Early Stage Prostate Cancer Research Articles

Detection of N,N-diacetyllactosamine (LacdiNAc) containing free prostate-specific antigen for early stage prostate cancer diagnostics and for identification of castration-resistant prostate cancer patients

Prostate cancer (PCa) is one of the most common cancer types among men and also acommon cause of death globally. With an increasing incidence, there is aneed for low-cost, reliable biomarkers present in samples, which could be provided non-invasively (without a need to perform prostate biopsy). Glycosylation changes of free-PSA (fPSA) are considered cancer-specific, while the level of different PSA forms can increase under other than cancerous conditions. In the present study, we investigated the role ofN,N-diacetyllactosamine (LacdiNAc) epitope of fPSA (i.e. glycoprofile of fPSA or gPSA) in combination with total-PSA (tPSA), prostate volume, and tPSA density (tPSA level divided by prostate volume i.e. PSAd) as biomarkers for monitoring of PCa development and progression in 105 men. Furthermore, we applied an genetic (evolutionary) algorithm to identify any suspicious individuals in abenign cohort having benign prostatic hyperplasia (BPH). We identified 3 suspicious men originally diagnosed with BPH using gPSA analysis. In thefollow-up we found out that two men should not be considered as BPH patients since multiparametric magnetic resonance imaging (mpMRI) identified one man with clinically significant PCa via Prostate Imaging – Reporting and Data System (PI RADS v2 = 4) and the second man was with High-gradeprostatic intraepithelial neoplasia (HG PIN), commonly described as apre-cancerous stage. Moreover, in the study we described for the first time that changed LacdiNAc on PSA can be applied to identify prostatitis patients and most importantly this is the first study suggesting that changed glycosylation on PSA can be applied to identify castration-resistant prostate cancer (CRPCa) patients.

Quo Vadis Advanced Prostate Cancer Therapy? Novel Treatment Perspectives and Possible Future Directions.

Prostate cancer is a very common disease, which is, unfortunately, often the cause of many male deaths. This is underlined by the fact that the early stages of prostate cancer are often asymptomatic. Therefore, the disease is usually detected and diagnosed at late advanced or even metastasized stages, which are already difficult to treat. Hence, it is important to pursue research and development not only in terms of novel diagnostic methods but also of therapeutic ones, as well as to increase the effectiveness of the treatment by combinational medicinal approach. Therefore, in this review article, we focus on recent approaches and novel potential tools for the treatment of advanced prostate cancer; these include not only androgen deprivation therapy, antiandrogen therapy, photodynamic therapy, photothermal therapy, immunotherapy, multimodal therapy, but also poly(ADP-ribose) polymerase, Akt and cyclin-dependent kinase inhibitors.

Ultrasound-guided transrectal implantation of fiducial markers for image-guided radiotherapy of prostate cancer without local anesthesia: Patient-reported gastrointestinal-genitourinary system complications and pain.

The present study evaluates procedure-associated pain and side effects in the gastrointestinal-genitourinary system in patients with early-stage prostate cancer who were treated with image-guided radiotherapy (IGRT), accompanied by an ultrasound-guided transrectal implantation of fiducial markers, without local anesthesia. A total of 46 patients who referred to our clinics between 2012 and 2017 with a diagnosis of early-stage prostate cancer were included in the study. Before undergoing radiotherapy, all patients were implanted with three intraprostatic fiducial markers through the ultrasound-guided transrectal approach without local anesthesia. The patients underwent radiotherapy after the clinical target volumes were established, in accordance with the respective risk groups, and localization of the markers was confirmed before each therapy session. The levels of procedure-associated pain and side effects were graded immediately after the procedure through the use of a patient-based scoring system. The faces pain scale - revised version was used for the measurement of the severity of procedure-associated pain. Of the total study sample, the facial expressions of 38 patients (35%) corresponded to level 0 in the study, seven (15%) to level 2, and a single patient (2%) to level 4. None of the facial expressions of the patients corresponded to levels 6, 8, or 10. The evaluation of procedure-related genitourinary and gastrointestinal system side effects indicated that nine patients (20%) experienced side effects, while no side effects were reported in 37 patients (80%). The reported side effects included rectal bleeding in two patients (4%), dysuria in three patients (6%), hematuria in five patients (11%), and frequent urination in five patients (11%). None of the patients experienced fever or hematospermia. All side effects were reported by the respondents as "a little," while only one patient answered positively to the question on the frequency of urination. Among the patients who answered "yes" and "a little" to the questions evaluating genitourinary and gastrointestinal system side effects, the severity of these events was reported as Grade 1, corresponding to mild adverse, in only 9 (20%) patients. None of the patients experienced a Grade 2 or higher severe adverse event. In the comparison of the severity of pain of the patients during the fiducial marker procedure without local anesthesia with the severity of pain during the biopsy, 24 patients (80%) reported "lower" levels of pain, while five patients (20%) reported "equal" levels of pain. None of the patients stated that they had experienced "more" pain. IGRT accompanied by an ultrasound-guided implantation of fiducial markers without local anesthesia can be considered a safe method, given the associated acceptable levels of pain, low side effect profiles, and high prostate-specific antigen control rates.

