Biological Behavior Of Prostate Cancer Research Articles

Immunohistochemical investigation of cytokine expression levels as biomarkers in transrectal ultrasound-guided needle biopsy specimens of prostate adenocarcinoma.

Cytokines influence the biological behaviour of prostate cancer (PC) and may influence patient outcome and serve as useful prognostic biomarkers. The aim of the present study was to evaluate cytokine expression levels in prostatic needle biopsy specimens and the association with clinicopathological characteristics of patients with PC. A total of 18 patients with PC who underwent transrectal ultrasound (TRUS) guided prostate biopsy were included in the clinical study. These patients were naïve to radiotherapy (RT) or androgen deprivation therapy prior to TRUS biopsy and clinical follow up data was collected. Cytokine expression levels were analysed by using immunohistochemistry and Spearman's correlation test was used to determine the correlation between cytokine expression and clinicopathological characteristics. Expression levels of pro-inflammatory TNF-α and IL-6 decreased as Gleason score (GS) increased; however, a statistically significant difference was not detected. A statically significant correlation was observed between needle biopsy specimen and pre-RT plasma sample expression levels of pro-inflammatory TNF-α and IL-6 (P=0.01 and P=0.05, respectively) and anti-inflammatory TGF-β1 (P=0.05). However, further studies are needed to confirm these results using a larger sample size to confirm the prognostic value of pro-inflammatory TNF-α and IL-6 and anti-inflammatory TGF-β1 in patients with PC.

Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer.

Prostate cancer (PCa), known as a heterogenous disease, has a high incidence and mortality rate around the world and seriously threatens public health. As an inevitable by-product of cellular metabolism, reactive oxygen species (ROS) exhibit beneficial effects by regulating signaling cascades and homeostasis. More and more evidence highlights that PCa is closely associated with age, and high levels of ROS are driven through activation of several signaling pathways with age, which facilitate the initiation, development, and progression of PCa. Nevertheless, excessive amounts of ROS result in harmful effects, such as genotoxicity and cell death. On the other hand, PCa cells adaptively upregulate antioxidant genes to detoxify from ROS, suggesting that a subtle balance of intracellular ROS levels is required for cancer cell functions. The current review discusses the generation and biological roles of ROS in PCa and provides new strategies based on the regulation of ROS for the treatment of PCa.

Association of macrophage inhibitory factor -173 gene polymorphism with biological behavior of prostate cancer.

Chronic inflammation is an important factor in the etiology of prostate cancer. Macrophage migration inhibitory factor (MIF) plays an important regulatory role in inflammatory responses. The aim of this study was to investigate the potential association between MIF-173 G/C polymorphism, and both biological behavior and incidence of prostate cancer. Analysis of polymorphic variants for MIF was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 128 subjects with prostate cancer and 135 controls. The frequency of MIF-173 *C allele was significantly (OR = 2.18, 95% CI = 1.32-3.61) higher in patients with prostate cancer (19.5%) than in healthy individuals (10%). Prostate cancer patients with Gleason scores ? 7 had higher frequency of MIF-173 *C allele than Gleason scores < 7 (86.1% vs. 27.1%, P = 0.003, OR = 3.18, 95%CI = 1.46-6.95). The frequency of MIF-173 *C allele was significantly different in patients with T1, T2 and ?T3 clinical stages of prostate cancer (15.2% vs. 42.6% and 47.8%, P = 0.003). Our data suggest that MIF-173 polymorphisms may be associated with a higher incidence of prostate cancer compared to controls. We believe that MIF-173 GC+CC genotype can be used as a predictive factor for aggressive behavior of prostate cancer including pathological stage and Gleason scores as well as metastatic potential.

Overexpression of spindle and kinetochore-associated protein 1 contributes to the progression of prostate cancer.

Spindle and kinetochore-associated protein 1 is a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation. Recently, spindle and kinetochore-associated protein 1 has been highlighted as a biomarker in various cancers; however, the precise role of spindle and kinetochore-associated protein 1 in prostate cancer remains unknown. This study aims to evaluate whether spindle and kinetochore-associated protein 1 affects the biological behaviors of prostate cancer. We investigated the expression of spindle and kinetochore-associated protein 1 in a series of prostate cancer tissues as well as in a panel of prostate cancer cell lines. Cell proliferation, migration, and invasion were evaluated in spindle and kinetochore-associated protein 1 knockdown prostate cancer cell lines by MTT and Transwell assays. Our results showed that the expression of spindle and kinetochore-associated protein 1 was remarkably upregulated in prostate cancer at both messenger RNA and protein levels compared with non-cancerous tissue. Knockdown of spindle and kinetochore-associated protein 1 repressed the ability of cell proliferation, migration, and invasion of prostate cancer cells. Moreover, inhibition of spindle and kinetochore-associated protein 1 could inhibit the activity of AKT and ERK pathway. In conclusion, our findings suggest that spindle and kinetochore-associated protein 1 could serve as a potential therapeutic target in prostate cancer patients.

