ResearchPad - prostate-gland https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Analytical performance of thrombospondin-1 and cathepsin D immunoassays part of a novel CE-IVD marked test as an aid in the diagnosis of prostate cancer]]> https://www.researchpad.co/article/elastic_article_15745 The Prostate Specific Antigen (PSA) test suffers from low specificity for the diagnosis of Prostate Cancer (PCa). We originally discovered two cancer-related proteins thrombospondin-1 (THBS1) and cathepsin D (CTSD) using a mass-spectrometry-based proteomics approach. The two serum proteins were shown to improve the diagnosis of high-grade PCa. Thus, we developed quantitative ELISAs for the determination of their concentration in human serum. Here we report their analytical performance in terms of limit of detection, specificity, precision, linearity and interferences, which were determined based on CLSI guidelines. Further, we investigated the influence of pre-analytical factors on concentration measurements. For this, blood from 4–6 donors was collected in different tubes and stored at room temperature for different times prior to centrifugation at different centrifugal forces and temperatures. Stability of THBS1 and CTSD under different storage temperatures was also evaluated. Our results show that the assays are specific, linear and sensitive enough to allow measurement of clinical samples. Precision in terms of repeatability and total within-laboratory coefficient of variation (CV) are 5.5% and 8.1% for THBS1 and 4.3% and 7.2% for CTSD, respectively. Relative laboratory-to-laboratory differences were -6.3% for THBS1 and -3% for CTSD. Both THBS1 and CTSD were stable in serum samples, with 80–120% recoveries of concentrations across donors, sample preparation and storage. In conclusion, the ELISAs as part of the novel commercial in vitro diagnostic test Proclarix are suitable for the use in clinical practice. THBS1 and CTSD can be accurately measured for their intended use independent of the lot and laboratory when conditions consistent with routine practice for PSA sampling and storage are used.

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<![CDATA[Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity]]> https://www.researchpad.co/article/elastic_article_14708 Estrogen receptor β (ERβ) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ERβ, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ERβ is expressed in both basal and luminal cells in the prostate while AR is expressed in luminal but not in the basal cell layer which harbors the prostate stem cells. To investigate the mechanisms of action of ERβ and its potential cross-talk with AR, we used RNA-seq to study the effects of estradiol or the synthetic ligand, LY3201, in AR-positive LNCaP PCa cells which had been engineered to express ERβ. Transcriptomic analysis indicated relatively few changes in gene expression with ERβ overexpression, but robust responses following ligand treatments. There is significant overlap of responsive genes between the two ligands, estradiol and LY3201 as well as ligand-specific alterations. Gene set analysis of down-regulated genes identified an enrichment of androgen-responsive genes, such as FKBP5, CAMKK2, and TBC1D4. Consistently, AR transcript, protein levels, and transcriptional activity were down-regulated following ERβ activation. In agreement with this, we find that the phosphorylation of the CAMKK2 target, AMPK, was repressed by ligand-activated ERβ. These findings suggest that ERβ-mediated signaling pathways are involved in the negative regulation of AR expression and activity, thus supporting a tumor suppressive role for ERβ in PCa.

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<![CDATA[Real-time adaptive planning method for radiotherapy treatment delivery for prostate cancer patients, based on a library of plans accounting for possible anatomy configuration changes]]> https://www.researchpad.co/article/5c818e8ad5eed0c484cc24c8

Background and purpose

In prostate cancer treatment with external beam radiation therapy (EBRT), prostate motion and internal changes in tissue distribution can lead to a decrease in plan quality. In most currently used planning methods, the uncertainties due to prostate motion are compensated by irradiating a larger treatment volume. However, this could cause underdosage of the treatment volume and overdosage of the organs at risk (OARs). To reduce this problem, in this proof of principle study we developed and evaluated a novel adaptive planning method. The strategy proposed corrects the dose delivered by each beam according to the actual position of the target in order to produce a final dose distribution dosimetrically as similar as possible to the prescribed one.

