18 expression were independent risk factors predicting high PSA recurrence after radical prostatectomy, with HRs of 2.757 (p = 0.022) and 2.271 (p = 0.045), respectively. Moreover, the G allele was also an independent predictor of poor cancer‐specific survival with an HR of 4.658 (p = 0.019) for patients with stage D2 prostate cancer. This is the first study to provide important evidence demonstrating that Mel‐18 is a tumor suppressor and possible therapeutic target, as well as a diagnostic marker for poor prognosis in prostate cancer patients. © 2009 UICC     

Prostate-specific Membrane Antigen (PSMA)-specific Monoclonal Antibodies in the Treatment of Prostate and Other Cancers

Prostate-specific membrane antigen (PSMA) is a cell surface glycoprotein that is expressed by prostate epithelial cells. PSMA-specific monoclonal antibodies have been utilized to characterize the biologic function and in vivo biodistribution of PSMA. PSMA is an attractive target protein for monoclonal antibody directed imaging or therapeutics for prostate cancer since its expression is relatively restricted to prostate epithelial cells and is over-expressed in prostate cancer, including in advanced stages. Currently, clinical usage of PSMA specific monoclonal antibodies has been limited to diagnostic immunohistochemistry and imaging of patients with prostate cancer. Novel applications for these antibodies will be discussed.     

Prostate stem cell antigen: a prospective therapeutic and diagnostic target

The development of novel clinical tools to combat cancer is an intense field of research and recent efforts have been directed at the identification of proteins that may provide diagnostic, prognostic and/or therapeutic applications due to their restricted expression. To date, a number of protein candidates have emerged as potential clinical tools in the treatment of prostate cancer. Discovered over ten year ago, prostate stem cell antigen (PSCA) is a cell surface antigen that belongs to the Ly-6/Thy-1 family of glycosylphosphatidylinositol-anchored proteins. PSCA is highly overexpressed in human prostate cancer, with limited expression in normal tissues, making it an ideal target for both diagnosis and therapy. Several studies have now clearly correlated the expression of PSCA with relevant clinical benchmarks, such as Gleason score and metastasis, while others have demonstrated the efficacy of PSCA targeting in treatment through various modalities. The purpose of this review is to present the current body of knowledge about PSCA and its potential role in the treatment of human prostate cancer.     

Effects of functional genetic polymorphisms in the CYP19A1 gene on prostate cancer risk and survival

CYP19 catalyzes the conversion of androgens to estrogens and is a critical enzyme affecting the sex hormone milieu. In this study, we investigated the functions of CYP19A1 polymorphisms and their associations with prostate cancer risk and clinical outcome. This case‐control study evaluated the effects of three single nucleotide polymorphisms (SNPs) in CYP19A1 on the risk of prostate cancer in 330 prostate cancer patients and 354 normal controls. The associations between each SNP and sex hormone levels were evaluated in 164 healthy male patients. The functions of the SNPs were determined by reporter gene assays in PC3 and DU145 cell lines. Prostate‐specific antigen nadir was evaluated in 142 patients with metastatic prostate cancer treated with androgen deprivation therapy. Cancer‐specific survival (CSS) was determined in 166 patients with metastatic prostate cancer, to evaluate the influence of the three SNPs. Each variant allele of the three SNPs significantly decreased the risk of prostate cancer. Haplotype analysis showed that the T‐A‐G haplotype (corresponding to rs2470152‐rs10459592‐rs4775936) increased the risk of prostate cancer, while the C‐C‐A haplotype decreased the risk. The estrone/androstenedione ratio was significantly higher in men with the C allele of rs2470152, the C allele of rs10459592, and the A allele of rs4775936 in a gene‐dosage‐dependent manner. Patients with the variant allele at rs4775936 had significantly shorter CSS. These results indicate that CYP19A1 polymorphisms may influence prostate cancer risk and survival by modifying promoter activity, with subsequent effects on the sex hormone milieu.     