SOX4 induces tumor invasion by targeting EMT-related pathway in prostate cancer

SOX4 (sex-determining region Y-related high-mobility group box 4) is associated with tumor progression and poor clinical outcome in several cancers. This study aims to evaluate whether SOX4 affects the biological behaviors of prostate cancer and further elucidate whether this effect works through the epithelial-mesenchymal transition pathway. We investigated the expression of SOX4 in a series of prostate cancer tissues and adjacent noncancerous tissues, as well as in a panel of prostate cancer cell lines. Cell proliferation, migration, and invasion were evaluated in SOX4 knockdown prostate cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assay. Our results showed that the expression of SOX4 was remarkably upregulated both in prostate cancer tissues and in cell lines. Knockdown of SOX4 repressed the ability of cell proliferation and migration of DU145 cells. Moreover, inhibition of SOX4 could reverse the epithelial-mesenchymal transition processes through upregulation of E-cadherin and downregulation of vimentin. This study provided evidence that SOX4 could serve as a potential therapeutic target in prostate cancer.

SATB1 promotes epithelial-mesenchymal transition and metastasis in prostate cancer.

Special AT-rich sequence-binding protein-1 (SATB1) is associated with cancer progression and poor clinical outcome. The present study aims to evaluate whether SATB1 affects the biological behaviors of prostate cancer (PCa), and furthermore, to elucidate whether this effect works through the epithelial-mesenchymal transition (EMT) pathway. Firstly, the expression of SATB1 was investigated in a series of PCa tissues as well as in a panel of PCa cell lines. Cell proliferation, migration and invasion were evaluated in SATB1 knockdown and overexpressed PCa cell lines by MTT and Transwell assays. The results showed that the expression of SATB1 was markedly upregulated in PCa tissues and all PCa cell lines (P<0.001). Ectopic expression of SATB1 promoted PCa cell proliferation and migration. Knockdown of SATB1 repressed the ability of cell proliferation and migration of PCa cells. In addition, inhibition of SATB1 could reverse the EMT processes through upregulation of E-cadherin and downregulation of vimentin. The present study provided evidence that SATB1 may act as a potential therapeutic target in PCa patients.

Overexpression of Glutathione S-transferase P1 Inhibits the Viability and Motility of Prostate Cancer via Targeting MYC and Inactivating the MEK/ERK1/2 Pathways.

Prostate cancer (PC) is one of the most common malignancies of men. Glutathione S-transferase P1 (GSTP1) has been suggested to play a protective role in the prostate. The proto-oncogene MYC has been extensively proved to be a key regulator of tumor transformation from early stage to malignant. Our study aims to investigate the mechanism of GSTP1 in the biological behavior of PC. Compared with normal prostate tissues, the expression of GSTP1 was decreased in PC tissues. Conversely, the level of MYC was increased in PC tissues compared with normal tissues. MYC was convinced a direct target of GSTP1. Besides, the overexpression of GSTP1 or MYC siRNA strongly reduced cell viability via decreasing the volume of cell spheres and cell proliferation rate. GSTP1 overexpression or MYC siRNA also decreased cell motility of PC via reducing the closing rate of scratch wounds and the number of invasive cells. We further explored the underlying mechanism, and found that the level of p-MEK and p-ERK1/2 was strongly decreased in PC3 cells with pcDNA-GSTP1 or MYC siRNA transfection compared with control group. The inhibitory effect on cell viability, p-MEK and p-ERK1/2 was stronger when pcDNA-GSTP1 and MYC siRNA function together. Finally, the in vivo experiment displayed that pcDNA-GSTP1 transfection reduced tumor growth and tumor volume in PC xenografts. The decreased level of metastasis-related proteins VEGF (vascular endothelial growth factor) and MMP (metal matrix proteinase)-9 in GSTP1 overexpression model mice was detected by immunohistochemistry. Besides, the expression of MYC, p-MEK and p-ERK1/2 was strongly inhibited in mice with pcDNA-GSTP1 transfection. Taken together, our research indicates that GSTP1 overexpression inhibits the viability and motility of PC in vitro and in vivo, and may through targeting MYC and inactivating MEK/ERK1/2 pathway.

