Mindfulness-based stress reduction for men on active surveillance for prostate cancer and their spouses: Design and methodology of a randomized controlled trial.

BACKGROUND: Although active surveillance (AS) is an increasingly adopted treatment paradigm for management of very low risk prostate cancer, many men and their partners face a variety of AS-related psychosocial stressors. Stressors may include anxiety and fear of progression, which may negatively affect short- and long-term psychosocial adjustment and influence early withdrawal from AS in order to seek definitive therapies such as surgery or radiation. Here we describe the protocol for an NCI-funded trial, which seeks to examine the efficacy of mindfulness training compared with a time/attention-matched health promotion control condition in a geographically generalizable sample of men on AS and their spouses. METHODS: Using a randomized, controlled, partially double-blinded study design, this study involves the delivery of 8 weeks of standardized mindfulness training (MBSR; mindfulness-based stress reduction) and patient reported outcomes over a 12-month period (proposed enrollment of 80 men on AS and spouses), compared with a health promotion control (proposed enrollment of 80 men on AS and spouses) that has been matched for time and attention. Baseline (T1) measures (e.g., anxiety, fear of progression, quality of life) are administered just prior to randomization to the two study arms, followed by repeated assessments at 2 months (T2), 6 months (T3) and 12 months (T4). CONCLUSION: This study has the potential to offer men and their partners on AS with important educational and self-regulatory skills to better cope and adjust with known stressors related to being placed on this protocol.

The Development of iManage-PC, an Online Symptom Monitoring and Self-management Tool for Men With Clinically Localized Prostate Cancer.

BACKGROUND: Prostate cancer (PC) often impacts 4 major aspects of health-related quality of life (HRQL): urinary, sexual, and bowel dysfunction, and anxiety. Online tools may be helpful in supporting the development of self-management skills that can improve HRQL. OBJECTIVE: The aim of this study was to develop and pilot-test an online symptom monitoring and self-management program, iManage-PC. METHODS: A literature search, input from experts, and feedback from patients were used to develop iManage-PC. A 4-week, single-arm pilot study was conducted with 96 men with prostate cancer. We evaluated system usability, acceptance, and satisfaction and examined preliminary effects on patient-reported outcomes. RESULTS: Rates of retention (94.8%) and adherence to symptom monitoring (95.0%-97.0%) were high. Most participants rated the tool as satisfactory and acceptable (81.2%-94.3%). Related-samples Wilcoxon signed rank tests revealed that participants reported increased self-efficacy related to their ability to manage their adverse effects (T = 1772.0, P < .001, r = 0.39), physical discomfort (T = 1259.0, P < .001, r = 0.40), and stress and worry (T = 1108.5, P = .001, r = 0.34). Global mental and physical health also improved (T = 1322.0, P = .032, r = 0.23, and T = 1409.0, P = .001, r = 0.35, respectively). CONCLUSIONS: Future research with such tools should examine the potential role of cut-score-derived management interventions to improve engagement, symptom management self-efficacy, and HRQL. IMPLICATIONS FOR PRACTICE: Our findings are consistent with a growing body of literature that supports the feasibility and acceptability of remotely delivered interventions.

Association of prostate cancer polygenic risk score with number and laterality of tumor cores in active surveillance patients.

BACKGROUND: Prostate cancer (PCa) is characterized by its tendency to be multifocal. However, few studies have investigated the endogenous factors that explain the multifocal disease. The primary objective of the current study is to test whether inherited PCa risk is associated with multifocal tumors in PCa patients. METHODS: Subjects in this study were PCa patients of European ancestry undergoing active surveillance at Johns Hopkins Hospital (N = 805) and NorthShore University HealthSystem (N = 432). The inherited risk was measured by genetic risk score (GRS), an odds ratio-weighted and population-standardized polygenic risk score based on known risk-associated single nucleotide polymorphisms. PCa multifocality was indirectly measured by the number and laterality of positive tumor cores from a 12-core systematic biopsy. RESULTS: In the combined cohort, 35.7% and 66.3% of patients had ≥2 tumor cores at the initial diagnostic biopsy and on at least one subsequent surveillance biopsy, respectively. For tumor laterality, 7.8% and 47.8% of patients had bilateral tumor cores at diagnostic and surveillance biopsies, respectively. We found, for the first time, that patients with higher numbers of positive cores at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values; p = .01 and p = 5.94E-04. Additionally, patients with bilateral tumors at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values than those with unilateral tumors; p = .04 and p = .01. In contrast, no association was found between GRS and maximum core length of tumor or tumor grade at diagnostic/surveillance biopsies (all p > .05). Finally, we observed a modest trend that patients with higher GRS quartiles had a higher risk for tumor upgrading on surveillance biopsies. The trend, however, was not statistically significant (p > .05). CONCLUSIONS: The associations of GRS with two measurements of PCa multifocality (core numbers and laterality) provide novel and consistent evidence for the link between inherited PCa risk and multifocal tumors.