Material and methods

Our adaptive planning method was tested on a phantom case and on a clinical case. For the first, a pilot study was performed on an in-silico pelvic phantom. A “library” of intensity modulated RT (IMRT) plans corresponding to possible positions of the prostate during a treatment fraction was generated at planning stage. Then a 3D random walk model was used to simulate possible displacements of the prostate during the treatment fraction. At treatment stage, at the end of each beam, based on the current position of the target, the beam from the library of plans, which could reproduce the best approximation of the prescribed dose distribution, was selected and delivered. In the clinical case, the same approach was used on two prostate cancer patients: for the first a tissue deformation was simulated in-silico and for the second a cone beam CT (CBCT) taken during the treatment was used to simulate an intra-fraction change. Then, dosimetric comparisons with the standard treatment plan and, for the second patient, also with an isocenter shift correction, were performed.

Results

For the phantom case, the plan generated using the adaptive planning method was able to meet all the dosimetric requirements and to correct for a misdosage of 13% of the dose prescription on the prostate. For the first clinical case, the standard planning method caused underdosage of the seminal vesicles, respectively by 5% and 4% of the prescribed dose, when the position changes for the target were correctly taken into account. The proposed adaptive planning method corrected any possible missed target coverage, reducing at the same time the dose on the OARs. For the second clinical case, both with the standard planning strategy and with the isocenter shift correction target coverage was significantly worsened (in particular uniformity) and some organs exceeded some toxicity objectives. While with our approach, the most uniform coverage for the target was produced and systematically the lowest toxicity values for the organs at risk were achieved.

Conclusions

In our proof of principle study, the adaptive planning method performed better than the standard planning and the isocenter shift methods for prostate EBRT. It improved the coverage of the treatment volumes and lowered the dose to the OARs. This planning method is particularly promising for hypofractionated IMRT treatments in which a higher precision and control on dose deposition are needed. Further studies will be performed to test more extensively the proposed adaptive planning method and to evaluate it at a full clinical level.

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<![CDATA[Structured reporting of prostate magnetic resonance imaging has the potential to improve interdisciplinary communication]]> https://www.researchpad.co/article/5c75abfdd5eed0c484d07f7d

Background

Effective interdisciplinary communication of imaging findings is vital for patient care, as referring physicians depend on the contained information for the decision-making and subsequent treatment. Traditional radiology reports contain non-structured free text and potentially tangled information in narrative language, which can hamper the information transfer and diminish the clarity of the report. Therefore, this study investigates whether newly developed structured reports (SRs) of prostate magnetic resonance imaging (MRI) can improve interdisciplinary communication, as compared to non-structured reports (NSRs).

Methods

50 NSRs and 50 SRs describing a single prostatic lesion were presented to four urologists with expert level experience in prostate cancer surgery or targeted MRI TRUS fusion biopsy. They were subsequently asked to plot the tumor location in a 2-dimensional prostate diagram and to answer a questionnaire focusing on information on clinically relevant key features as well as the perceived structure of the report. A validated scoring system that distinguishes between “major” and “minor” mistakes was used to evaluate the accuracy of the plotting of the tumor position in the prostate diagram.

Results

The mean total score for accuracy for SRs was significantly higher than for NSRs (28.46 [range 13.33–30.0] vs. 21.75 [range 0.0–30.0], p < 0.01). The overall rates of major mistakes (54% vs. 10%) and minor mistakes (74% vs. 22%) were significantly higher (p < 0.01) for NSRs than for SRs. The rate of radiologist re-consultations was significantly lower (p < 0.01) for SRs than for NSRs (19% vs. 85%). Furthermore, SRs were rated as significantly superior to NSRs in regard to determining the clinical tumor stage (p < 0.01), the quality of the summary (4.4 vs. 2.5; p < 0.01), and overall satisfaction with the report (4.5 vs. 2.3; p < 0.01), and as more valuable for further clinical decision-making and surgical planning (p < 0.01).

Conclusions

Structured reporting of prostate MRI has the potential to improve interdisciplinary communication. Through SRs, expert urologists were able to more accurately assess the exact location of single prostate cancer lesions, which can facilitate surgical planning. Furthermore, structured reporting of prostate MRI leads to a higher satisfaction level of the referring physician.