Assessment of Simulated SARS-CoV-2 Infection and Mortality Risk Associated With Radiation Therapy Among Patients in 8 Randomized Clinical Trials

During the COVID-19 pandemic, cancer therapy may put patients at risk of SARS-CoV-2 infection and mortality. The impacts of proposed alternatives on reducing infection risk are unknown. To investigate how the COVID-19 pandemic is associated with the risks and benefits of standard radiation therapy (RT). This comparative effectiveness study used estimated individual patient-level data extracted from published Kaplan-Meier survival figures from 8 randomized clinical trials across oncology from 1993 to 2014 that evaluated the inclusion of RT or compared different RT fractionation regimens. Included trials were Dutch TME and TROG 01.04 examining rectal cancer; CALGB 9343, OCOG hypofractionation trial, FAST-Forward, and NSABP B-39 examining early stage breast cancer, and CHHiP and HYPO-RT-PC examining prostate cancer. Risk of SARS-CoV-2 infection and mortality associated with receipt of RT in the treatment arms were simulated and trials were reanalyzed. Data were analyzed between April 1, 2020, and June 30, 2020. COVID-19 risk associated with treatment was simulated across different pandemic scenarios, varying infection risk per fractions (IRFs) and case fatality rates (CFRs). Overall survival was evaluated using Cox proportional hazards modeling under different pandemic scenarios. Estimated IPLD from a total of 14 170 patients were included in the simulations. In scenarios with low COVID-19-associated risks (IRF, 0.5%; CFR, 5%), fractionation was not significantly associated with outcomes. In locally advanced rectal cancer, short-course RT was associated with better outcomes than long-course chemoradiation (TROG 01.04) and was associated with similar outcomes as RT omission (Dutch TME) in most settings (eg, TROG 01.04 median HR, 0.66 [95% CI, 0.46-0.96]; Dutch TME median HR, 0.91 [95% CI, 0.80-1.03] in a scenario with IRF 5% and CFR 20%). Moderate hypofractionation in early stage breast cancer (OCOG hypofractionation trial) and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19 (eg, OCOG hypofractionation trial median HR, 0.89 [95% CI, 0.74-1.06]; CHHiP median HR, 0.87 [95% CI, 0.75-1.01] under high-risk scenario with IRF 10% and CFR 30%). More aggressive hypofractionation (FAST-Forward, HYPO-RT-PC) and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios (eg, FAST-Forward median HR, 0.58 [95% CI, 0.49-0.68]; HYPO-RT-PC median HR, 0.60 [95% CI, 0.48-0.75] under scenario with IRF 10% and CFR 30%). In this comparative effectiveness study of data from 8 clinical trials of patients receiving radiation therapy to simulate COVID-19 risk and mortality rates, treatment modification was not associated with altered risk from COVID-19 in lower-risk scenarios and was only associated with decreased mortality in very high COVID-19-risk scenarios. This model, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the potential impact of treatment modifications and supports the continued delivery of standard evidence-based care with appropriate precautions against COVID-19.