Effects of β adrenergic receptor blocker carvedilol and cholinergic receptor blocker scopolamine on biological behaviors of prostate cancer in mice

Objective To investigate the effects of β adrenergic receptor blocker carvedilol and cholinergic receptor blocker scopolamine on the biological behaviors of prostate cancer in C57BL/6 mice. Methods From June 2014 to November 2014, sixty male C57BL/6 mice, 10 weeks old, were injected with RM-1 cells (0.5×106) into bilateral dorsal prostate capsules of each mice by microsyringe and were randomly divided into three groups, including carvedilol group (K), scopolamine group (D) and saline group (N) after modeling. In K group, the carvedilol (10 mg/kg) was given to mice through gastric tube. The normal saline was given to them by subcutaneous injection. In D group, the normal saline was given to mice through gastric tube. Meanwhile, the scopolamine (1 mg/kg) was injected subcutaneously. In N group, daily normal saline was given by through gastric tube and subcutaneous injection. At the seventh day of postoperation, five mouse were sacrificed in each group every three days to observe the local growth, invasion and metastasis of prostate cancer to pelvic nodes and liver. Immunohistochemical determination of prostate tumor was made by TH staining and VAChT staining in each group. Results The volume of the prostate cancer was gradually increased in three groups. There was no statistical difference of prostate volume among three groups on the day 7 and 10 post-operatively (all P>0.05). The prostate volume of K group, D group and N group on the day 13 were 0.05±0.04, 0.18±0.08, 0.14±0.05 cm3, respectively (P 0.05). The AOD of TH and VAChT in prostate cancer of K group, D group and N group on the day 10 were [(0.0114±0.016), (0.114±0.002), (0.059±0.008)] and [(0.025±0.011), (0.0226±0.003), (0.009±0.003)], respectively (P 0.05). Conclusions β adrenergic receptor blocker carvedilol can suppress the growth of prostate cancer and cholinergic receptor blocker scopolamine may can inhibit metastasis of prostate cancer. Key words: Prostatic carcinoma; Mouse; Carvedilol; Scopolamine

The PI3K/AKT pathway in the pathogenesis of prostate cancer.

Despite recent advances in our understanding of the biological behavior of prostate cancer (PCa), PCa is becoming the most common malignancy in men worldwide. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in prostate carcinogenesis. Inflammatory cytokines (CCR9, IL-6, and TLR3) regulate PI3K/AKT signaling during apoptosis of PCa cells, and PI3K/AKT signaling participates with androgen-, 1alpha,25(OH)2-vitamin D3-, and prostaglandin-associated mechanisms and is regulated by ErbB, EGFR, and the HER family during cell growth. During metastasis of PCa cells, the PI3K/AKT/NF-kappaB/BMP-2-Smad axis, PTEN/PI3K/AKT pathway, and PI3K/AKT/mTOR signaling regulates tumor cell metastasis and invasion. The present review focuses on the PI3K/AKT signal pathway and discusses the role of the PI3K/AKT signal pathway in PCa tumorigenesis.

Expression of bone sialoprotein in prostate cancer and its clinical significance

Objective To investigate the expression of bone sialoprotein (BSP) in prostate cancer and its clinical significance. Methods Prostate cancer tissues of different pathological grades (68 cases) and benign prostatic hyperplasia tissues (22 cases) were selected. SP method was used to detect the expression of BSP. Serum total prostate-specific antigen (tPSA) levels of prostate cancer were detected by electrochemiluminescence immunoassay before the operation. Results Compared with no or low expression in the adjacent normal glandular tissues, the detectable levels of BSP were examined in most of the prostate cancer tissues. The expression rate of BSP in prostate cancer tissues was higher than that in benign prostatic hyperplasia tissues [76.47 % (52/68) vs 13.64 % (3/22), χ2 = 27.614, P< 0.001]. The expression rates of BSP in well differentiated, moderately differentiated and poorly differentiated tissues according to cell differentiating degree (Gleason system) were 75.0 % (12/16), 77.5 % (31/40) and 75.0 % (9/12) respectively. There was no significant difference in various pathological grading (χ2 = 0.057, P= 0.972). The expression rates of BSP in pathological stage pT2, pT3 and pT4 tissues were 62.16 % (23/37), 95.24 % (20/21) and 90.0 % (9/10) respectively. A statistically significant association was found between BSP expression and pathological stage (χ2 = 9.338, P= 0.009). Serum tPSA level of prostate cancer group with BSP expression was higher than that with no BSP expression [(69.06±25.52) μg/L vs (38.00±21.64) μg/L, F= 19.355, P< 0.001]. Conclusion The high expression of BSP in prostate cancer has a relationship with pathological stage and serum tPSA level, it may play an important role in the biological behaviour of prostate cancer. Key words: Prostatic neoplasms; Bone sialoprotein; Prostate-specific antigen; Immunohistochemistry

Repression of metadherin inhibits biological behavior of prostate cancer cells and enhances their sensitivity to cisplatin.