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<![CDATA[Histogram analysis of prostate cancer on dynamic contrast-enhanced magnetic resonance imaging: A preliminary study emphasizing on zonal difference]]> https://www.researchpad.co/article/5c6c75d9d5eed0c4843d02ed

Background

This study evaluated the performance of histogram analysis in the time course of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for differentiating cancerous tissues from benign tissues in the prostate.

Methods

We retrospectively analyzed the histograms of DCE-MRI of 30 patients. Histograms within regions of interest(ROI) in the peripheral zone (PZ) and transitional zone (TZ) were separately analyzed. The maximum difference wash-in slope (MWS) and delay phase slope (DPS) were defined for each voxel. Differences in histogram parameters, namely the mean, standard deviation (SD), the coefficient of variation (CV), kurtosis, skewness, interquartile range (IQR), percentile (P10, P25, P75, P90, and P90P10), Range, and modified full width at half-maximum (mFWHM) between cancerous and benign tissues were assessed.

Results

In the TZ, CV for ROIs of 7.5 and 10mm was the only significantly different parameter of the MWS (P = 0.034 and P = 0.004, respectively), whereas many parameters of the DPS (mean, skewness, P10, P25, P50, P75 and P90) differed significantly (P = <0.001–0.016 and area under the curve [AUC] = 0.73–0.822). In the PZ, all parameters of the MWS exhibited significant differences, except kurtosis and skewness in the ROI of 7.5mm(P = <0.001–0.017 and AUC = 0.865–0.898). SD, IQR, mFWHM, P90P10 and Range were also significant differences in the DPS (P = 0.001–0.035).

Conclusion

The histogram analysis of DCE-MRI is a potentially useful approach for differentiating prostate cancer from normal tissues. Different histogram parameters of the MWS and DPS should be applied in the TZ and PZ.

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<![CDATA[Intensity-modulated radiotherapy for prostate cancer with seminal vesicle involvement (T3b): A multicentric retrospective analysis]]> https://www.researchpad.co/article/5c79b004d5eed0c4841e3c37

Objectives

No study has reported clinical results of external-beam radiotherapy specifically for T3b prostate cancer. The possibility of escalating the dose to the involved seminal vesicles (ISV) while respecting the dose constraints in the organs at risk is thus so far not clearly demonstrated. The objective of the study was to analyze the dose distribution and the clinical outcome in a large series of patients who received IMRT for T3b prostate cancer.

Materials and methods

This retrospective analysis included all patients who received IMRT and androgen deprivation therapy for T3b prostate cancer, between 2008 and 2017, in six French institutions, with available MRI images and dosimetric data.

Results

A total of 276 T3b patients were included. The median follow-up was 26 months. The median (range) prescribed doses (Gy) to the prostate and to the ISV were 77 (70–80) and 76 (46–80), respectively. The dose constraint recommendations were exceeded in less than 12% of patients for the rectum and the bladder. The 5-year risks of biochemical and clinical recurrences and cancer-specific death were 24.8%, 21.7%, and 10.3%, respectively. The 5-year risks of local, pelvic lymph node, and metastatic recurrences were 6.4%, 11.3%, and 15%, respectively. The number of involved lymph nodes (≤ 2 or ≥ 3) on MRI was the only significant prognostic factor in clinical recurrence (HR 9.86) and death (HR 2.78). Grade ≥ 2 acute and 5-year late toxicity rates were 13.2% and 12% for digestive toxicity, and 34% and 31.5% for urinary toxicity, respectively. The dose to the pelvic lymph node and the age were predictive of late digestive toxicity.

Conclusion

IMRT for T3b prostate cancer allows delivery of a curative dose in the ISV, with a moderate digestive toxicity but a higher urinary toxicity. Lymph node involvement increases the risk of recurrence and death.

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<![CDATA[Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate]]> https://www.researchpad.co/article/5c536a9fd5eed0c484a476f6

The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development.

