Molecular assays for the detection of prostate tumor derived nucleic acids in peripheral blood

<p>Abstract</p> <p>Background</p> <p>Prostate cancer is the second leading cause of cancer mortality in American men. Although serum PSA testing is widely used for early detection, more specific prognostic tests are needed to guide treatment decisions. Recently, the enumeration of circulating prostate epithelial cells has been shown to correlate with disease recurrence and metastasis following definitive treatment. The purpose of our study was to investigate an immunomagnetic fractionation procedure to enrich circulating prostate tumor cells (CTCs) from peripheral blood specimens, and to apply amplified molecular assays for the detection of prostate-specific markers (PSA, PCA3 and TMPRSS2:ERG gene fusion mRNAs).</p> <p>Results</p> <p>As few as five prostate cancer cells were detected per 5 mL of whole blood in model system experiments using anti-EpCAM magnetic particles alone or in combination with anti-PSMA magnetic particles. In our experiments, anti-EpCAM magnetic particles alone exhibited equivalent or better analytical performance with patient samples compared to a combination of anti-EpCAM + anti-PSMA magnetic particles. Up to 39% of men with advanced prostate cancer tested positive with one or more of the molecular assays tested, whereas control samples from men with benign prostate hyperplasia gave consistently negative results as expected. Interestingly, for the vast majority of men who tested positive for PSA mRNA following CTC enrichment, their matched plasma samples also tested positive, although CTC enrichment gave higher overall mRNA copy numbers.</p> <p>Conclusion</p> <p>CTCs were successfully enriched and detected in men with advanced prostate cancer using an immunomagnetic enrichment procedure coupled with amplified molecular assays for PSA, PCA3, and TMPRSS2:ERG gene fusion mRNAs. Our results indicate that men who test positive following CTC enrichment also exhibit higher detectable levels of non-cellular, circulating prostate-specific mRNAs.</p

The Prostate Low Dose, Alternating Electric Current Inhibits Growth of Prostate Cancer

BACKGROUND. A number of minimally invasive technologies exist for the treatment of prostate cancer (CaP), each with their associated morbidities. We sought to test the efficacy of low dose alternating electric current (LDAEC) to inhibit CaP growth in a preclinical setting and determine its effect on normal tissue. METHODS. In the first study, two power settings, 15 or 25 mA of current, and two treatment times, 15 or 60 min, were evaluated in C4-2B CaP xenografts. In the second study, power was regulated to maintain an intra-tumoral temperature of 458C in C4-2B and LuCaP 35 tumors. In both studies, tumor volume, serum PSA levels, survival and histology were analyzed. In a third study, LDAEC was applied to mice hamstrings with evaluation of gait and histology. RESULTS. The most effective tumor volume reduction in the first study was seen with tumors treated with 25 mA for 15 min (62 AE 9.4% decrease, P ¼ 0.001). Longer treatment time did not enhance treatment effect. Using 458C to govern delivery of LDAEC resulted in a near 100% reduction in tumor volume in 8/10 mice with C4-2B tumors (P &lt; 0.001) with similar inhibition of LuCaP 35 tumors (P ¼ 0.01). This treatment, although resulting in skeletal muscle necrosis, did not affect nerves, smooth muscle and blood vessels. CONCLUSION. LDAEC demonstrates efficacy against C4-2B and LuCaP 35 CaP xenografts while causing no harm to nerves and blood vessels. These results warrant further investigations into the use of LDAEC as a treatment for CaP. Prostate

Clinical Study of Docetaxel, Prednisone and Bevacizunab in the Treatment of Hormone Refractory Prostate Cancer

Objective: To observe the clinical therapeutic effect of docetaxel, prednisone and bevacizunab in the treatment of hormone refractory prostate cancer. Methods: A total of 100 patients with hormone refractory prostate cancer were selected and randomly divided into 2 groups: chemotherapy group and combined group, 50 cases, respectively. Patients in chemotherapy group were given oral administration of hexadecadrol, 8 mg/d, intravenous drip of docetaxel, 40 mg/m2, orally taking of prednisone, 5 mg/d. Patients in combined group was added with bevacizumab, 5 mg/kg (which was diluted to 100 mL of chloride sodium injection) based on regimen of chemotherapy group. All patients were followed up every month after the end of treatment for recording reoccurrence, metastasis and deaths. Additionally, serum prostate-specific antigen (PSA), free prostate-specific antigen (fPSA)/total prostate-specific antigen (tPSA) before and after chemotherapy, prostate volume, maximum flow rate, the quality of life (QOL) were measured and evaluated. The progression-free survival (PFS) and the overall survival (OS) were analyzed by Kaplan-Meier method. Results: After treatment, the level of PSA in combined group was lower than that in chemotherapy group (P&lt;0.01) while fPSA/tPSA in combined group was higher than that in chemotherapy group after treatment (P&lt;0.01). The prostate volume of two groups decreased, the maximum flow rate and QOL score of two groups increased, but with no difference between two groups (P&gt;0.05). The median PFS and OS in combined group were 13 months and 20 months, respectively, higher than those in chemotherapy group (10 months and 17 months) (P&lt;0.01). The occurrence rate of adverse reactions was 66.00% in combined group and 56.00% in chemotherapy group, but with no significance between them (P&gt;0.05). Conclusion: Docetaxel combined with Bevacizunab can prolong the survival time of patients with hormone refractory prostate cancer, but its therapeutic effect still needs to be further verified. Additionally, with the in-depth of studies on hormone refractory prostate cancer in translational medicine, immunotherapy, targeted therapy, individualized treatment and multidrug therapy will surely become the research hotspot for hormone refractory prostate cancer

