Influence of the neural microenvironment on prostate cancer

Background

Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease.

Method

We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy.

Result

Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non‐neoplastic epithelial cells.

Conclusion

Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer.

     

Correlations of SELENOF and SELENOP genotypes with serum selenium levels and prostate cancer

Background

Selenium status is inversely associated with the incidence of prostate cancer. However, supplementation trials have not indicated a benefit of selenium supplementation in reducing cancer risk. Polymorphisms in the gene encoding selenoprotein 15 (SELENOF) are associated with cancer incidence/mortality and present disproportionately in African Americans. Relationships among the genotype of selenoproteins implicated in increased cancer risk, selenium status, and race with prostate cancer were investigated.

Methods

Tissue microarrays were used to assess SELENOF levels and cellular location in prostatic tissue. Sera and DNA from participants of the Chicago‐based Adiposity Study Cohort were used to quantify selenium levels and genotype frequencies of the genes for SELENOF and the selenium‐carrier protein selenoprotein P (SELENOP). Logistic regression models for dichotomous patient outcomes and regression models for continuous outcome were employed to identify both clinical, genetic, and biochemical characteristics that are associated with these outcomes.

Results

SELENOF is dramatically reduced in prostate cancer and lower in tumors derived from African American men as compared to tumors obtained from Caucasians. Differing frequency of SELENOF polymorphisms and lower selenium levels were observed in African Americans as compared to Caucasians. SELENOF genotypes were associated with higher histological tumor grade. A polymorphism in SELENOP was associated with recurrence and higher serum PSA.

Conclusions

These results indicate an interaction between selenium status and selenoprotein genotypes that may contribute to the disparity in prostate cancer incidence and outcome experienced by African Americans.

     

Characterization of autoimmune inflammation induced prostate stem cell expansion

BACKGROUND

The presence of inflammation in prostate cancer (PCa) and benign prostate hyperplasia (BPH) has been well described but the cellular mechanisms by which inflammation modulates the prostate are currently unclear. Prostate stem cells (PSC) not only maintain prostate homeostasis but also are considered to be the cell of origin of PCa and an important contributor to BPH. However, the impact of inflammation on PSC is not well understood. Therefore, we initiated studies to evaluate the effect of inflammation on PSC.

METHOD

Ovalbumin specific CD8⁺ T cells were intravenously delivered to intact and castrated prostate ovalbumin expressing transgenic‐3 (POET‐3) mice to induce inflammation. Lin (CD45/CD31)^?Sca1⁺CD49f⁺ cells (LSC) and progenitor cells within LSC were determined by flow cytometry. Sorted LSC were subjected to a prostate sphere forming assay to evaluate PSC clonal propagation, proliferation, immediate differentiation, and self‐renewal ability. Density of individual spheres was measured by a cantilever‐based resonator weighing system. Morphology and characterization of prostate spheres was determined by hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC). Finally, immediate PSC differentiation in sphere formation was determined by immunofluorescence for epithelial cytokeratin markers cytokeratin (CK) 5 and CK8.

RESULT

Data presented here demonstrate a significant expansion of the proliferative (BrdU⁺) LSC population, including CK5⁺, p63⁺, CK18⁺ cells, as well as intermediate cells (CK5⁺/CK8⁺) in inflamed prostates. Histological images reveal that PSC from inflamed prostates produce significantly larger spheres, indicating that the enhanced proliferation observed in LSC is sustained in vitro in the absence of inflammatory mediators. In addition, cultures from inflamed PSC yielded increased number of tubule‐like spheres. These tube‐like spheres grown from PSCs isolated from inflamed mice exhibited stratification of a CK8⁺ luminal‐like layer and a CK5⁺ basal‐like layer. Notably, the numbers of spheres formed by inflamed and non‐inflamed PSC were equal, suggesting that even though proliferation is enhanced by inflammation, the homeostatic level of PSC is maintained.

CONCLUSION

Induction of inflammation promotes PSC expansion and immediate differentiation through highly proliferative progenitor cells while the homeostasis of PSC is maintained. Prostate 75:1620–1631, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.

     

Differential gene expression profiling of functionally and developmentally distinct human prostate epithelial populations

BACKGROUND

Human fetal prostate buds appear in the 10th gestational week as solid cords, which branch and form lumens in response to androgen 1. Previous in vivo analysis of prostate epithelia isolated from benign prostatectomy specimens indicated that Epcam⁺CD44^?CD49f^Hi basal cells possess efficient tubule initiation capability relative to other subpopulations 2. Stromal interactions and branching morphogenesis displayed by adult tubule‐initiating cells (TIC) are reminiscent of fetal prostate development. In the current study, we evaluated in vivo tubule initiation by human fetal prostate cells and determined expression profiles of fetal and adult epithelial subpopulations in an effort to identify pathways used by TIC.