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<![CDATA[A new plan quality objective function for determining optimal collimator combinations in prostate cancer treatment with stereotactic body radiation therapy using CyberKnife]]> https://www.researchpad.co/article/5c06f034d5eed0c484c6d3a1

Stereotactic body radiation therapy with CyberKnife for prostate cancer has long treatment times compared with conventional radiotherapy. This arises the need for designing treatment plans with short execution times. We propose an objective function for plan quality evaluation, which was used to determine an optimal combination between small and large collimators based on short treatment times and clinically acceptable dose distributions. Data from 11 prostate cancer patients were used. For each patient, 20 plans were created based on all combinations between one small (⌀ 10–25 mm) and one large (⌀ 35–60 mm) Iris collimator size. The objective function was assigned to each combination as a penalty, such that plans with low penalties were considered superior. This function considered the achievement of dosimetric planning goals, tumor control probability, normal tissue complication probability, relative seriality parameter, and treatment time. Two methods were used to determine the optimal combination. First, we constructed heat maps representing the mean penalty values and standard deviations of the plans created for each collimator combination. The combination giving a plan with the smallest mean penalty and standard deviation was considered optimal. Second, we created two groups of superior plans: group A plans were selected by histogram analysis and group B plans were selected by choosing the plan with the lowest penalty from each patient. In both groups, the most used small and large collimators were assumed to represent the optimal combination. The optimal combinations obtained from the heat maps included the 25 mm as a small collimator, giving small/large collimator sizes of 25/35, 25/40, 25/50, and 25/60 mm. The superior-group analysis indicated that 25/50 mm was the optimal combination. The optimal Iris combination for prostate cancer treatment using CyberKnife was determined to be a collimator size between 25 mm (small) and 50 mm (large).

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<![CDATA[Development of a prediction model for late urinary incontinence, hematuria, pain and voiding frequency among irradiated prostate cancer patients]]> https://www.researchpad.co/article/5b600f86463d7e3af00e5a8b

Background and purpose

Incontinence, hematuria, voiding frequency and pain during voiding are possible side effects of radiotherapy among patients treated for prostate cancer. The objective of this study was to develop multivariable NTCP models for these side effects.

Material and methods

This prospective cohort study was composed of 243 patients with localized or locally advanced prostate cancer (stage T1-3). Genito-urinary (GU) toxicity was assessed using a standardized follow-up program. The GU toxicity endpoints were scored using the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE 3.0) scoring system. The full bladder and different anatomical subregions within the bladder were delineated. A least absolute shrinkage and selection operator (LASSO) logistic regression analysis was used to analyze dose volume effects on the four individual endpoints.

Results

In the univariable analysis, urinary incontinence was significantly associated with dose distributions in the trigone (V55-V75, mean). Hematuria was significantly associated with the bladder wall dose (V40-V75, mean), bladder dose (V70-V75), cardiovascular disease and anticoagulants use. Pain during urinating was associated with the dose to the trigone (V50-V75, mean) and with trans transurethral resection of the prostate (TURP). In the final multivariable model urinary incontinence was associated with the mean dose of the trigone. Hematuria was associated with bladder wall dose (V75) and cardiovascular disease, while pain during urinating was associated with trigone dose (V75) and TURP. No significant associations were found for increase in voiding frequency.

Conclusions

Radiation-induced urinary side effects are associated with dose distributions to different organs as risk. Given the dose effect relationships found, decreasing the dose to the trigone and bladder wall may reduce the incidence of incontinence, pain during voiding and hematuria, respectively.

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<![CDATA[Effect of Preoperative Risk Group Stratification on Oncologic Outcomes of Patients with Adverse Pathologic Findings at Radical Prostatectomy]]> https://www.researchpad.co/article/5989da06ab0ee8fa60b75e10

Background

Current National Comprehensive Cancer Network guidelines recommend postoperative radiation therapy based only on adverse pathologic findings (APFs), irrespective of preoperative risk group. We assessed whether a model incorporating both the preoperative risk group and APFs could predict long-term oncologic outcomes better than a model based on APFs alone.