Establishing a common metric for self-reported anxiety in patients with prostate cancer: Linking the Memorial Anxiety Scale for Prostate Cancer with PROMIS Anxiety.

BACKGROUND: Anxiety is a common patient concern and clinical endpoint in prostate cancer outcomes research. It is measured using different self-report instruments that are not directly comparable, thereby making clinical trials, clinical performance measurement, and comparative effectiveness research challenging when anxiety is the outcome of interest. The objective of the current study was to enable a common reporting metric of anxiety so that scores on commonly used anxiety measures could be converted into Patient-Reported Outcomes Measurement Information System (PROMIS) scores for ease of application, interpretation, and comparability. METHODS: Using an internet health panel, a total of 806 men with clinically localized prostate cancer completed items from the National Institutes of Health PROMIS Anxiety Short Form (version 7a) and the 18-item Memorial Anxiety Scale for Prostate Cancer (MAX-PC). A common metric was created using analyses based on item response theory, producing score crosswalk tables. The linking relationships were evaluated by resampling small subsets and estimating confidence intervals for the differences between the observed and linked PROMIS scores. RESULTS: Results of factor analysis and item response theory model fit supported the hypothesis that both scales measure essentially the same concept. Therefore, crosswalk tables appear to be justified and increasingly robust with increasing sample sizes. CONCLUSIONS: MAX-PC Anxiety results can be expressed on the PROMIS Anxiety metric for the purposes of clinical performance measurement, clinical trial outcomes, comparative effectiveness research, and other efforts to compare anxiety results across studies that use any one of these measures.

Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer.

BACKGROUND: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). OBJECTIVE: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. RESULTS AND LIMITATIONS: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval [CI]=1.004-3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26-5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS ≥4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point. CONCLUSIONS: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. PATIENT SUMMARY: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer.

BACKGROUND: Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. METHODS: A case-case study of 703 lethal PCa patients and 1455 patients with low-risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2. Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. RESULTS: In the entire study population, 40 (1.85%) patients were identified as carrying one of 15 different germline CHEK2 pathogenic or likely pathogenic mutations. CHEK2 mutations were detected in 16 (2.28%) of 703 lethal PCa patients compared with 24 (1.65%) of 1455 low-risk PCa patients (P = 0.31). No association was found between CHEK2 mutation status and early-diagnosis or PCa-specific survival time. However, the most common mutation in CHEK2, c.1100delC (p.T367 fs), had a significantly higher carrier rate (1.28%) in lethal PCa patients than low-risk PCa patients of European American origin (0.16%), P = 0.0038. The estimated Odds Ratio of this mutation for lethal PCa was 7.86. The carrier rate in lethal PCa was also significantly higher than that (0.46%) in 32 461 non-Finnish European subjects from the Exome Aggregation Consortium (ExAC) (P = 0.01). CONCLUSIONS: While overall CHEK2 mutations were not significantly more common in men with lethal compared to low-risk PCa, the specific CHEK2 mutation, c.1100delC, appears to contribute to an increased risk of lethal PCa in European American men.

Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death.

BACKGROUND: Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. OBJECTIVE: To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively. RESULTS AND LIMITATIONS: The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed. CONCLUSIONS: Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. PATIENT SUMMARY: Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.

Factors Affecting Quality of Life at Different Intervals After Treatment of Localized Prostate Cancer: Unique Influence of Treatment Decision Making Satisfaction, Personality and Sexual Functioning.