Prospective, randomized, multicenter study of intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: 12-month results

IntroductionVertebral endplates, innervated by the basivertebral nerve (BVN), are a source of chronic low back pain correlated with Modic changes. A randomized trial comparing BVN ablation to standard care (SC) recently reported results of an interim analysis. Here, we report the results of the full randomized trial, including the 3-month and 6-month between-arm comparisons, 12-month treatment arm results, and 6-month outcomes of BVN ablation in the former SC arm.MethodsProspective, open label, 1:1 randomized controlled trial of BVN ablation versus SC in 23 US sites with follow-up at 6 weeks, 3, 6, 9, and 12 months. SC patients were re-baselined and followed up for 6 months post BVN ablation. The primary endpoint was the between-arm comparison of mean Oswestry Disability Index (ODI) change from baseline. Secondary endpoints were Visual Analog Scale (VAS), Short Form (SF-36), EuroQual Group 5 Dimension 5-Level Quality of Life (EQ-5D-5L), responder rates, and rates of continued opioid use.Results140 were randomized. Results from BVN ablation (n=66) were superior to SC (n=74) at 3 months for the primary endpoint (mean ODI reduction, difference between arms of -20.3 (CI -25.9 to -14.7 points; p&lt;0.001)), VAS pain improvement (difference of -2.5 cm between arms (CI -3.37 to -1.64, p&lt;0.001)) and quality of life outcomes. At 12 months, basivertebral ablation demonstrated a 25.7±18.5 point reduction in mean ODI (p&lt;0.001), and a 3.8±2.7 cm VAS reduction (p&lt;0.001) from baseline, with 64% demonstrating ≥50% reduction and 29% pain free. Similarly, the former SC patients who elected BVN ablation (92%) demonstrated a 25.9±15.5 point mean ODI reduction (p&lt;0.001) from baseline. The proportion of opioid use did not change in either group (p=0.56).Discussion/conclusionBVN ablation demonstrates significant improvements in pain and function over SC, with treatment results sustained through 12 months in patients with chronic low back pain of vertebrogenic origin

HE3235 Inhibits Growth of Castration-Resistant Prostate Cancer12

Treatments for advanced prostate cancer (CaP) typically involve androgen deprivation therapy. However, most patients eventually develop castration-resistant CaP (CRPC) for which highly effective therapies are limited. We explored the efficacy of a novel agent, HE3235, in inhibiting growth of CRPC in preclinical models. Castrated male mice were implanted subcutaneously with LuCaP35V CaP xenografts in the presence and absence of 5′-androstenediol (AED) and treated with HE3235. To investigate the effect of HE3235 on CaP tumor in the bone, castrated mice were injected intratibially with C4-2B CaP cells and treated with HE3235. Serum prostate-specific antigen (PSA) levels, tumor volume, immunohistochemistry, gene expression, and levels of intratumoral androgens were analyzed. HE3235 significantly prolonged the tumor doubling time of LuCaP35V, decreased androgen receptor expression, and lowered levels of intratumoral testosterone by ∼89% and dihydrotestosterone by ∼63% in both the presence and the absence of AED. HE3235 inhibited tumor growth in the bone environment. Weights of tumored tibiae of HE3235-treated animals were lower than those of control (P = .031), and normalized PSA levels were also significantly decreased at the end of study by HE3235 treatment (P = .0076). HE3235 inhibits the growth of subcutaneous CRPC as well as CRPC in the bone environment. Our data show that HE3235 exhibits a wide range of effects, including alteration of androgen receptor signaling and reductions in levels of intratumoral androgens. Our results support ongoing clinical investigations into the effectiveness of HE3235 in the setting of CRPC and warrants further studies into the mechanisms behind the effects of HE3235

Inhibition of CCL2 Signaling in Combination with Docetaxel Treatment Has Profound Inhibitory Effects on Prostate Cancer Growth in Bone

The C-C chemokine ligand 2 (CCL2) stimulates migration, proliferation, and invasion of prostate cancer (PCa) cells, and its signaling also plays a role in the activation of osteoclasts. Therefore targeting CCL2 signaling in regulation of tumor progression in bone metastases is an area of intense research. The objective of our study was to investigate the efficacy of CCL2 blockade by neutralizing antibodies to inhibit the growth of PCa in bone. We used a preclinical model of cancer growth in the bone in which PCa C4-2B cells were injected directly into murine tibiae. Animals were treated for ten weeks with neutralizing anti-CCL2 antibodies, docetaxel, or a combination of both, and then followed an additional nine weeks. CCL2 blockade inhibited the growth of PCa in bone, with even more pronounced inhibition in combination with docetaxel. CCL2 blockade also resulted in increases in bone mineral density. Furthermore, our results showed that the tumor inhibition lasted even after discontinuation of the treatment. Our data provide compelling evidence that CCL2 blockade slows PCa growth in bone, both alone and in combination with docetaxel. These results support the continued investigations of CCL2 blockade as a treatment for advanced metastatic PCa