METHODS

Immunostaining and FACS analysis based on Epcam, CD44, and CD49f expression demonstrated the majority (99.9%) of fetal prostate epithelial cells (FC) were Epcam⁺CD44^? with variable levels of CD49f expression. Fetal populations isolated via cell sorting were implanted into immunocompromised mice. Total RNA isolation from Epcam⁺CD44^?CD49f^Hi FC, adult Epcam⁺CD44^?CD49f^Hi TIC, Epcam⁺CD44⁺CD49f^Hi basal cells (BC), and Epcam⁺CD44^?CD49f^Lo luminal cells (LC) was performed, followed by microarray analysis of 19 samples using the Affymetrix Gene Chip Human U133 Plus 2.0 Array. Data was analyzed using Partek Genomics Suite Version 6.4. Genes selected showed >2‐fold difference in expression and P < 5.00E‐2. Results were validated with RT‐PCR.

RESULTS

Grafts retrieved from Epcam⁺CD44^? fetal cell implants displayed tubule formation with differentiation into basal and luminal compartments, while only stromal outgrowths were recovered from Epcam‐ fetal cell implants. Hierarchical clustering revealed four distinct groups determined by antigenic profile (TIC, BC, LC) and developmental stage (FC). TIC and BC displayed basal gene expression profiles, while LC expressed secretory genes. FC had a unique profile with the most similarities to adult TIC. Functional, network, and canonical pathway identification using Ingenuity Pathway Analysis Version 7.6 compiled genes with the highest differential expression (TIC relative to BC or LC). Many of these genes were found to be significantly associated with prostate tumorigenesis.

CONCLUSIONS

Our results demonstrate clustering gene expression profiles of FC and adult TIC. Pathways associated with TIC are known to be deregulated in cancer, suggesting a cell‐of‐origin role for TIC versus re‐emergence of pathways common to these cells in tumorigenesis. Prostate 75: 764–776, 2015. © The Authors. The Prostate, published by Wiley Periodicals, Inc.

     

A two‐drug combination simulation study for metastatic castrate resistant prostate cancer

Background

Prostate cancer often evolves resistance to androgen deprivation therapy leading to a lethal metastatic castrate‐resistant form. Besides androgen independence, subpopulations of the tumor are genetically heterogeneous. With the advent of tumor genome sequencing we asked which has the greater influence on reducing tumor size: genetic background, heterogeneity, or drug potency?

Methods

A previously developed theoretical evolutionary dynamics model of stochastic branching processes is applied to compute the probability of tumor eradication with two targeted drugs. Publicly available data sets were surveyed to parameterize the model.

Results

Our calculations reveal that the greatest influence on successful treatment is the genetic background including the number of mutations overcoming resistance. Another important criteria is the tumor size at which it is still possible to achieve tumor eradication, for example, 2‐4 cm large tumors have at best a 10% probability to be eradicated when 50 mutations can confer resistance to each drug.

Conclusion

Overall, this study finds that genetic background and tumor heterogeneity are more important than drug potency in treating mCRPC. It also points toward identifying metastatic sites early using biochemical assays and/or dPET.

     

A five‐CpG DNA methylation score to predict metastatic‐lethal outcomes in men treated with radical prostatectomy for localized prostate cancer

Background

Prognostic biomarkers for localized prostate cancer (PCa) could improve personalized medicine. Our group previously identified a panel of differentially methylated CpGs in primary tumor tissue that predict disease aggressiveness, and here we further validate these biomarkers.

Methods

Pyrosequencing was used to assess CpG methylation of eight biomarkers previously identified using the HumanMethylation450 array; CpGs with strongly correlated (r >0.70) results were considered technically validated. Logistic regression incorporating the validated CpGs and Gleason sum was used to define and lock a final model to stratify men with metastatic‐lethal versus non‐recurrent PCa in a training dataset. Coefficients from the final model were then used to construct a DNA methylation score, which was evaluated by logistic regression and Receiver Operating Characteristic (ROC) curve analyses in an independent testing dataset.