PURPOSE: Using patient reported outcomes measures we identified the most informative set of factors associated with quality of life in a large sample of men treated for localized prostate cancer. MATERIALS AND METHODS: We examined relationships with quality of life using FACIT (Functional Assessment of Chronic Illness Therapy). We also hypothesized variables in a sample of men diagnosed with localized prostate cancer who represented different time points since treatment, including less than 12 months in 70, 1 to 3 years in 344, greater than 3 to 5 years in 291 and greater than 5 years in 97. Correlative measures included subscales of MAX-PC (Memorial Anxiety Scale for Prostate Cancer), short forms of PROMIS® and SOMS (Surgical Outcomes Measurement System), TDM-SATS (Treatment Decision-Making Satisfaction Scale) and subscales of the BFI (Big Five Inventory) of personality. RESULTS: Quality of life was significantly associated with hypothesized variables across different time cohorts. In regression models several factors accounted for most of the variability in quality of life scores depending on time since treatment, including 47%, 22%, 29% and 27% at less than 12 months, 1 to 3 years, greater than 3 to 5 years and greater than 5 years, respectively. Upon examining the unique contribution of these variables, treatment decision making satisfaction was the only variable to have a significant and unique contribution to quality of life across all 4 time cohorts (standardized coefficients 0.33, 0.27, 0.31 and 0.49, respectively, p <0.01). In the cohort with 1 to 3 years since treatment erectile function and neurotic personality style also had unique associations with quality of life (standardized coefficients 0.25 and -0.20, respectively). CONCLUSIONS: When considering the short-term and the longer term quality of life of a man after treatment for localized prostate cancer, our findings highlight the importance of treatment decision making satisfaction, erectile function and personality.

Variation in Testosterone Levels and Health-related Quality of Life in Men Diagnosed With Prostate Cancer on Active Surveillance.

OBJECTIVE: To determine the extent to which low testosterone levels impact health-related quality of life in patients undergoing active surveillance (AS) for prostate cancer. MATERIALS AND METHODS: Eligible AS patients were grouped as having low, low-normal, or normal testosterone levels (<300 vs 300-400 vs ≥400 ng/dL). Patients were surveyed with the Expanded Prostate Cancer Index Composite-26 (EPIC-26), Patient Reported Outcomes Measurement Information System (PROMIS), Memorial Anxiety Scale for Prostate Cancer, and treatment outlook satisfaction questions at enrollment and successively during follow-up. RESULTS: The cohort consisted of 223 patients, 74 (33%) of which had low testosterone levels. The mean age was 66.8 ± 7.2 years, with 85% being Caucasian. Mean prostate-specific antigen did not differ between groups. Obesity was significantly higher for men with low testosterone levels (P < .01). All PROMIS-Global items were comparatively lower in men with lower testosterone. EPIC-26 scores for the sexual domain were worse in men with lower testosterone. After age and obesity adjustment, men with normal testosterone levels had significantly better PROMIS Physical, Overall, and Mental Health, EPIC-26 Hormonal, and treatment satisfaction responses when compared to those patients with low testosterone levels. Those with normal testosterone levels reported hormonal EPIC-26 domain responses 65% higher than for those with low testosterone, and 12% higher treatment satisfaction during 2-year follow-up when corrected for age and obesity (P < .05). CONCLUSION: Men with testosterone levels ≥400 ng/dL reported some improved measures of health-related quality of life including greater satisfaction with treatment outcome. These findings are hypothesis generating in the controversial area of exogenous testosterone administration in men on AS.

A Longitudinal Study of Predictors of Sexual Dysfunction in Men on Active Surveillance for Prostate Cancer.