Methods

We retrospectively reviewed 4,404 men who underwent radical prostatectomy (RP) at our institution between 1992 and 2014. After excluding patients receiving neoadjuvant therapy or with incomplete pathological or follow-up data, 3,092 men were included in the final analysis. APFs were defined as extraprostatic extension (EPE), seminal vesicle invasion (SVI), or a positive surgical margin (PSM). The adequacy of model fit to the data was compared using the likelihood-ratio test between the models with and without risk groups, and model discrimination was compared with the concordance index (c-index) for predicting biochemical recurrence (BCR) and prostate cancer-specific mortality (PCSM). We performed multivariate Cox proportional hazard model and competing risk regression analyses to identify predictors of BCR and PCSM in the total patient group and each of the risk groups.

Results

Adding risk groups to the model containing only APFs significantly improved the fit to the data (likelihood-ratio test, p <0.001) and the c-index increased from 0.693 to 0.732 for BCR and from 0.707 to 0.747 for PCSM. A RP Gleason score (GS) ≥8 and a PSM were independently associated with BCR in the total patient group and also each risk group. However, only a GS ≥8 and SVI were associated with PCSM in the total patient group (GS ≥8: hazard ratio [HR] 5.39 and SVI: HR 3.36) and the high-risk group (GS ≥8: HR 6.31 and SVI: HR 4.05).

Conclusion

The postoperative estimation of oncologic outcomes in men with APFs at RP was improved by considering preoperative risk group stratification. Although a PSM was an independent predictor for BCR, only a RP GS ≥8 and SVI were associated with PCSM in the total patient and high-risk groups.

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<![CDATA[Inhibition of chronic prostate inflammation by hyaluronic acid through an immortalized human prostate stromal cell line model]]> https://www.researchpad.co/article/5989db5cab0ee8fa60be00cf

Benign prostatic hyperplasia (BPH) is the most common urologic disease among elderly men. A well-established in vitro cell model is required to determine the therapeutic mechanism of BPH inflammation. In this study, we attempted to establish an immortalized human prostate stromal cell line by transfecting with HPV-16 E6/E7 and designated as ihPSC. No significant difference was found in fibroblast-like morphology between primary hPSC and ihPSC. The ihPSC possessed a significantly higher cell proliferation rate than primary hPSC. The prostate-specific markers and proteins including cytoskeleton (α-SMA and vimentin) and smooth muscle (calponin), especially the androgen receptor (AR) were also examined in ihPSC, almost identical to the primary hPSC. To create an in vitro model featuring chronic prostatic inflammation, ihPSC was stimulated with IFN-γ+IL-17 and then treated with the high molecular weight hyaluronic acid hylan G-F 20 as an alternative strategy for inhibiting BPH inflammation. Hylan G-F 20 could dose-dependently diminish the inflammation-induced proliferation in ihPSC. The enhanced expressions of inflammatory molecules including IL-1β, IL-6, IL-8, cyclooxygenase 2 (COX2), inducible nitrogen oxide synthase (iNOS), and Toll-like receptor 4 (TLR4) were all abolished by hylan G-F 20. For inflammatory signaling, hylan G-F 20 can also diminish the IFN-γ+IL-17-increased expression of iNOS and p65 in ihPSC. These findings suggest that ihPSC could provide a mechanism-based platform for investigating prostate inflammation. The hylan G-F 20 showed strong anti-inflammatory effects by decreasing inflammatory cytokines and signalings in the ihPSC, indicating its therapeutic potentials in BPH treatment in the future.

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<![CDATA[Exposure to maternal obesogenic diet worsens some but not all pre-cancer phenotypes in a murine genetic model of prostate cancer]]> https://www.researchpad.co/article/5989db5aab0ee8fa60bdf69f

Prostate cancer research has been predominantly focused on adult exposures and risk factors. However, because the prostate develops during gestation and early life, exposure to external factors, such as obesity, during development could affect the prostate cancer progression in adults. Our previous work demonstrated that exposure to a high fat/high sugar (HF/HS) diet during gestation and until weaning stimulated prostate hyperplasia and altered the Pten/Akt pathway in adult mice fed a normal diet after weaning. Here, we asked whether maternal exposure to HF/HS would worsen prostate phenotypes in mice lacking Pten, a widely accepted driver of prostate cancer. We found that, at six weeks of age, both Chow (control)—and HF/HS-exposed Pten knockout mice showed evidence of murine PIN that included ducts with central comedo necrosis but that the HF/HS exposure did not influence murine PIN progression. The Pten knockout mice exposed to HF/HS in utero had significantly more mitotic cells than Pten knockouts exposed to Chow diet. In the Pten null background, the maternal HF/HS diet enhanced proliferation but did not have an additive effect on Akt activation. We observed neuroendocrine differentiation in Pten knockout mice, a phenotype that had not been previously described in this model.