Results

Five CpGs were technically validated and all were retained (P < 0.05) in the final model. The 5‐CpG and Gleason sum coefficients were used to calculate a methylation score, which was higher in men with metastatic‐lethal progression (P = 6.8 × 10^?6) in the testing dataset. For each unit increase in the score there was a four‐fold increase in risk of metastatic‐lethal events (odds ratio, OR = 4.0, 95%CI = 1.8–14.3). At 95% specificity, sensitivity was 74% for the score compared to 53% for Gleason sum alone. The score demonstrated better prediction performance (AUC = 0.91; pAUC = 0.037) compared to Gleason sum alone (AUC = 0.87; pAUC = 0.025).

Conclusions

The DNA methylation score improved upon Gleason sum for predicting metastatic‐lethal progression and holds promise for risk stratification of men with aggressive tumors. This prognostic score warrants further evaluation as a tool for improving patient outcomes.

     

Establishing prostate cancer patient derived xenografts: Lessons learned from older studies

Background

Understanding the progression of prostate cancer to androgen‐independence/castrate resistance and development of preclinical testing models are important for developing new prostate cancer therapies. This report describes studies performed 30 years ago, which demonstrate utility and shortfalls of xenografting to preclinical modeling.

Methods

We subcutaneously implanted male nude mice with small prostate cancer fragments from transurethral resection of the prostate (TURP) from 29 patients. Successful xenografts were passaged into new host mice. They were characterized using histology, immunohistochemistry for marker expression, flow cytometry for ploidy status, and in some cases by electron microscopy and response to testosterone. Two xenografts were karyotyped by G‐banding.

Results

Tissues from 3/29 donors (10%) gave rise to xenografts that were successfully serially passaged in vivo. Two, (UCRU‐PR‐1, which subsequently was replaced by a mouse fibrosarcoma, and UCRU‐PR‐2, which combined epithelial and neuroendocrine features) have been described. UCRU‐PR‐4 line was a poorly differentiated prostatic adenocarcinoma derived from a patient who had undergone estrogen therapy and bilateral castration after his cancer relapsed. Histologically, this comprised diffusely infiltrating small acinar cell carcinoma with more solid aggregates of poorly differentiated adenocarcinoma. The xenografted line showed histology consistent with a poorly differentiated adenocarcinoma and stained positively for prostatic acid phosphatase (PAcP), epithelial membrane antigen (EMA) and the cytokeratin cocktail, CAM5.2, with weak staining for prostate specific antigen (PSA). The line failed to grow in female nude mice. Castration of three male nude mice after xenograft establishment resulted in cessation of growth in one, growth regression in another and transient growth in another, suggesting that some cells had retained androgen sensitivity. The karyotype (from passage 1) was 43–46, XY, dic(1;12)(p11;p11), der(3)t(3:?5)(q13;q13), ‐5, inv(7)(p15q35) x2, +add(7)(p13), add(8)(p22), add(11)(p14), add(13)(p11), add(20)(p12), ‐22, +r4[cp8].

Conclusions

Xenografts provide a clinically relevant model of prostate cancer, although establishing serially transplantable prostate cancer patient derived xenografts is challenging and requires rigorous characterization and high quality starting material. Xenografting from advanced prostate cancer is more likely to succeed, as xenografting from well differentiated, localized disease has not been achieved in our experience. Strong translational correlations can be demonstrated between the clinical disease state and the xenograft model. Prostate 75: 628–636, 2015. © The Authors. The Prostate published by Wiley Periodicals, Inc.

     

The Relationship Between Metformin and Serum Prostate‐Specific Antigen Levels

BACKGROUND

Metformin is the first‐line oral antihyperglycemic of choice for individuals with type 2 diabetes. Recent evidence supports a role for metformin in prostate cancer chemoprotection. However, whether metformin indeed influences prostate biology is unknown. We aimed to study the association between metformin and serum prostate‐specific antigen (PSA) levels—the primary prostate cancer biomarker.

METHODS

We conducted a cross‐sectional study of 326 prostate cancer‐free men with type 2 diabetes were recruited between 2004 and 2013 at St. Michael's Hospital. Men were excluded if they had a PSA ≥10‐ng/ml, or used >2,550‐mg/d metformin or supplemental androgens. Multivariate linear regressions quantified the association between metformin dose and log‐PSA. Secondary analyses quantified the association between other antihyperglycemics (sulfonylureas, thiazolidinediones) and PSA; sensitivity analyses tested covariate interactions.