AIM: The aim of this study was to examine the relationship between sexual dysfunction, repeat biopsies and other demographic and clinical factors in men on active surveillance (AS). METHODS: Patient-reported outcomes (PROs) measures were administered at enrollment and every 6 months to assess quality of life (QOL), psychosocial and urological health outcomes. Using mixed-effects models, we examined the impact of repeat biopsies, total number of cores taken, anxiety, age, and comorbidity on sexual function over the first 24 months of enrolling in AS. MAIN OUTCOME MEASURES: PROs included the Expanded Prostate Cancer Index Composite-26 (EPIC-26) Sexual Function (SF) subscale, the American Urological Association-Symptom Index (AUA-SI), and the Memorial Anxiety Scale for Prostate Cancer (MAX-PC). RESULTS: At enrollment (n = 195), mean age was 66.5 ± 6.8 with a mean EPIC-26 SF score of 61.4 ± 30.4. EPIC-26 SF scores steadily decreased to 53.9 ± 30.7 at 24 months (P < 0.01). MAX-PC scores also progressively decreased over time (P = 0.03). Factors associated with lower EPIC-26 scores over time included age, unemployed status, diabetes, coronary artery disease, and hypertension (all P < 0.05). Higher prostate-specific antigen (PSA) was associated with a more rapid decline in EPIC-26 SF over time (P = 0.03). In multivariable analysis, age, diabetes, and PSA × time interaction remained significant predictors of diminished sexual function. Anxiety, number of biopsies, and total cores taken did not predict sexual dysfunction or change over time in our cohort. CONCLUSIONS: Men on AS experienced a gradual decline in sexual function during the first 24 months of enrollment. Older age, PSA × time, and diabetes were all independent predictors of diminished sexual function over time. Anxiety, AUA-SI, the number of cores and the number of biopsies were not predictors of reduced sexual function in men in AS.

The prognostic significance of perineural invasion and race in men considering active surveillance.

OBJECTIVE: To determine the importance of perineural invasion (PNI) on diagnostic biopsy in men enrolled in active surveillance (AS). PATIENTS AND METHODS: Eligibility criteria for AS included clinical stage ≤ T2a and Gleason score ≤6, ≤3 cores positive, maximum single core involvement <50%, and total tumour volume ≤5% on diagnostic biopsy. All men received 12-core confirmation biopsy at ≤6 months. AS 'failure' on confirmatory biopsy was defined as failure to meet one or more eligibility criteria. Risk of AS failure was compared in men with and without PNI. RESULTS: For the 165 men comprising the study population, the mean (sd) age was 66.9 (6.5) years and the median (interquartile, IQR) PSA level of men at study entry was 4.4 (3.2-6.0) ng/mL. The median (IQR) follow-up was 5.5 (1.1-9.9) months. In all, 8.5% (14/165 men) had PNI on diagnostic biopsy. Compared with those without PNI, men with PNI tended to have more cores involved with cancer, at a mean (sd) of 2.0 (0.7) vs 1.6 (0.8) cores (P = 0.08) but did not have significantly a greater mean (sd) total tumour length on diagnostic biopsy, at 3.0 (2.1) vs 2.3 (3.6) mm (P = 0.27). Men with PNI on diagnostic biopsy were significantly more likely to meet criteria for disease progression on confirmatory biopsy (57% [8/14] vs 21% [32/151]; P = 0.006). PNI remained a significant predictor for AS failure after adjustment for number of positive cores, maximum percentage core involvement, and total tumour length (odds ratio 4.4, 95% confidence interval 1.4-14.2). CONCLUSIONS: PNI on diagnostic biopsy is associated with disease progression on confirmatory biopsy. The presence of PNI should factor into appropriate patient selection and counselling in AS.

Primary care physician PSA screening practices before and after the final U.S. Preventive Services Task Force recommendation.

OBJECTIVES: In May 2012, United States Preventive Services Task Force (USPSTF) finalized its recommendation against prostate-specific antigen (PSA) screening in all men. We aimed to assess trends in PSA screening frequency amongst primary care physicians (PCPs) surrounding the May 2012 USPSTF recommendation. METHODS AND MATERIALS: The electronic data warehouse was used to identify men aged between 40 and 79 years with no history of prostate cancer or urology visit who were evaluated by an internal medicine or family practice physician between 2007 and 2012. Analyses were directed toward PSA testing within 6-month time period from June to November, with particular focus on the 2011 (pre-USPSTF recommendation) and 2012 (post-USPSTF recommendation) cohorts. The primary outcome measure was proportion of men with at least 1 PSA test during the 6-month pre- and post-USPSTF recommendation periods. RESULTS: A total of 112,221 men met inclusion criteria. There was a significant decrease in screening frequency between the 2011 and 2012 cohorts (8.6% vs. 7.6%, P = 0.0001; adjusted odds ratio 0.89, 95% confidence interval 0.83-0.95). This decrease was most evident amongst patients aged 40 to 49 years (5.6% vs. 4.6%, P = 0.004) and 70 to 79 years (7.9% vs. 6.2%, P = 0.01). A significant decrease was also observed in patients with highest previous PSA value<1.0 (P<0.0001) and 1.0 to 2.49 ng/ml (P = 0.0074). CONCLUSIONS: Since the USPSTF recommendation was finalized, there is evidence of continuing decreases in PSA testing by PCPs. PCPs may be shifting toward more selective screening practices, as decreases in screening are most pronounced in the youngest and oldest patients and in those with history of PSA values<2.5 ng/ml.