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<![CDATA[Diagnostic value of urodynamic bladder outlet obstruction to select patients for transurethral surgery of the prostate: Systematic review and meta-analysis]]> https://www.researchpad.co/article/5989db4fab0ee8fa60bdbc43

Purpose

To investigate the diagnostic value of urodynamic bladder outlet obstruction (BOO) in the selection of patients for transurethral surgery of the prostate.

Materials and methods

We systematically searched online PubMed, Embase, and Cochrane Library databases from January 1989 to June 2014.

Results

A total of 19 articles met the eligibility criteria for this systematic review. The eligible studies included a total of 2321 patients with a median number of 92 patients per study (range: 12–437). Of the 19 studies, 15 conducted conventional transurethral prostatectomy (TURP), and 7 used other or multiple modalities. In urodynamic bladder outlet obstruction (BOO) positive patients, the pooled mean difference (MD) was significant for better improvement of the International Prostate Symptom Score (IPSS) (pooled MD, 3.48; 95% confidence interval [CI], 1.72–5.24; p < 0.01; studies, 16; participants, 1726), quality of life score (QoL) (pooled MD, 0.56; 95% CI, 0.14–1.02; p = 0.010; studies, 9; participants, 1052), maximal flow rate (Qmax) (pooled MD, 3.86; 95% CI, 2.17–5.54; p < 0.01; studies, 17; participants, 1852), and post-void residual volume (PVR) (pooled MD, 32.46; 95% CI, 23.34–41.58; p < 0.01; studies, 10; participants, 1219) compared with that in non-BOO patients. Some comparisons showed between-study heterogeneity despite the strict selection criteria of the included studies. However, there was no clear evidence of publication bias in this meta-analysis.

Conclusions

Our meta-analysis results showed a significant association between urodynamic BOO and better improvements in all treatment outcome parameters. Preoperative UDS may add insight into postoperative outcomes after surgical treatment of benign prostatic hyperplasia.

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<![CDATA[Quantification of Arachidonic Acid and Its Metabolites in Rat Tissues by UHPLC-MS/MS: Application for the Identification of Potential Biomarkers of Benign Prostatic Hyperplasia]]> https://www.researchpad.co/article/5989da04ab0ee8fa60b75457

To evaluate the potential relationship between benign prostatic hyperplasia (BPH) and the arachidonic acid (AA) metabolome, a UHPLC—MS/MS method has been developed and validated for simultaneous determination of AA and its cyclooxygenase(COX) and lipoxygenase(LOX) pathway metabolites (15-HETE, 12-HETE, TXA2, 5-HETE, AA, PGI2, PGF, 8-HETE, PGD2, PGE2 and LTB4) in rat tissues. The analytes were extracted from tissue samples with a protein precipitation procedure and then separated on a Shim-pack XR-ODSC18 column with 0.05% formic acid in water (pH adjusted with dilute ammonia) and methanol:acetonitrile (20:80, v/v). Detection was performed on a UHPLC—MS/MS system with electrospray negative ionization (ESI) and a multiple reaction-monitoring mode. The lower limits of quantification (LLOQ) were 0.25–50 ng/mL for all of the analytes in the prostate, seminal, bladder, liver and kidney tissues. The absolute recoveries of the analytes from all of the tissues were more than 50%. By means of the method developed, the AA metabolites in tissue samples from Sham and BPH group rats were determined. The eleven biomarkers in the BPH group prostate, seminal, bladder, liver and kidney tissues were significantly higher than those of the sham group, indicating that BPH fortified the inducible expression of COX and LOX, as well as increased the production of AA and eicosanoids. The method described here offers a useful tool for the evaluation of complex regulatory eicosanoids responses in vivo.