Cancer biomarkers: knowing the present and predicting the future

In recent years the discovery of cancer biomarkers has become a major focus of cancer research. The widespread use of prostate-specific antigen in prostate cancer screening has motivated researchers to identify suitable markers for screening different types of cancer. Biomarkers are also useful for diagnosis, monitoring disease progression, predicting disease recurrence and therapeutic treatment efficacy. With the advent of new and improved genomic and proteomic technologies such as DNA and tissue microarray, two-dimensional gel eletrophoresis, mass spectrometry and protein assays coupled with advanced bioinformatic tools, it is possible to develop biomarkers that are able to reliably and accurately predict outcomes during cancer management and treatment. In years to come, a serum or urine test for every phase of cancer may drive clinical decision making, supplementing or replacing currently existing invasive techniques.     

Therapeutic options for first-line metastatic castration-resistant prostate cancer: Suggestions for clinical practise in the CHAARTED and LATITUDE era

In few years the scenario of metastatic prostate carcinoma treatment has radically changed due to improved knowledge of those mechanisms responsible of prostatic cancer cells survival and proliferation.Five new therapeutic agents (abiraterone acetate, enzalutamide, cabazitaxel, radium-223, sipuleucel-T), all able to improve overall survival, have been introduced in the management of metastatic castration-resistant prostate cancer.Moreover, recent evidences showed that adding docetaxel chemotherapy or abiraterone acetate to androgen deprivation therapy significantly increases overall survival of de novo castration-sensitive metastatic prostate cancer patients.Due to this rapid therapeutic evolution clinicians face one crucial challenge: the choice of the best treatment sequencing.In particular, there are no prospective data to guide clinical decision in patients with progressive disease after docetaxel or abiraterone acetate treatment for castration sensitive disease.In this review we provide an overview of the therapeutic agents available for both castration-sensitive and castration-resistant prostate cancer.We propose some biological and clinical insights helpful in selecting the most appropriate treatment for patients progressing after metastatic castration-sensitive prostate cancer treatment with docetaxel or abiraterone acetate.     

Hypertension as a predictive biomarker in bevacizumab treatment for colorectal cancer patients

To assess preoperative parameters that may be predictive of pathologic stage T2a (pT2a) and pathologic Gleason score (pGS) ?? 6 disease in low-risk prostate cancer patients considering active surveillance. A cohort of 1,495 men with low-risk prostate cancer between 1993 and 2009 was utilized. Preoperative assessment focused on patient age, race, diagnostic PSA level, clinical stage, diagnostic biopsy Gleason score, and prostate cancer laterality. Kaplan?CMeier curves and a Cox regression model were used for analysis of PSA recurrence. Preoperative parameters were analyzed by univariate and multivariate logistic regression methods. Of 1,495 patients, 187 (12.5 %) were identified with pT2a and pGS ?? 6 disease. Of the 187 men with pT2a and pGS ?? 6 disease, only 6 (3.2 %) cases had PSA recurrence. Kaplan?CMeier PSA recurrence-free survival curves identified a difference between prostate cancers with pT2a and pGS ?? 6 and prostate cancers with >pT2a or pGS ?? 7 disease (p = 0.002). Only biopsy tumor unilaterality (OR, 10.452; p ?? 0.001) and low diagnostic PSA levels (OR, 0.887; p = 0.003) were independent predictors of prostate cancers with pT2a and pGS ?? 6 disease on univariate and multivariate logistic regression. Biopsy tumor unilaterality and low diagnostic PSA levels are the independent predictors of pT2a and pGS ?? 6 disease in low-risk prostate cancer patients. Unilateral cancer by prostate biopsy and low diagnostic PSA level may be the reference to improving the selection of appropriate candidates for active surveillance within a low-risk prostate cancer cohort.     

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Darolutamide is a novel androgen receptor (AR) antagonist with a distinct chemical structure compared to other AR antagonists and currently in clinical Phase 3 trials for prostate cancer. Using cell-based transactivation assays, we demonstrate that darolutamide, its diastereomers and its main metabolite keto-darolutamide are strong, competitive antagonists for AR wild type, and also for several mutants identified in prostate cancer patients for which other AR antagonists show reduced antagonism or even agonism. Darolutamide, its two diastereomers and main metabolite are also strong antagonists in assays measuring AR N/C interaction and homodimerization. Molecular modeling suggests that the flexibility of darolutamide allows accommodation in the W742C/L mutated AR ligand-binding pocket while for enzalutamide the loss of the important hydrophobic interaction with W742 leads to reduced AR interaction. This correlates with an antagonistic pattern profile of coregulator recruitment for darolutamide. In vitro efficacy studies performed with androgen-dependent prostate cancer cell lines show that darolutamide strongly reduces cell viability and potently inhibits spheroid formation. Also, a marked down-regulation of androgen target genes paralleled by decreased AR binding to gene regulatory regions is seen. In vivo studies reveal that oral dosing of darolutamide markedly reduces growth of the LAPC-4 cell line-derived xenograft and of the KuCaP-1 patient-derived xenograft. Altogether, these results substantiate a unique antagonistic profile of darolutamide and support further development as a prostate cancer drug.     

Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets

Biomarkers are used as tools in cancer diagnostics and in treatment stratification. In most cancers, there are increased levels of one or several members of the matrix metalloproteinases (MMPs). This is a family of proteolytic enzymes that are involved in many phases of cancer progression, including angiogenesis, invasiveness, and metastasis. It has therefore been expected that MMPs could serve as both diagnostic and prognostic markers in cancer patients, but despite a huge number of studies, it has been difficult to establish MMPs as cancer biomarkers. In the present paper, we assess some of the challenges associated with MMP research as well as putative reasons for the conflicting data on the value of these enzymes as diagnostic and prognostic markers in cancer patients. We also review the prognostic value of a number of MMPs in patients with lung, colorectal, breast, and prostate cancers. The review also discusses MMPs as potential target molecules for therapeutic agents and new strategies for development of such drugs.     

前列腺干细胞抗原在前列腺癌诊断与治疗中的应用

人们对前列腺癌理想的诊断和治疗方式的探寻从未停止.近些年来,随着对前列腺干细胞抗原(prostate stem cell antigen,PSCA)研究地不断深入,特别是应用于前列腺癌诊治方面的新成果不断推出,使人们对PSCA充满期望.本文重点对PSCA的生物学特性及其在前列腺癌诊断方法和免疫治疗方面的新进展进行综述.     

Incidence of multiple primary bladder and prostate cancer in a central region of Italy. Umbria, 1994-2004

The aim of this study was to determine the incidence of multiple bladder-prostate cancers in the population of the Italian region of Umbria and to clarify some diagnostic aspects. Prostate and bladder cancer incidence data in Umbria were obtained from cancer registry records. In the period from 1994 to 2004, 3,470 new patients with bladder cancer and 5,430 new patients with prostate cancer were registered. Among these patients there were 238 who presented multiple bladder and prostate cancers. Synchronous cancers were detected in 74 of these patients. Fifty-four of them had simultaneous tumors (diagnosed during the same hospitalization), while in 16 patients bladder cancer was detected earlier than prostate cancer and in 4 patients the opposite occurred. This study confirmed an increase in prostate cancer diagnoses in patients with bladder cancer. The increase was mainly accounted for by the detection of prostate cancers during cystectomies performed for bladder carcinoma.     

Relatives of Prostate Cancer Patients have an Increased Risk of Prostate and Stomach Cancers: A Population-Based, Cancer Registry study in Finland

Objective: Five to ten percent of prostate cancers may be caused by inherited genetic defects. In order to explore the nature of inherited cancer risks in the genetically homogeneous Finnish population, we investigated the incidence of prostate cancer and other cancers in first-degree relatives of prostate cancer patients by linking the population-based parish records on relatives with the Finnish Cancer Registry (FCR) data. Methods: The study population was composed of first-degree relatives of two groups of prostate cancer patients diagnosed in Finland during 1988–1993: (1) all early-onset (60years) patients (n=557) from the entire country, (2) a sample (n=989) of prostate cancer patients diagnosed at an age of >60years. A total of 11,427 first-degree relatives were identified through parish records, and their cancer incidence was determined based on a total of 299,970 person-years. Standardized incidence ratios (SIR) were calculated based on expected cancer rates in the general population. Results: The SIR of prostate cancer was increased in both Cohort 1 (2.5, 95% CI 1.9–3.2) and Cohort 2 (1.7, 95% CI 1.4–2.1). The risk of prostate cancer was high for relatives of patients diagnosed at an early age, and then leveled off for patients in the median age of prostate cancer diagnosis (70–79 years). However, the prostate cancer risk for relatives of patients diagnosed 80years was again statistically significantly elevated (SIR 1.8, 95% CI 1.3–2.6), suggesting a contribution of genetic factors to prostate cancer also at a late age of onset. Gastric cancer was the only other cancer type with a significantly elevated risk among the relatives. Increased risk of gastric cancer was seen only in male relatives of prostate cancer patients diagnosed at an early age, with the highest risk detected for the male relatives of prostate cancer patients diagnosed at an age of 55 years or less (SIR 5.0, 95% CI 2.8–8.2). Conclusions: Our population-based study indicates that hereditary factors may play an important role in the development of prostate cancer among the relatives of men diagnosed both at younger and older ages. This finding is relevant in the context of our observations that HPCX (hereditary prostate cancer susceptibility locus on Xq27-28) linkage in Finland is found exclusively among families with late age of onset. The association of gastric cancer with prostate cancer has not been reported previously, and may reflect the effects of a novel predisposition locus, which increases the risk to both of these common tumor types.     