A Caenorhabditis elegans behavioral assay distinguishes early stage prostate cancer patient urine from controls.

ABSTRACTCurrent methods for non-invasive prostate cancer (PrCa) detection have a high false-positive rate and often result in unnecessary biopsies. Previous work has suggested that urinary volatile organic compound (VOC) biomarkers may be able to distinguish PrCa cases from benign disease. The behavior of the nematode Caenorhabditis elegans has been proposed as a tool to take advantage of these potential VOC profiles. To test the ability of C. elegans Bristol N2 to distinguish PrCa cases from controls, we performed chemotaxis assays using human urine samples collected from men screened for PrCa. Behavioral response of nematodes towards diluted urine from PrCa cases was compared to response to samples from cancer-free controls. Overall, we observed a significant attraction of young adult-stage C. elegans nematodes to 1:100 diluted urine from confirmed PrCa cases and repulsion of C. elegans to urine from controls. When C. elegans chemotaxis index was considered alongside prostate-specific antigen levels for distinguishing cancer from cancer-free controls, the accuracy of patient classification was 81%. We also observed behavioral attraction of C. elegans to two previously reported VOCs to be increased in PrCa patient urine. We conclude nematode behavior distinguishes PrCa case urine from controls in a dilution-dependent manner.

Abstract P26: Re-analyzing randomized trials with incorporation of COVID-19 risk associated with cancer therapy

Abstract Background: Cancer therapy may put patients at risk of mortality from COVID-19. The impact of abbreviated treatment courses on outcomes in the setting of COVID-19 is unknown. We incorporated COVID-19-associated risks in re-analysis of practice-defining randomized trials in oncology that compared different radiation therapy (RT) regimens. Methods: We extracted individual patient level data (IPLD) from published survival curves from randomized trials in rectal cancer (Dutch TME, TROG 01.04), early stage breast cancer (CALGB 9343, OCOG hypofractionation trial, FAST-Forward, NSABP B-39), and localized prostate cancer (CHHiP, HYPO-RT-PC). Trials were simulated with incorporation of varying risk of SARS-CoV-2 infection and mortality associated with receipt of therapy. Results: IPLD from 14,170 patients were re-analyzed. In scenarios with low COVID-19-associated risks (0.5% infection risk per fraction [IRF], 5% case fatality rate [CFR]), fractionation did not significantly affect outcomes. In locally advanced rectal cancer, short-course RT appeared preferable to long-course chemoradiation (TROG 01.04) or RT omission (Dutch TME) in most settings. While moderate hypofractionation in early stage breast cancer (OCOG hypofractionation trial) and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19, more aggressive hypofractionation (FAST-Forward, HYPO-RT-PC) and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios (≥5% IRF; ≥ 20% CFR). In settings where RT can be omitted, such as favorable early stage breast cancer in the elderly (CALGB 9343), RT was associated with worse survival in higher risk pandemic scenarios (≥5% IRF, ≥ 20% CFR). Conclusions: Our framework, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the impact of treatment recommendations across oncology. The magnitude of potential benefit from abbreviated RT courses depends on the degree of hypofractionation and local COVID-19-associated risk. Abbreviated RT courses should be prioritized when possible and are increasingly beneficial in higher risk pandemic settings. With increased understanding and precautions against COVID-19 that can minimize risks for patients, our results support the continued use of evidence-based treatments for cancer patients in the COVID-19 era. Citation Format: Shervin Tabrizi, Lorenzo Trippa, Daniel Cagney, Ayal A. Aizer, Shyam Tanguturi, Steffen Ventz, Geoffrey Fell, Jennifer R. Bellon, Harvey Mamon, Paul Nguyen, Anthony V. D'Amico, Daphne Haas-Kogan, Brian M. Alexander, Rifaquat Rahman. Re-analyzing randomized trials with incorporation of COVID-19 risk associated with cancer therapy [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P26.

P2PSA-associated parameters are significant predictors of reclassification of first-year protocol biopsy on active surveillance for early-stage prostate cancer patients: From the PRIAS-JAPAN study.