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<![CDATA[Gene Expression Differences in Prostate Cancers between Young and Old Men]]> https://www.researchpad.co/article/5989da05ab0ee8fa60b75a21

Prostate cancer incidence is increasing in younger men. We investigated whether men diagnosed with Gleason 7 (3+4) T2 prostate cancer at younger ages (≤ 45 years, young cohort) had different mRNA and miRNA expression profiles than men diagnosed at older ages (71–74 years, older cohort). We identified differentially expressed genes (DEGs) related to tumor-normal differences between the cohorts. Subsequent pathway analysis of DEGs revealed that the young cohort had significantly more pronounced inflammatory and immune responses to tumor development compared to the older cohort. Further supporting a role of inflammation-induced immune-suppression in the development of early-onset prostate cancer, we observed significant up-regulation of CTLA4 and IDO1/TDO2 pathways in tumors of the young cohort. Moreover, over-expression of CTLA4 and IDO1 was significantly associated with biochemical recurrence. Our results provide clues on the mechanisms of tumor development and point to potential biomarkers for early detection and treatment for prostate cancer in young men.

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<![CDATA[Multi-drug loaded micelles delivering chemotherapy and targeted therapies directed against HSP90 and the PI3K/AKT/mTOR pathway in prostate cancer]]> https://www.researchpad.co/article/5989db50ab0ee8fa60bdc10e

Background

Advanced prostate cancers that are resistant to all current therapies create a need for new therapeutic strategies. One recent innovative approach to cancer therapy is the simultaneous use of multiple FDA-approved drugs to target multiple pathways. A challenge for this approach is caused by the different solubility requirements of each individual drug, resulting in the need for a drug vehicle that is non-toxic and capable of carrying multiple water-insoluble antitumor drugs. Micelles have recently been shown to be new candidate drug solubilizers for anti cancer therapy.

Methods

This study set out to examine the potential use of multi-drug loaded micelles for prostate cancer treatment in preclinical models including cell line and mouse models for prostate cancers with Pten deletions. Specifically antimitotic agent docetaxel, mTOR inhibitor rapamycin, and HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin were incorporated into the micelle system (DR17) and tested for antitumor efficacy.

Results

In vitro growth inhibition of prostate cancer cells was greater when all three drugs were used in combination compared to each individual drug, and packaging the drugs into micelles enhanced the cytotoxic effects. At the molecular level DR17 targeted simultaneously several molecular signaling axes important in prostate cancer including androgen receptor, mTOR, and PI3K/AKT. In a mouse genetic model of prostate cancer, DR17 treatment decreased prostate weight, which was achieved by both increasing caspase-dependent cell death and decreasing cell proliferation. Similar effects were also observed when DR17 was administered to nude mice bearing prostate cancer cells xenografts.

Conclusion

These results suggest that combining these three cancer drugs in multi-drug loaded micelles may be a promising strategy for prostate cancer therapy.

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<![CDATA[The Zinc-Schiff Base-Novicidin Complex as a Potential Prostate Cancer Therapy]]> https://www.researchpad.co/article/5989db4cab0ee8fa60bda8e3

Prostate cancer cells control energy metabolism by chelating intracellular zinc. Thus, zinc delivery has been a popular therapeutic approach for prostate cancer. Here, we propose the use of the membrane-penetrating peptide Novicidin connected to zinc-Schiff base as a carrier vehicle for the delivery of zinc to prostate cells. Mass spectrometry, electrochemistry and spectrophotometry confirmed the formation/stability of this complex and provided insight regarding the availability of zinc for complex interactions. This delivery system showed minor toxicity in normal PNT1A cells and high potency towards PC3 tumor cells. The complex preferentially penetrated PC3 tumor cells in contrast to confinement to the membranes of PNT1A. Furthermore, zinc uptake was confirmed in both cell lines. Molecular analysis was used to confirm the activation of zinc stress (e.g., ZnT-1) and apoptosis (e.g., CASP-1). Our results strongly suggest that the zinc-Schiff base-Novicidin complex has great potential as a novel anticancer drug.