RESULTS

Median PSA was 0.9‐ng/ml (IQR: 0.5–1.6‐ng/ml). Metformin dose associated positively with BMI, HbA1c, diabetes duration, and number of statin, acetylsalicylic acid, diuretic users, and number of antihyperglycemics used, and negatively with LDL‐C. In multivariate models, PSA changed by ?8% (95%CI: ?13 to ?2%, P = 0.011) per 500‐mg/d increase in metformin. Men with diabetes for ≥6 years (n = 163) saw a greater difference in PSA per 500‐mg/d metformin (?12% [95% CI: ?19 to ?4%, P = 0.002], P‐interaction = 0.018). Serum PSA did not relate with sulfonylureas, thiazolidinediones, or total number of antihyperglycemic agents used. Our findings are limited by the cross‐sectional design of this study.

CONCLUSIONS

Metformin dose‐dependently inversely associated with serum PSA, independent of other antihyperglycemic medications. Whether metformin confers a dose‐dependent benefit on prostate tumorigenesis and progression warrants investigation. Prostate 76:1445–1453, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.

     

Prostate‐specific antigen screening impacts on biochemical recurrence in patients with clinically localized prostate cancer

Objective

To clarify the impact of prostate‐specific antigen screening on surgical outcomes of prostate cancer.

Methods

Patients who underwent radical prostatectomy were divided into two groups according to prostate‐specific antigen testing opportunity (group 1, prostate‐specific antigen screening; group 2, non‐prostate‐specific antigen screening). Perioperative clinical characteristics were compared using the Wilcoxon rank‐sum and χ²‐tests. Cox proportional hazards models were used to identify independent predictors of postoperative biochemical recurrence‐free survival.

Results

In total, 798 patients (63.2%) and 464 patients (36.8%) were categorized into groups 1 and 2, respectively. Group 2 patients were more likely to have a higher prostate‐specific antigen level and age at diagnosis and larger prostate volume. Clinical T stage, percentage of positive cores and pathological Gleason score did not differ between the groups. The 5‐year biochemical recurrence‐free survival rate was 83.9% for group 1 and 71.0% for group 2 (P < 0.001). On multivariate analysis, prostate‐specific antigen testing opportunity (hazard ratio 2.530; P < 0.001) was an independent predictive factor for biochemical recurrence after surgery, as well as pathological T stage, pathological Gleason score, positive surgical margin and lymphovascular invasion. Additional analyses showed that prostate‐specific antigen screening had a greater impact on biochemical recurrence in a younger patients, patients with a high prostate‐specific antigen level, large prostate volume and D'Amico high risk, and patients meeting the exclusion criteria of the Prostate Cancer Research International Active Surveillance study.

Conclusions

Detection by screening results in favorable outcomes after surgery. Prostate‐specific antigen screening might contribute to reducing biochemical recurrence in patients with localized prostate cancer.

     

Epigenetic markers in circulating cell‐free DNA as prognostic markers for survival of castration‐resistant prostate cancer patients

Background

: Noninvasive biomarkers to guide personalized treatment for castration‐resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell‐free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis.

Methods

: In this prospective study, patients were included before starting new treatment after developing CRPC. The blood samples were collected prior to start of the treatment and at three time points thereafter. cfDNA was extracted from 1.5 mL of plasma and before performing a methylation‐specific PCR, bisulfate modification was carried out.

Results

: The median levels of cfDNA, GSTP1, and APC copies in the baseline samples of CRPC patients (n = 47) were higher than in controls (n = 30). In the survival analysis, the group with baseline marker levels below median had significant less PCa‐related deaths (P‐values <0.02) and did not reach the median survival point. The survival distributions for the groups were statistically significant for the cfDNA concentration, GSTP1 and APC copies, as well as PSA combined with GSTP1 + APC (P‐values <0.03). Furthermore, there were strong positive correlations between PSA and marker response after starting treatment (P‐values <0.04).

Conclusions

: In conclusion, this study showed the kinetics of methylated cfDNA (GSTP1 and APC) in plasma of CRPC patients after starting treatment. Furthermore, the value of the markers before treatment is prognostic for overall survival. These results are promising for developing a test to guide treatment‐decision‐making for CRPC patients.

     

Laser prostate ablation and enucleation: Analysis of a national cohort

Objective

To compare characteristics and outcomes of benign prostatic hyperplasia patients undergoing prostate laser ablation with those undergoing laser enucleation using a nationwide cohort.

Methods

Men who underwent prostate laser ablation (n=10054) or laser enucleation (n=1705) between 2011 and 2015 were identified by the common procedural terminology code as recorded in the National Surgical Quality Improvement Program database. Preoperative, intraoperative and postoperative parameters were compared between the groups using univariate and multivariate analysis.