Metadherin (MTDH), also known as astrocyte-elevated gene-1, was first cloned in 2002 and has been confirmed as an oncogene in numerous types of cancer by previous studies. Overexpression of MTDH has been observed in multiple types of cancer, including breast, esophageal, prostate, cervical and non-small-cell lung cancer, as well as neuroblastoma and hepatocellular carcinoma. However, at present, few investigations into MTDH-associated prostate cancer have been performed. A previous study suggested that MTDH was expressed at higher levels in prostate cancer samples, compared with those of benign prostatic hyperplasia. The present study aimed to elucidate the effects of MTDH as an oncogene associated with the biological behavior of prostate cancer cells and chemotherapy-sensitivity to cisplatin in vitro. It was demonstrated that the inhibition of MTDH expression promoted cell apoptosis, reduced cell viability and weakened the invasive ability of prostate cancer cells. In addition, the suppression of MTDH expression increased cell sensitivity to cisplatin. Furthermore, it was demonstrated that MTDH-associated phosphoinositide 3-kinase/Akt signaling pathways may be involved in mediating the biological behavior of prostate cancer.

Prostate carcinoma: correlation of histopathology with serum prostate specific antigen

Prostate Specific Antigen (PSA) is the first line test in screening of prostate cancer. The increase in PSA depends on differentiation of tumour cells. Gleason grading is one of the most powerful predictors of biological behaviour and influential factors used to determine treatment. PSA, when combined with Gleason score and clinical stage, improves the prediction of pathological stage for prostate carcinoma. Aims of this study were to study the histopathological features and Gleason grading in Prostatic Carcinoma and to correlate pretreatment PSA levels with Gleason grade. The study was undertaken in a tertiary care hospital over a period of two years.Fifty one cases of prostatic carcinoma were studied. Grading done by Gleason grading system, was correlated with serum PSA levels. Software statistical package for social sciences (SPSS), version 16 was used. P value 10ng/ml). 5.9 % had PSA value in normal range (< 4 ng/ml). Though there was a comparative increase in PSA level with increase in Gleason grade, it was not statistically significant (‘p’ value = 0.75). To conclude, a proportion of tumours with Gleason score 8-10 are so poorly differentiated that they produce relatively little PSA. Refinement in estimation and interpretation of PSA values may be considered to improve the sensitivity and specificity of PSA. Gleason grading is a better predictor of biological behaviour of prostate cancer.

MiR-223-3p targeting SEPT6 promotes the biological behavior of prostate cancer.

MicroRNAs (miRNAs) present frequently altered expression in urologic cancers including prostate, bladder, and kidney cancer. The altered expression of miR-223 has been reported in cancers and other diseases in recent researches. MiR-223 is up-regulated in systemic lupus erythematosus and rheumatoid arthritis. In neoplastic diseases, miR-223 is proved to be up-expressed in plasma or serum and cancer tissues compared with normal tissues in pancreatic cancer, gastric cancer, et al. However, whether altered expression of miR-223 is associated with prostate cancer (PCa) and what it is potential functions in PCa remained unveiled. In this study, we firstly found miR-223-3p were up-regulated in prostate cancer tissues and then we study functional role of miR-223-3p in PCa using DU145, PC3 and LNCaP cell lines. Our data suggested that miR-223-3p might target gene SEPT6 and promoted the biological behavior of prostate cancer. Notably, we found increasing SEPT6 expression might reverse the biological activity induced by miR-223-3p, which might be a potential therapeutic target for PCa.