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<![CDATA[Deformable registration of 3D ultrasound volumes using automatic landmark generation]]> https://www.researchpad.co/article/5c95523ed5eed0c4846f322e

US image registration is an important task e.g. in Computer Aided Surgery. Due to tissue deformation occurring between pre-operative and interventional images often deformable registration is necessary. We present a registration method focused on surface structures (i.e. saliencies) of soft tissues like organ capsules or vessels. The main concept follows the idea of representative landmarks (so called leading points). These landmarks represent saliencies in each image in a certain region of interest. The determination of deformation was based on a geometric model assuming that saliencies could locally be described by planes. These planes were calculated from the landmarks using two dimensional linear regression. Once corresponding regions in both images were found, a displacement vector field representing the local deformation was computed. Finally, the deformed image was warped to match the pre-operative image. For error calculation we used a phantom representing the urinary bladder and the prostate. The phantom could be deformed to mimic tissue deformation. Error calculation was done using corresponding landmarks in both images. The resulting target registration error of this procedure amounted to 1.63 mm. With respect to patient data a full deformable registration was performed on two 3D-US images of the abdomen. The resulting mean distance error was 2.10 ± 0.66 mm compared to an error of 2.75 ± 0.57 mm from a simple rigid registration. A two-sided paired t-test showed a p-value < 0.001. We conclude that the method improves the results of the rigid registration considerably. Provided an appropriate choice of the filter there are many possible fields of applications.

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<![CDATA[Feature Selection and Cancer Classification via Sparse Logistic Regression with the Hybrid L1/2 +2 Regularization]]> https://www.researchpad.co/article/5989dad0ab0ee8fa60bb5d2c

Cancer classification and feature (gene) selection plays an important role in knowledge discovery in genomic data. Although logistic regression is one of the most popular classification methods, it does not induce feature selection. In this paper, we presented a new hybrid L1/2 +2 regularization (HLR) function, a linear combination of L1/2 and L2 penalties, to select the relevant gene in the logistic regression. The HLR approach inherits some fascinating characteristics from L1/2 (sparsity) and L2 (grouping effect where highly correlated variables are in or out a model together) penalties. We also proposed a novel univariate HLR thresholding approach to update the estimated coefficients and developed the coordinate descent algorithm for the HLR penalized logistic regression model. The empirical results and simulations indicate that the proposed method is highly competitive amongst several state-of-the-art methods.

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<![CDATA[Association between Adult Height and Risk of Colorectal, Lung, and Prostate Cancer: Results from Meta-analyses of Prospective Studies and Mendelian Randomization Analyses]]> https://www.researchpad.co/article/5989da26ab0ee8fa60b80c95

Background

Observational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using height-associated genetic variants identified in a genome-wide association study (GWAS), to evaluate the association of adult height with these cancers.

Methods and Findings

A systematic review of prospective studies was conducted using the PubMed, Embase, and Web of Science databases. Using meta-analyses, results obtained from 62 studies were summarized for the association of a 10-cm increase in height with cancer risk. Mendelian randomization analyses were conducted using summary statistics obtained for 423 genetic variants identified from a recent GWAS of adult height and from a cancer genetics consortium study of multiple cancers that included 47,800 cases and 81,353 controls. For a 10-cm increase in height, the summary relative risks derived from the meta-analyses of prospective studies were 1.12 (95% CI 1.10, 1.15), 1.07 (95% CI 1.05, 1.10), and 1.06 (95% CI 1.02, 1.11) for colorectal, prostate, and lung cancers, respectively. Mendelian randomization analyses showed increased risks of colorectal (odds ratio [OR] = 1.58, 95% CI 1.14, 2.18) and lung cancer (OR = 1.10, 95% CI 1.00, 1.22) associated with each 10-cm increase in genetically predicted height. No association was observed for prostate cancer (OR = 1.03, 95% CI 0.92, 1.15). Our meta-analysis was limited to published studies. The sample size for the Mendelian randomization analysis of colorectal cancer was relatively small, thus affecting the precision of the point estimate.

Conclusions

Our study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers.

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