Results

Prostate laser ablation patients were older, had more comorbidities and were more likely to have abnormal laboratory values. Enucleations were significantly longer and more likely to result in a hospital stay >1day. Enucleation patients were also more likely to require a blood transfusion postoperatively, but less likely to experience urinary tract infection and sepsis on both univariate and multivariate analysis adjusted for preoperative and intraoperative factors.

Conclusions

Although laser enucleation and prostate laser ablation are both considered minimally invasive techniques, significant differences in patient selection, intraoperative factors and postoperative complications are identified in this national cohort. The present study shows that despite similar outcomes in prospective single‐center studies, prostate laser ablation and laser enucleation have distinct practice patterns in a broader national context.

     

Intrauterine growth restriction and prematurity influence regulatory T cell development in newborns

Purpose

The aim of this study was to determine the relationship of birth weight and gestational age with regulatory T cells (T_regs) in cord blood of human newborns.

Methods

Cord blood mononuclear cells (CBMCs) of 210 newborns were analyzed using flow cytometry to identify T_regs (CD3⁺, CD4⁺, CD25^high, FoxP3^high) and measure FoxP3 mean fluorescence intensity (MFI). Suppressive index (SI) was calculated as FoxP3 MFI per T_reg.

Results

Mode of delivery had no significant effect on T_regs at birth. Term babies with growth restriction had fewer T_regs than their appropriate weight counterparts but equivalent SI. Preterm babies had higher percentages of T_regs, but lower SI than term controls. SI steadily increased through gestation.

Conclusions

Intrauterine growth restriction is correlated with fewer circulating T_regs and prematurity with decreased functionality of T_regs compared to term appropriate weight infants. This may have implications in diseases such as necrotizing enterocolitis that disproportionately affect premature and lower birth weight infants.     

Oral administration of cernitin pollen extract (Cernilton®) for 30 days might be useful to avoid unnecessary biopsy in prostate biopsy candidates: A preliminary study

Objectives

To assess the effect of cernitin pollen extract on serum prostate‐specific antigen level prostate biopsy candidates, and to develop an ideal protocol to avoid an unnecessary biopsy procedure.

Methods

A total of 61 patients were administrated cernitin pollen extract tablets (two tablets t.i.d.) for 30 days, and then underwent a prostate biopsy with ≥12 systematic and targeted biopsy cores obtained. Serum prostate‐specific antigen levels were examined before and after administration of the pollen extract, and the change in serum prostate‐specific antigen and the rate of change were analyzed in relation to negative and positive biopsy results for cancer.

Results

The mean change in serum prostate‐specific antigen and rate of change after administration of cernitin pollen extract in all patients were ?0.6 ± 1.4 ng/mL and ?7.6 ± 16.1%, respectively, which were significantly different from the baseline values (P = 0.0003 and P = 0.0005, respectively). When prostate‐specific antigen change values and rates were compared between patients negative and positive for cancer, a significant difference between those groups was observed (P = 0.04 and P = 0.03, respectively).

Conclusions

The present study is the first to show that an ideal protocol using cernitin pollen extract has the potential to avoid an unnecessary prostate biopsy procedure in patients with elevated prostate‐specific antigen, possibly caused by inflammation. Additional studies with greater numbers of participants are required to confirm our findings and develop an ideal protocol.

     

Association among plasma 1,25(OH)2D,ratio of 1,25(OH)2D to 25(OH)D,and prostate cancer aggressiveness

Background

African-American (AA) men tend to present with more aggressive prostate cancer (Gleason score >7) than European-American (EA) men. Vitamin D and its metabolites are implicated in prostate cancer biology with vitamin D deficiency, indicated by its metabolite levels in serum or plasma, usually observed in AA men.

Objective

To determine if 1, 25-dihydroxy vitamin D3 [1,25(OH)₂D] plasma levels in AA and EA prostate cancer patients alter the risk of having aggressive prostate cancer.

Design

Research subjects from the North Carolina-Louisiana Prostate Cancer Project (AA n = 435 and EA n = 532) were included. Plasma metabolites 1,25(OH)₂D and 25-hydroxyvitamin D3 [25(OH)D] were measured using liquid chromatography with tandem mass spectrophotometry. Research subjects were classified into low (Gleason sum < 7, stage T1-T2, and Prostate-specific antigen (PSA) < 9 ng/mL) or high (Gleason sum > 8 or Gleason sum = 7 with 4 + 3, or PSA > 20 ng/mL, or Gleason sum = 7 and stage T3-T4) aggressive disease.