153 Background: 44 Japanese institutions have joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study as PRIAS-JAPAN. As an side study, PRIAS-JAPAN investigates the usefulness of [-2] proPSA (p2PSA), a precursor of PSA, as a predictive marker for the reclassification during active surveillance patients. In this study, we aimed to evaluate the usefulness of p2PSA related parameters to predict the reclassification of first year protocol biopsy (1yr PBx). Methods: 19 institutions participated in this side study which started in January 2013. All participants were eligible for PRAIS inclusion criteria. These patients were required to receive blood sampling on every visit and protocol biopsy after inclusion. PSA and PSA isoforms (free-PSA, p2PSA) were measured in serum samples and parameters (%free-PSA, %p2PSA, phi) were also calculated. Mann-Whitney U test was used to compare continuous variables between reclassification and non-reclassification groups. Fisher's exact test and Chi-squared test with yates' continuity correction were used for categorical variables. Multivariable logistic regression models were used to predict the risk of reclassification. To assess the predictive power for reclassification, we plotted ROC curves and calculated the AUC. Decision curve analysis (DCA) was used to evaluate whether adding variables to the baseline (age, PSA, prostate volume) model would yield net clinical benefit. Results: From January 2013 to July 2017, this study enrolled 237patients. 99 patients were excluded for the reason of discontinuation of AS, non-adherence of protocol blood sampling and rejection of biopsy. 138patients were able to analyzed PSA, PSA isoforms and its parameters at the time of inclusion and 1yr PBx. Patients who showed reclassification were significantly higher level of %p2PSA at inclusion and %p2PSA and phi just before 1yr PBx. Multivariate analyses showed %p2PSA at inclusion (p= 0.04), %p2PSA (p= 0.01) and Phi (p= 0.008) before 1yr PBx were statistically significant predictors of reclassification at 1yr PBx. ROC analysis revealed that %p2PSA before 1yr PBx (AUC 0.674) and phi before 1yr PBx (AUC 0.669) were a significant discriminant factor in predicting reclassification. DCA analysis showed that phi before 1yr PBx had a highest net benefit in the range of clinically plausible risk threshold (10–40%). Conclusions: %p2PSA and Phi before 1yr PBx have good prediction power and phi is a most useful indicator of clinical decision making about active surveillance. Clinical trial information: UMIN 000009876.

Characterization of the perioperative changes of exosomal immune-related cytokines induced by prostatectomy in early-stage prostate cancer patients

BackgroundMyeloid-derived suppressor cells (MDSCs) are relevant in prostate cancer microenvironment collaborating in tumor development. The main tumor marker used in this disease, prostate-specific antigen (PSA), does not provide information related to this tumor microenvironment. Cancer cells secrete exosomes carrying bioactive molecules contributing to MDSCs recruitment and induction. The aim of this study was to characterize the perioperative changes of exosomal cytokines relevant in MDSCs recruitment induced by prostatectomy in prostate cancer patients. MethodsBlood was drawn from 26 early-stage prostate cancer patients before and after radical prostatectomy and from 16 healthy volunteers. Serum exosomes were separated by precipitation. Cytokines related with MDSC cell recruitment and activation CCL2, CXCL2, CXCL5, CXCL8, CXCL12, MIF, S100A9 and TGF-ß were measured in serum and serum-derived exosomes using immunometric assays. ResultsAll cytokines were detected both in serum and exosomes, except for CXCL12, which was detected only in serum. Exosomes were enriched specially in MIF, TGF-ß and CXCL2. Presurgical MIF levels in exosomes correlated negatively with serum PSA. Also, presurgical TGF-ß decreased both in serum and exosomes as Gleason score rises. Patientś presurgical exosomes had increased CCL2, CXCL5 and TGF-ß levels than exosomes from healthy controls. These differences were not observed when cytokines were analyzed in serum, except for TGF-ß. Cytokine levels of CCL2, CXCL5 decreased in patients’ postsurgical exosomes, while TGF-ß further increased. On the contrary, S100A9 levels were lower in patientś presurgical exosomes but increased after radical prostatectomy. ConclusionsBlood exosomal content in cytokines constitute an attractive source to evaluate MDSCs immunomodulators providing additional information related to tumor microenvironment in prostate cancer.