2233 RANKL PATHWAY PROTEINS AS RISK PARAMETERS FOR BIOCHEMICAL RECURRENCE IN PATIENTS UNDERGOING RADICAL PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Markers (II)1 Apr 20132233 RANKL PATHWAY PROTEINS AS RISK PARAMETERS FOR BIOCHEMICAL RECURRENCE IN PATIENTS UNDERGOING RADICAL PROSTATECTOMY Tilman Todenhöfer, Jörg Hennenlotter, Alexander Wald, Philipp Leidenberger, Gunnar Blumenstock, Jens Mundhenk, Stefan Aufderklamm, Georgios Gakis, Ursula Kühs, Andrea Hohneder, Arnulf Stenzl, and Christian Schwentner Tilman TodenhöferTilman Todenhöfer Tübingen, Germany More articles by this author , Jörg HennenlotterJörg Hennenlotter Tübingen, Germany More articles by this author , Alexander WaldAlexander Wald Tübingen, Germany More articles by this author , Philipp LeidenbergerPhilipp Leidenberger Tübingen, Germany More articles by this author , Gunnar BlumenstockGunnar Blumenstock Tübingen, Germany More articles by this author , Jens MundhenkJens Mundhenk Tübingen, Germany More articles by this author , Stefan AufderklammStefan Aufderklamm Tübingen, Germany More articles by this author , Georgios GakisGeorgios Gakis Tübingen, Germany More articles by this author , Ursula KühsUrsula Kühs Tübingen, Germany More articles by this author , Andrea HohnederAndrea Hohneder Tübingen, Germany More articles by this author , Arnulf StenzlArnulf Stenzl Tübingen, Germany More articles by this author , and Christian SchwentnerChristian Schwentner Tübingen, Germany More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2142AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The development of bone metastases from prostate cancer is closely linked to the activity of the receptor activator of the NF-kB Ligand (RANKL) pathway. Recent evidence exists that this pathway might play a role for tumor biology before metastatic disease becomes manifest. We aimed to assess the prognostic impact of proteins of the RANKL pathway in serum samples of patients undergoing radical prostatectomy (RP). METHODS In total, 178 patients undergoing RP between 2004 and 2006 were included. Serum concentrations of soluble RANKL (sRANKL) and osteoprotegerin (OPG) were determined retrospectively using Enzyme Linked Immunosorbent Assay (ELISA). Results of serum measurements were correlated to clinical and patient follow-up data using the Wilcoxon-Mann-Whitney test, the Kaplan-Maier method, and single variable or multifactorial Cox proportional hazards analysis. RESULTS Increased sRANKL (p=0.01), decreased OPG (p=0.01) and an increased sRANKL/OPG Ratio (p=0.004) were significant risk factors for biochemical recurrence (BCR). In multifactorial analysis adjusted for classical risk factors for BCR, sRANKL and sRANKL/OPG ratio were confirmed as independent prognostic factors even when considered as continuous variables. Neither sRANKL nor OPG showed a clear association with classical histopathologic factors such as pT, pN, PSA, Gleason score or R status. CONCLUSIONS Increased activity of the RANKL pathway in the serum of patients with prostate cancer undergoing RP is a risk factor for biochemical recurrence. The RANKL pathway seems to contribute to the biological behavior of prostate cancer already in an organ-confined stage of the disease. Whether serum proteins of this pathway are also able to predict response to RANKL-inhibition in patients without bone metastases remains to be elucidated. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e916 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tilman Todenhöfer Tübingen, Germany More articles by this author Jörg Hennenlotter Tübingen, Germany More articles by this author Alexander Wald Tübingen, Germany More articles by this author Philipp Leidenberger Tübingen, Germany More articles by this author Gunnar Blumenstock Tübingen, Germany More articles by this author Jens Mundhenk Tübingen, Germany More articles by this author Stefan Aufderklamm Tübingen, Germany More articles by this author Georgios Gakis Tübingen, Germany More articles by this author Ursula Kühs Tübingen, Germany More articles by this author Andrea Hohneder Tübingen, Germany More articles by this author Arnulf Stenzl Tübingen, Germany More articles by this author Christian Schwentner Tübingen, Germany More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Excellent Long-Term Outcomes with Prostate Brachytherapy in Young Men Less Than 55 Years Old