Results

Research subjects in the second and third tertiles of plasma levels of 1, 25(OH)₂D had lower odds of high aggressive prostate cancer (AA [OR_T2vsT1: 0.66, 95%CI: 0.39-1.12; OR_T3vsT1: 0.83, 95%CI: 0.49-1.41] and EA [OR_T2vsT1: 0.68, 95%CI: 0.41-1.11; OR_T3vsT1: 0.67, 95%CI: 0.40-1.11]) compared with the first tertile, though confidence intervals included the null. Greater 1,25(OH)₂D/25(OH)D molar ratios were associated with lower odds of high aggressive prostate cancer more evidently in AA (OR_Q4vsQ1: 0.45, CI: 0.24-0.82) than in EA (OR_Q4vsQ1: 0.64, CI: 0.35-1.17) research subjects.

Conclusions

The 1,25(OH)₂D/25(OH)D molar ratio was associated with decreased risk of high aggressive prostate cancer in AA men, and possibly in EA men. Further studies analyzing vitamin D polymorphisms, vitamin D binding protein levels, and prostatic levels of these metabolites may be useful. These studies may provide a better understanding of the vitamin D pathway and its biological role underlying health disparities in prostate cancer.

     

Evaluating the predictive accuracy and the clinical benefit of a nomogram aimed to predict survival in node‐positive prostate cancer patients: External validation on a multi‐institutional database

Objectives

To assess the predictive accuracy and the clinical value of a recent nomogram predicting cancer‐specific mortality‐free survival after surgery in pN1 prostate cancer patients through an external validation.

Methods

We evaluated 518 prostate cancer patients treated with radical prostatectomy and pelvic lymph node dissection with evidence of nodal metastases at final pathology, at 10 tertiary centers. External validation was carried out using regression coefficients of the previously published nomogram. The performance characteristics of the model were assessed by quantifying predictive accuracy, according to the area under the curve in the receiver operating characteristic curve and model calibration. Furthermore, we systematically analyzed the specificity, sensitivity, positive predictive value and negative predictive value for each nomogram‐derived probability cut‐off. Finally, we implemented decision curve analysis, in order to quantify the nomogram's clinical value in routine practice.

Results

External validation showed inferior predictive accuracy as referred to in the internal validation (65.8% vs 83.3%, respectively). The discrimination (area under the curve) of the multivariable model was 66.7% (95% CI 60.1–73.0%) by testing with receiver operating characteristic curve analysis. The calibration plot showed an overestimation throughout the range of predicted cancer‐specific mortality‐free survival rates probabilities. However, in decision curve analysis, the nomogram's use showed a net benefit when compared with the scenarios of treating all patients or none.

Conclusions

In an external setting, the nomogram showed inferior predictive accuracy and suboptimal calibration characteristics as compared to that reported in the original population. However, decision curve analysis showed a clinical net benefit, suggesting a clinical implication to correctly manage pN1 prostate cancer patients after surgery.

     

Impact of a novel biopsy instrument with a 25‐mm side‐notch needle on the detection of prostate cancer in transrectal biopsy

Objectives

To evaluate the impact of a novel biopsy instrument that extends the length of the side‐notch on the detection of prostate cancer in transrectal needle biopsy.

Methods

We collaborated with a biopsy needle manufacturer and developed a novel biopsy instrument (PRIMECUT II long‐notch type) with a 25‐mm side‐notch length and 28‐mm stroke length to take longer tissue cores. The sampled core length, cancer detection rate, pain and complications of 489 patients who underwent transrectal biopsy using the long‐notch needle were compared with those of 469 patients who underwent biopsy using a normal instrument with a 19‐mm side‐notch length and 22‐mm stroke length.

Results

The mean length of tissue taken by the long‐notch needle was significantly longer than that of tissue taken by the normal‐notch needle (16.3 vs 22.4 mm, P < 0.001). The overall cancer detection rate was 42.0% for the normal‐notch needle and 51.1% for the long‐notch needle (P = 0.005). In patients with a prostate volume of 20–40 mL, the cancer detection rate for the long‐notch needle was especially higher than that for the normal‐notch needle (74.2% vs 47.5%, P < 0.001). Multivariate analysis showed that the long‐notch needle improved cancer detection significantly (odds ratio 1.702, P < 0.001). There were no differences of pain during biopsy and complication between the two groups.

Conclusions

The novel biopsy instrument with a 25‐mm side‐notch can take longer tissue samples safely and has a significantly higher rate of prostate cancer detection in transrectal biopsy.