The impact of prostate biopsy on urinary symptoms, erectile function, and anxiety.

Transrectal ultrasound-guided prostate needle biopsy (PB) is considered the gold standard for the diagnosis of prostate cancer. Recently, lower urinary tract symptoms and erectile dysfunction have been reported following PB. We reviewed the literature on PB and these symptoms and summarized known findings between these conditions and other variables, such as periprostatic nerve block, saturation biopsy, serial biopsies, and psychological factors associated with PB and cancer. A PubMed search was performed using keywords "prostate biopsy," "complications," "erectile dysfunction," "lower urinary tract symptoms," "anxiety," and "quality of life." Eleven key papers are discussed and personal experience is drawn upon. Based upon available evidence, PB appears to be associated with short-term exacerbation of urinary symptoms in some men, as well as associated with anxiety and temporary erectile dysfunction, without a distinct relationship to periprostatic nerve block or the number of cores biopsied. Additional studies are warranted to determine the definitive etiology of these symptoms and to determine if interventions could reduce patient morbidity. In the interim, patients should be educated and counseled about these risks before undergoing PB.

CCR9 mediates PI3K/AKT-dependent antiapoptotic signals in prostate cancer cells and inhibition of CCR9-CCL25 interaction enhances the cytotoxic effects of etoposide.

Despite recent advances in treatment and management of prostate cancer (PCa), it remains the second leading cause of cancer-related deaths among men in the US. Chemotherapy is one of the treatment alternatives for hormone refractory metastatic PCa. However, current chemotherapeutic regimens provide palliative benefit but relatively modest survival advantage primarily due to chemo-resistance and upregulated antiapoptotic machineries in PCa cells. Therefore, blocking the mechanisms responsible for suppression of apoptosis might improve current chemotherapeutic regimens. In this study, we show that CC chemokine receptor-9 (CCR9) and its natural ligand CCL25 interaction upregulates antiapoptotic proteins (i.e., PI3K, AKT, ERK1/2 and GSK-3beta) and downregulate activation of caspase-3 in PCa cells. Significant downregulation of these CCR9-mediated antiapoptotic proteins in the presence of a PI3K inhibitor (wortmannin), further suggests that the antiapoptotic action of CCR9 is primarily regulated through PI3K. Furthermore, the cytotoxic effect of etoposide was significantly inhibited in the presence of CCL25, and this inhibitory effect of CCL25 was abrogated when CCR9-CCL25 interaction was blocked using anti-CCR9 monoclonal antibodies. In conformation to these in vitro studies, significant reduction in tumor burden was found in mice receiving CCL25 neutralizing antibodies and etoposide together as compared to both as a single agent. These results suggest that the CCR9-CCL25 axis mediates PI3K/AKT-dependent antiapoptotic signals in PCa cells and could be a possible reason for low apoptosis and modest chemotherapeutic response. Therefore, targeting CCR9-CCL25 axis with cytotoxic agents may provide better therapeutic outcomes than using cytotoxic agents alone.

Clinical and biological significance of CXCR5 expressed by prostate cancer specimens and cell lines.

Chemokines and chemokine receptors have been shown to be involved in metastatic process of prostate cancer (PCa). In this study, we show primary PCa tissues and cell lines (LNCaP and PC3) express CXCR5, a specific chemokine receptor for CXCL13. Expression of CXCR5 was significantly higher (p < 0.001) in PCa cases than compared to normal match (NM) tissues. CXCR5 intensity correlated (R(2) = 0.97) with Gleason score. While prostate tumor tissues with Gleason scores >or= 7, displayed predominantly nuclear CXCR5 expression patterns, PCa specimens with Gleason scores

Serum CXCL13 positively correlates with prostatic disease, prostate-specific antigen and mediates prostate cancer cell invasion, integrin clustering and cell adhesion.