PurposeControversy exists as to the biological behavior of prostate cancer in younger patients and consequently to their optimal treatment. Some physicians have advocated a primary surgical approach in young patients. The purpose of this study was to evaluate the long-term outcomes of low-dose-rate (LDR) prostate brachytherapy based treatment in this younger cohort of patients.Materials and MethodsFour thousand men have undergone prostate seed implantation at our institution since July 1997. All patients are followed prospectively in our IRB-approved database and assessed for clinical and biochemical recurrence based on the Phoenix definition. Risk stratification was assigned per NCCN guidelines. Patients with initial PSA >50 were not included in this analysis. This analysis reviews 170 consecutive patients treated at ages ≤55 years old. Twenty-two percent of patients were treated with LDR Iodine-125 seed implant monotherapy, and 78% Palladium-103 seed implant combined with 45 Gray external radiation. Seed implants were performed using a dynamic intraoperative dosimetry technique. Combination therapy was primarily employed in intermediate- and high-risk groups. Sixty percent of patients received short course hormone therapy for a median duration of 6 months.ResultsWith a median followup of 80 months, 94% of all patients were free from biochemical failure (FFBF). On subset analysis, 98% of low-risk, 95% of intermediate-risk, and 84% of high-risk patients were FFBF. Grade 3 complications occurred in only 2.9% of patients. These consisted mostly of urinary retention and its subsequent management. No grade 4 complications occurred.ConclusionsProstate seed implant based treatments resulted in excellent long-term outcomes with minimal morbidity in this young cohort of patients. These results compared favorably to surgical and other series. PurposeControversy exists as to the biological behavior of prostate cancer in younger patients and consequently to their optimal treatment. Some physicians have advocated a primary surgical approach in young patients. The purpose of this study was to evaluate the long-term outcomes of low-dose-rate (LDR) prostate brachytherapy based treatment in this younger cohort of patients. Controversy exists as to the biological behavior of prostate cancer in younger patients and consequently to their optimal treatment. Some physicians have advocated a primary surgical approach in young patients. The purpose of this study was to evaluate the long-term outcomes of low-dose-rate (LDR) prostate brachytherapy based treatment in this younger cohort of patients. Materials and MethodsFour thousand men have undergone prostate seed implantation at our institution since July 1997. All patients are followed prospectively in our IRB-approved database and assessed for clinical and biochemical recurrence based on the Phoenix definition. Risk stratification was assigned per NCCN guidelines. Patients with initial PSA >50 were not included in this analysis. This analysis reviews 170 consecutive patients treated at ages ≤55 years old. Twenty-two percent of patients were treated with LDR Iodine-125 seed implant monotherapy, and 78% Palladium-103 seed implant combined with 45 Gray external radiation. Seed implants were performed using a dynamic intraoperative dosimetry technique. Combination therapy was primarily employed in intermediate- and high-risk groups. Sixty percent of patients received short course hormone therapy for a median duration of 6 months. Four thousand men have undergone prostate seed implantation at our institution since July 1997. All patients are followed prospectively in our IRB-approved database and assessed for clinical and biochemical recurrence based on the Phoenix definition. Risk stratification was assigned per NCCN guidelines. Patients with initial PSA >50 were not included in this analysis. This analysis reviews 170 consecutive patients treated at ages ≤55 years old. Twenty-two percent of patients were treated with LDR Iodine-125 seed implant monotherapy, and 78% Palladium-103 seed implant combined with 45 Gray external radiation. Seed implants were performed using a dynamic intraoperative dosimetry technique. Combination therapy was primarily employed in intermediate- and high-risk groups. Sixty percent of patients received short course hormone therapy for a median duration of 6 months. ResultsWith a median followup of 80 months, 94% of all patients were free from biochemical failure (FFBF). On subset analysis, 98% of low-risk, 95% of intermediate-risk, and 84% of high-risk patients were FFBF. Grade 3 complications occurred in only 2.9% of patients. These consisted mostly of urinary retention and its subsequent management. No grade 4 complications occurred. With a median followup of 80 months, 94% of all patients were free from biochemical failure (FFBF). On subset analysis, 98% of low-risk, 95% of intermediate-risk, and 84% of high-risk patients were FFBF. Grade 3 complications occurred in only 2.9% of patients. These consisted mostly of urinary retention and its subsequent management. No grade 4 complications occurred. ConclusionsProstate seed implant based treatments resulted in excellent long-term outcomes with minimal morbidity in this young cohort of patients. These results compared favorably to surgical and other series. Prostate seed implant based treatments resulted in excellent long-term outcomes with minimal morbidity in this young cohort of patients. These results compared favorably to surgical and other series.

1049 RANKL pathway proteins as risk parameters for biochemical recurrence in patients undergoing radical prostatectomy

INTRODUCTION AND OBJECTIVES: The development of bone metastases from prostate cancer is closely linked to the activity of the receptor activator of the NF-kB Ligand (RANKL) pathway. Recent evidence exists that this pathway might play a role for tumor biology before metastatic disease becomes manifest. We aimed to assess the prognostic impact of proteins of the RANKL pathway in serum samples of patients undergoing radical prostatectomy (RP). METHODS: In total, 178 patients undergoing RP between 2004 and 2006 were included. Serum concentrations of soluble RANKL (sRANKL) and osteoprotegerin (OPG) were determined retrospectively using Enzyme Linked Immunosorbent Assay (ELISA). Results of serum measurements were correlated to clinical and patient follow-up data using the Wilcoxon-Mann-Whitney test, the Kaplan-Maier method, and single variable or multifactorial Cox proportional hazards analysis. RESULTS: Increased sRANKL (p 0.01), decreased OPG (p 0.01) and an increased sRANKL/OPG Ratio (p 0.004) were significant risk factors for biochemical recurrence (BCR). In multifactorial analysis adjusted for classical risk factors for BCR, sRANKL and sRANKL/OPG ratio were confirmed as independent prognostic factors even when considered as continuous variables. Neither sRANKL nor OPG showed a clear association with classical histopathologic factors such as pT, pN, PSA, Gleason score or R status. CONCLUSIONS: Increased activity of the RANKL pathway in the serum of patients with prostate cancer undergoing RP is a risk factor for biochemical recurrence. The RANKL pathway seems to contribute to the biological behavior of prostate cancer already in an organ-confined stage of the disease. Whether serum proteins of this pathway are also able to predict response to RANKL-inhibition in patients without bone metastases remains to be elucidated.