     

Primary whole‐gland ablation for localized prostate cancer with high‐intensity focused ultrasound: The important predictors of biochemical recurrence

Objectives

To identify predictive factors of biochemical recurrence for patients undergoing high‐intensity focused ultrasound treatment for localized prostate cancer.

Methods

We retrospectively identified patients receiving whole‐gland prostate ablation with high‐intensity focused ultrasound for localized prostate cancer from 2009 to 2015. All the patients received pre‐high‐intensity focused ultrasound radical transurethral resection of the prostate. We included perioperative parameters as follows: age, preoperative prostate volume, stage of operation, initial prostate‐specific antigen, T stage, postoperative prostate‐specific antigen nadir, Gleason score, time to prostate‐specific antigen nadir and the presence of prostate‐specific antigen biochemical recurrence. Multivariable Cox regression and Kaplan–Meier analysis were used for investigating predictors of recurrence, and receiver operating characteristic analysis was used for the cut‐off values of prostate‐specific antigen nadir.

Results

Among 182 patients, 26.9% had prostate‐specific antigen biochemical recurrence after high‐intensity focused ultrasound during the median follow‐up period of 32.21 months. Gleason score ≥7 (Gleason score 7, hazard ratio 2.877, P = 0.027), stage ≥T2b (T2b, hazard ratio 3.16, P = 0.027) and prostate‐specific antigen nadir (hazard ratio 1.11, P < 0.001) were statistically significant, whereas there was no significance in prostate volume and initial prostate‐specific antigen. We posit that a cut‐off level of prostate‐specific antigen nadir 0.43 ng/mL might be considered as an independent predictive factor for prostate‐specific antigen biochemical recurrence in high‐intensity focused ultrasound patients in multivariate analysis (P < 0.001, hazard ratio 7.39, 95% confidence interval 3.56–15.37), and created a new nadir‐related prediction model for biochemical recurrence prediction.

Conclusions

Postoperative prostate‐specific antigen nadir of 0.43 ng/mL can be considered an important predictive factor for biochemical recurrence in primary whole‐prostate gland high‐intensity focused ultrasound treatment, and the nadir‐related prediction model might provide a reference for early salvage treatment. Furthermore, Gleason score ≥7, stage ≥T2b might be associated with unfavorable outcomes, although prostate volume and higher initial prostate‐specific antigen appear not to be associated with biochemical recurrence for the high‐intensity focused ultrasound treatment.

     

Combination of solifenacin with tamsulosin reduces prostate volume and vascularity as opposed to tamsulosin monotherapy in patients with benign prostate enlargement and overactive bladder symptoms: Results from a randomized pilot study

Objectives

To identify the potential influence of antimuscarinics on morphometric parameters of the prostate in patients with benign prostatic enlargement and overactive bladder.

Methods

Non‐neurological patients with prostate volume >30 mL, predominately storage lower urinary tract symptoms, three or more urgency episodes per 24 h, maximum flow rate ≥10 mL/s and post‐void residual ≤100 mL were recruited for this study. They were randomized to receive either tamsulosin or tamsulosin + solifenacin. Patients were submitted to transrectal and transvesical ultrasonography, pressure‐flow study and prostate‐specific antigen test, and completed the International Prostate Symptom Score, bladder diary and overactive bladder questionnaire at induction and at 6 months. End‐study changes in morphometric prostate parameters (total prostate and adenoma volumes, prostate vascularity), as measured by transrectal ultrasound, were the principal outcomes.

Results

A reduction in total prostate volume (mean ?9.5%) was noted in the combination group, as opposed to an increase in the monotherapy group (+9.2%; P < 0.001). Similar changes were reflected in adenoma volume (monotherapy +17.4% vs combination ?12.5%, P = 0.001) and in prostate vascularity (monotherapy +149.3% vs combination ?19.8%, P = 0.001). Both treatment regimens improved the International Prostate Symptom Score (P = 0.001); monotherapy improved the voiding subscale (P = 0.01) more, whereas combination therapy improved the storage subscale (P = 0.024). Cystometric capacity improved in the combination group (P < 0.001). Post‐void residual was increased in the combination group (+34.79%), as opposed to a decrease in the monotherapy group (?17.05%; P = 0.001).

Conclusions

The results of this pilot study suggest that solifenacin might affect morphometric properties of the prostate, decreasing total prostate and adenoma volume, as well as vascularity. A molecular effect of antimuscarinics on the prostate, in parallel with their expected bladder effect, warrants further investigation.