Progress and controversies: Radiation therapy for prostate cancer

Answer questions and earn CME/CNE Radiation therapy remains a standard treatment option for men with localized prostate cancer. Alone or in combination with androgen‐deprivation therapy, it represents a curative treatment and has been shown to prolong survival in selected populations. In this article, the authors review recent advances in prostate radiation—treatment techniques, photon versus proton radiation, modification of treatment fractionation, and brachytherapy—all focusing on disease control and the impact on morbidity. Also discussed are refinements in the risk stratification of men with prostate cancer and how these are better for matching patients to appropriate treatment, particularly around combined androgen‐deprivation therapy. Many of these advances have cost and treatment burden implications, which have significant repercussions given the prevalence of prostate cancer. The discussion includes approaches to improve value and future directions for research. CA Cancer J Clin 2014;64:389–407. © 2014 American Cancer Society.     

Association between Trichomonas vaginalis and prostate cancer mortality

We previously observed a positive association between seropositivity for the parasite Trichomonas vaginalis and risk of clinically significant prostate cancer at diagnosis. Here, we examined whether T. vaginalis seropositivity was associated with increased prostate cancer-specific or all-cause mortality among prostate cancer patients. We studied 736 men with prostate cancer from the Physicians’ Health Study (PHS) and 749 men with prostate cancer from the Health Professionals Follow-Up Study (HPFS). We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between T. vaginalis serostatus and progression to death from prostate cancer and from all causes. In PHS, 423 men died of any cause during a median follow-up of 13.8 years from the date of cancer diagnosis, among whom 131 died of prostate cancer. In HPFS, there were 287 deaths, including 77 deaths from prostate cancer, during a median follow-up of 12.8 years. We found no association between T. vaginalis serostatus and either prostate cancer mortality or all-cause mortality in either the PHS or HPFS. While previous studies suggest a possible role for T. vaginalis in the development of clinically significant prostate cancer, our findings do not support the hypothesis that T. vaginalis serostatus is associated with mortality among prostate cancer patients.     

Magnetic nanoparticle hyperthermia for prostate cancer

Magnetic nanoparticles are increasingly used for clinical applications such as drug delivery, magnetic resonance imaging and magnetic fluid hyperthermia. A novel method of interstitial heating of tumours following direct injection of magnetic nanoparticles has been evaluated in humans in recent clinical trials. In prostate cancer this approach has been investigated in two separate phase I studies, employing magnetic nanoparticle thermotherapy alone and in combination with permanent seed brachytherapy. The feasibility and good tolerability was shown in both trials, using the first prototype of an alternating magnetic field applicator. As with any other heating technique, this novel approach requires specific tools for planning, quality control and thermal monitoring, based on appropriate imaging and modelling techniques. In these first clinical trials a newly developed method for planning and non-invasive calculations of the 3-dimensional temperature distribution based on computed tomography was validated.

Limiting factors of the new approach at present are patient discomfort at high magnetic field strengths and irregular intratumoural heat distribution. Until these limitations are overcome and thermoablation can safely be applied as a monotherapy, this treatment modality is being evaluated in combination with irradiation in patients with localised prostate cancer.