Serum receptor activator of nuclear factor κB ligand (RANKL) levels predict biochemical recurrence in patients undergoing radical prostatectomy

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is increasing evidence that the receptor activator of nuclear factor κB ligand (RANKL) pathway not only contributes to the development of bone metastases, but also influences tumour biology in earlier stages of cancer. The study shows that preoperative serum levels of RANKL and its inhibitor osteoprotegerin (OPG) have a prognostic impact in patients undergoing radical prostatectomy for clinically localized prostate cancer. Both high levels of RANKL and a higher RANKL/OPG ratio are independent predictors of early biochemical recurrence in these patients. To assess the prognostic impact of proteins of the receptor activator of nuclear factor κB (RANKL) pathway in serum samples from patients undergoing radical prostatectomy. We retrospectively determined soluble RANKL (sRANKL) and osteoprotegerin (OPG) by ELISA in serum samples of 178 patients undergoing radical prostatectomy between 2004 and 2006. Clinical and patient follow-up data were analysed using the Wilcoxon-Mann-Whitney test, the Kaplan-Maier method, and single variable or multifactorial Cox proportional hazards analysis. Higher serum sRANKL levels (P = 0.01), lower serum OPG levels (P = 0.01) and a higher sRANKL/OPG ratio (P = 0.004) were significant risk factors for biochemical recurrence (BCR). In multifactorial analysis, adjusted for the common risk factors for BCR, sRANKL and sRANKL/OPG ratio were confirmed as independent prognostic factors. Neither sRANKL nor OPG showed a clear association with histopathological factors such as pT stage, pN Gleason score or resection margin status, nor were they associated with prostate-specific antigen level. Greater activity of the RANKL pathway in the serum of patients with prostate cancer undergoing radical prostatectomy is a risk factor for BCR. The RANKL pathway seems to contribute to the biological behaviour of prostate cancer even at the organ-confined stage of the disease.

Diagnostic value of DNA alteration: loss of heterozygosity or allelic imbalance—promising for molecular staging of prostate cancers

The biological behavior of prostate cancer is uncertain, and therefore, search for molecular prognostic markers associated with disease progression seems to be essential. We performed microsatellite allelotyping of DNA isolated from primary prostate tumors biopsies (prostate adenocarcinoma, PCa). We evaluated the frequency of allelic imbalance (AI), including loss of heterozygosity and/or microsatellite imbalance (LOH/MSI) as well as the association of these DNA alterations with clinicopathological variables. We assessed the significance of LOH/MSI alterations in selected imprinted and non-imprinted chromosomal regions (IR and NIR) in PCa. A total of 50 biopsies of prostate tumor (containing >75 % tumor cells) were histologically examined confirming prostate carcinoma. Microsatellite allelotyping using 16 microsatellite markers linked to the following chromosomal regions: 1p31.2, 3p21.3–25.3, 7q32.2, 9p21.3, 11p15.5, 12q23.2, and 16q22.1 was performed. The incidence of LOH/MSI alterations in prostate tumor cells was the highest for chromosomal regions 7q32.2 and 16q22.1 (31.25 and 26.60 %, respectively), followed by 1p31.2 and 3p21.3–25.3 (26.50 and 17.40 %, respectively). Statistically significant increase in LOH/MSI alterations has been observed for markers: D1S2137 (1p region; p = 0.00032), D9S974 (9p region; p = 0.0017), and D16S3025 (16q region; p = 0.0017). Statistically significant differences in frequency of LOH/MSI alterations in particular chromosomal regions have been found for 1p31.2, 7q32.2 and 16q22.1 (p = 0.027, p = 0.012 and p = 0.031, respectively). We documented statistically significant association between Fractional Allele Loss (FAL) index and advanced tumor stage (p < 0.05). We suggest that genomic instability of LOH/MSI type is a frequent event in prostate carcinogenesis and assessed as FAL index has clinical value for the molecular staging of prostate cancer in (TRUS)-guided prostate biopsy material.