     

En Bloc Resection of Primary Malignant Bone Tumor in the Cervical Spine Based on 3‐Dimensional Printing Technology

Objective

To investigate the feasibility and safety of en bloc resection of cervical primary malignant bone tumors by a combined anterior and posterior approach based on a three‐dimensional (3‐D) printing model.

Methods

Five patients with primary malignant bone tumors of the cervical spine underwent en bloc resection via a one‐stage combined anteroposterior approach in our hospital from March 2013 to June 2014. They comprised three men and two women of mean age 47.2 years (range, 26–67 years). Three of the tumors were chondrosarcomas and two chordomas. Preoperative 3‐D printing models were created by 3‐D printing technology. Sagittal en bloc resections were planned based on these models and successfully performed. A 360° reconstruction was performed by spinal instrumentation in all cases. Surgical margins, perioperative complications, local control rate and survival rate were assessed.

Results

All patients underwent en bloc excision via a combined posterior and anterior approach in one stage. Mean operative time and estimated blood loss were 465 minutes and 1290 mL, respectively. Mean follow‐up was 21 months. Wide surgical margins were achieved in two patients and marginal resection in three; these three patients underwent postoperative adjuvant radiation therapy. One vertebral artery was ligated and sacrificed in each of three patients. Nerve root involved by tumor was sacrificed in three patients with preoperative upper extremity weakness. One patient (Case 3) had significant transient radiculopathy with paresis postoperatively. Another (Case 4) with C ₄ and C ₅ chordoma had respiratory difficulties and pneumonia after surgery postoperatively. He recovered completely after 2 weeks’ management with a tracheotomy tube and antibiotics in the intensive care unit. No cerebrovascular complications and wound infection were observed. No local recurrence or instrumentation failure were detected during follow‐up.

Conclusion

Though technically challenging, it is feasible and safe to perform en bloc resection of cervical primary bone tumors. This is the most effective means of managing cervical spine tumors. Preoperative 3‐D printing modelling enables better anatomical understanding of the relationship between the tumor and cervical spine and can assist in planning the surgical procedure.

     

Effects of hexanic extract of serenoa repens (permixon® 160 mg) on inflammation biomarkers in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia

Background

Chronic prostatic inflammation (CPI) could be a cause of symptomatic or complicated benign prostatic hyperplasia (BPH). In previous in vitro and in vivo studies, Hexanic Extract of Serenoa repens (HESr) namely Permixon^® has demonstrated potent anti‐inflammatory properties. With the aim to provide new insight onto HESr anti‐inflammatory properties in human we explore its effect on CPI biomarkers in men with lower urinary tract symptoms (LUTS) related to BPH using a non‐invasive method and investigate links between biomarkers and clinical symptoms.

Methods

An international, randomized, double‐blind, parallel‐group, tamsulosin‐controlled study was carried out in 206 men with BPH‐related LUTS. Patients received oral daily HESr 320mg or tamsulosin 0.4 mg during 3 months. The first urine stream after digital rectal examination (DRE) was collected at Day 1 and Day 90 and mRNA was extracted from prostatic epithelial cells desquaming in the lumen of the glands and seminal plasma fluid after DRE. mRNA quantification of the 29 most significant published inflammation markers in BPH and protein detection in urine was performed.

Results

At D90, a decrease in mean gene expression was observed for 65.4% of the markers detected in the HESr group versus 46.2% in the tamsulosin group. In the 15 most frequently expressed genes, this difference was higher (80% vs. 33% respectively). Three proteins (MCP‐1/CCL2, IP‐10/CXCL10, and MIF) were detected. At D90, a decrease in the number of patients who expressed MCP‐1/CCL2 and IP‐10/CXCL10 was observed only in the HESr group. Moreover, MIF expression was significantly reduced by HESr compared with tamsulosin (P = 0.007). Finally, in contrast to tamsulosin, the subgroup of patients treated by HESr and who over expressed MIF at baseline, had a higher response to the International Prostate Symptom Score (I‐PSS) than those who did not over express this protein (mean I‐PSS change: ?6.4 vs. ?4.5 respectively). As the study is exploratory, results should be confirmed in a powered clinical study.

Conclusions

These results showed for the first time at clinical level the anti‐inflammatory properties of HESr, already indicated in BPH‐related LUTS. Thus, HESr could be of interest to prevent unfavourable evolution in patients with CPI. Prostate 75:1857–1867, 2015. © 2015 The Authors. The Prostate Published by Wiley Periodicals, Inc.