Chemokines and their corresponding receptor interactions have been shown to be involved in prostate cancer (PCa) progression and organ-specific metastasis. We have recently shown that PCa cell lines and primary prostate tumors express CXCR5, which correlates with PCa grade. In this study, we present the first evidence that CXCL13, the only ligand for CXCR5, and IL-6 were significantly elevated in PCa patient serum compared to serum from subjects with benign prostatic hyperplasia (BPH), or high-grade prostatic intraepithelial neoplasia (HGPIN) as well as normal healthy donors (NHD). Serum CXCL13 levels significantly (p<0.0001) correlated with serum prostate-specific antigen (PSA), whereas serum IL-6 levels significantly (p<0.0003) correlated with CXCL13 serum levels. CXCL13 was found to be a better predictor of PCa than PSA. CXCL13 was highly expressed by human bone marrow endothelial (HBME) cells and osteoblasts (OBs), but not osteoclasts (OCs), following treatment with physiologically relevant levels of interleukin-6 (IL-6). We further demonstrate that CXCL13, produced by IL-6-treated HBME cells, was able to induce PCa cell invasion in a CXCR5-dependent manner. CXCL13-mediated PCa cell adhesion to HBME cells and alpha(v)beta(3)-integrin clustering was abrogated by CXCR5 blockade. These results demonstrate that the CXCL13-CXCR5 axis is significantly associated with PCa progression.

CXCL10 blockade protects mice from cyclophosphamide-induced cystitis.

BACKGROUND: Alterations in serum CXCR3 ligand levels were examined in interstitial cystitis (IC) patients; similar expression patterns in serum as well as CXCR3, CXCR3 ligands, and cytokines expressed by peripheral and local leukocyte subpopulations were characterized during cyclophosphamide (CYP)-induced acute cystitis in mice. RESULTS: Serum levels of monokine-induced by interferon-gamma (IFN-gamma) (MIG/CXCL9), IFN-gamma-inducible protein-10 (IP-10/CXCL10), and IFN-gamma-inducible T cell alpha chemoattractant (I-TAC/CXCL11) were elevated in patients with IC. These clinical features closely correlated with CYP-induced cystitis in mice. Serum levels of these CXCR3 ligands and local T helper type 1 (Th1) cytokines were also increased. We demonstrate that CXCR3 as well as CXCL9, CXCL10 and CXCL11 mRNA were significantly expressed by urinary bladder lymphocytes, while CXCR3 and CXCL9 transcripts were significantly expressed by iliac lymph node leukocytes following CYP treatment. We also show that the number of CD4+ T cells, mast cells, natural killer (NK) cells, and NKT cells were increased at systemic (spleen) and mucosal (urinary bladder and iliac lymph nodes) sites, following CYP-induced cystitis in mice. Importantly, CXCL10 blockade attenuated these increases caused by CYP. CONCLUSION: Antibody (Ab)-mediated inhibition of the most abundant serum CXCR3 ligand, CXCL10, in mice decreased the local production of CXCR3 ligands as well as Th1 cytokines expressed by local leukocytes, and lowered corresponding serum levels to reduce the severity of CYP-induced cystitis. The present study is among the first to demonstrate some of the cellular and molecular mechanisms of chemokines in cystitis and may represent new drug target for this disease.

Global expression analysis of prostate cancer-associated stroma and epithelia.

Characterization of gene expression profiles in tumor cells and the tumor microenvironment is an important step in understanding neoplastic progression. To date, there are limited data available on expression changes that occur in the tumor-associated stroma as either a cause or consequence of cancer. In the present study, we employed a 54,000 target oligonucleotide microarray to compare expression profiles in the 4 major components of the microenvironment: tumor epithelium, tumor-associated stroma, normal epithelium, and normal stroma. Cells from 5 human, whole-mount prostatectomy specimens were microdissected and the extracted and amplified mRNA was hybridized to an Affymetrix Human Genome U133 Plus 2.0 GeneChip. Using the intersection of 2 analysis methods, we identified sets of differentially expressed genes among the 4 components. Forty-four genes were found to be consistently differentially expressed in the tumor-associated stroma; 35 were found in the tumor epithelium. Interestingly, the tumor-associated stroma showed a predominant up-regulation of transcripts compared with normal stroma, in sharp contrast to the overall down-regulation seen in the tumor epithelium relative to normal epithelium. These data provide insight into the molecular changes occurring in tumor-associated stromal cells and suggest new potential targets for future diagnostic, imaging, or therapeutic intervention.