Highlights of This Issue

Hypoxia is important in many human cancers and influences clinical behavior, development of metastases, and patient survival. This prospective study by Milosevic and colleagues in 247 men with intermediate-risk prostate cancer demonstrates, for the first time, that tumor hypoxia measured prior to treatment is associated with early biochemical recurrence after escalated-dose radiotherapy. This pattern of recurrence is compatible with the presence of hypoxia-driven occult metastases. The results of this study provide new insight about the biologic behavior of prostate cancer after radiotherapy and have important implications for combining radiotherapy with hypoxia-targeted therapeutics or other systemic anticancer treatments.Immune thrombocytopenia (ITP) is one of the most frequently observed autoimmune complications in patients with chronic lymphocytic leukemia (CLL). Visco and colleagues provide insights into the pathobiology of this event by showing a significant association between ITP occurrence and immunoglobulin heavy-chain variable (IGHV) unmutated gene status, unfavorable cytogenetic lesions, and stereotyped conformation of the B-cell receptor (BCR). In particular, they show that stereotyped IGHV subsets #1 and #7 were significantly the most represented among patients developing ITP. Moreover, they show a prognostic implication for stereotyped BCR subset #7, which was significantly associated with shorter time to ITP development independently of IGHV mutational status. These findings strongly support a role for specific BCR triggering in the pathogenesis of this immune complication in CLL.A distinct need exists for novel risk stratification markers to improve outcome in childhood ependymoma. Using interphase FISH, Kilday and colleagues evaluated a prognostic role for 1q25 copy number gain across 3 pediatric European clinical trial cohorts defined according to patient age and adjuvant therapy administered. Gain of 1q25 was shown to be an independent marker of tumor progression for all patients, particularly for younger children treated with primary postoperative chemotherapy. Moreover, incorporating tumor 1q25 status with the degree of surgical resection enabled a novel patient risk-group classification system that was reproducible across all trial groups, thereby advocating the prospective evaluation of 1q25 gain in future international trials of pediatric ependymoma.Ma and colleagues present their findings from an evaluation of the dual inhibitor of polo-like kinase 1 and phosphoinositide 3-kinase, ON-01910.Na (rigosertib), in combination with gemcitabine in advanced cancer patients with a focus on pancreatic adenocarcinoma. This phase I trial represents the translation of preclinical work that identified rigosertib as a rational agent to modulate the vulnerability of pancreatic cancer to gemcitabine. This clinical study assessed the combination of rigosertib and gemcitabine, its pharmacology, and its preliminary efficacy in patients with pancreatic cancer, finding acceptable tolerability and hints of activity. This study serves as an example of rapid translation of solid preclinical findings to the clinic.

Effects of complete denervation of sympathetic adrenergenic nerve on biological behaviors of prostate cancer in mice

Objective To investigate the effects of complete denervation of sympathetic adrenergic nerves on the biological behaviors of prostate cancer in C57BL/6 mice. Methods Fifty male C57BL/6 mice, 10 weeks old, were randomly divided into two groups. By using a micro-syringe, RM-1 cells (0. 5 ×106) were injected into bilateral dorsal prostate capsules of mice, at the same time, bilateral hypogastric sympathetic nerves of the mice were cut (experimental group) or not (control group). At the sixth day postoperation, 5 mice were sacrificed in each group every three days to observe the local growth, invasion and metastasis of prostate cancer to pelvic nodes and other organs. An immunohistochemical determination of the hypogastric nerves was made by using an antibody against tyrosine hydroxylase ( TH) , a marker for sympathetic nerves. At the 15th day, 10 mice left were fed to death to calculate the life span of tumor-bearing mice. Results The volume of the prostate was gradually increased and confirmed as prostate cancer histologically. The prostate volume in experimental group was (0. 034 ± 0. 008) , (0. 339 ±0. 040) , (0. 829 ±0. 090) , ( 1. 169 ±0. 093) cm3 on the day 6, 9, 12, 15 after operation, respectively,while that in control group was (0.034 ± 0. 008), (0. 316 ± 0. 050), (0. 824 ± 0.071), (1. 236 ±0. 103) cm3, respectively (all P ＞ 0. 05). At the 12th day, muscle tissues around the prostate invasion by prostate cancer were observed in 3 cases of experimental group and 4 cases of control group; at the 15th day, invasion of seminal vesicles and bladder was found in 4 cases of experimental group and 4 cases of control group. Three and 4 mice had metastasis of pelvic nodes at 12th day and 15th day respectively in the experimental group, and 4 and 4 respectively in control group. At the 15th day post operation, in control group, liver parenchyma metastasis and renal pelvis metastasis were observed in 1 and 1 case, respectively, while in experimental group, no distant metastasis was observed. The life span of tumor-bearing mice in the experimental and control groups was (15.80±0.84) and (16.00±0.71) days, respectively (P＞0. 05 ) . Conclusion Complete denervation of sympathetic adrenergic nerves seems to have no significant effects on the local growth, invasion and pelvic nodes metastasis of prostate cancer in C57BL/6 mice, but may have some inhibition effects on its distant metastasis. Key words: Prostatic carcinoma; Sympathetic denervation; Biology; Mouse