A Pooled Toxicity Analysis of Moderately Hypofractionated Proton Beam Therapy and Intensity Modulated Radiation Therapy in Early-Stage Prostate Cancer Patients.

Data comparing moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) are lacking. We aim to compare late toxicity profiles of patients with early-stage prostate cancer treated with moderately hypofractionated PBT and IMRT. This multi-institutional analysis included patients with low- or intermediate-risk biopsy-proven prostate adenocarcinoma from 7 tertiary referral centers treated from 1998 to 2018. All patients were treated with moderately hypofractionated radiation, defined as 250 to 300 cGy per daily fraction given for 4 to 6 weeks, and stratified by use of IMRT or PBT. Primary outcomes were late genitourinary (GU) and gastrointestinal (GI) toxicity. Adjusted toxicity rates were calculated using inverse probability of treatment weighting, accounting for race, National Comprehensive Cancer Network risk group, age, pretreatment International Prostate Symptom Score (GU only), and anticoagulant use (GI only). A total of 1850 patients were included: 1282 IMRT (median follow-up 80.0 months) and 568 PBT (median follow-up 43.9 months). Overall toxicity rates were low, with the majority of patients experiencing no late GU (56.6%, n = 1048) or late GI (74.4%, n = 1377) toxicity. No difference was seen in the rates of late toxicity between the groups, with late grade 3+ GU toxicity of 2.0% versus 3.9% (odds ratio [OR] 0.47; 95% confidence interval 0.17-1.28) and late grade 2+ GI toxicity of 14.6% versus 4.7% (OR 2.69; confidence interval 0.80-9.05) for the PBT and IMRT cohorts, respectively. On multivariable analysis, no factors were significantly predictive of GU toxicity, and only anticoagulant use was significantly predictive of GI toxicity (OR 1.90; P = .008). In this large, multi-institutional analysis of 1850 patients with early-stage prostate cancer, treatment with moderately hypofractionated IMRT and PBT resulted in low rates of toxicity. No difference was seen in late GI and GU toxicity between the modalities during long-term follow-up. Both treatments are safe and well tolerated.

Value of 11C-Choline PET/CT-Based Multi-Metabolic Parameter Combination in Distinguishing Early-Stage Prostate Cancer From Benign Prostate Diseases.

PurposeThe most common disadvantage of 11C-choline positron emission tomography and computed tomography (PET/CT) in diagnosing early-stage prostate cancer (PCa) is its poor sensitivity. In spite of many efforts, this imaging modality lacks the ideal parameter of choline metabolism for the diagnosis of PCa, and the single metabolic parameter, that is, maximal standardized uptake value (SUVmax), based on this imaging modality is insufficient. 11C-choline PET/CT-based multi-metabolic parameter combination can help break this limitation.Materials and MethodsBefore surgery, SUVmax of choline, which is the most common metabolic parameter of 11C-choline PET/CT, mean standardized uptake value (SUVmean), prostate-to-muscle (P/M) ratio, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from 74 patients with histologically proven PCa were quantified. A total of 13 patients with focal chronic prostatitis without severe features and 30 patients with benign prostate hyperplasia were used for comparison. Univariable and multivariable analyses were performed to compare the patient characteristics and metabolic parameters of 11C-choline PET/CT. The performance of single parameters and the combination of parameters were assessed by using logistic regression models.ResultsThe comparable c-statistics, which mean the area under the ROC curve in the logistic regression model, of SUVmax, SUVmean, and P/M ratio are 0.657, 0.667, and 0.672, respectively. The c-statistic significantly rose to 0.793 when SUVmax and SUVmean were combined with the P/M ratio. This parameter combination performed the best for PCa cases with all biochemical recurrence risks and for PCa patients grouped by different risk. The greatest improvement over a single parameter, such as P/M ratio, was noted in the group of low-risk PCa, with values of 0.535 to 0.772 for the three-parameter combination. And in the histopathological level, the Ki-67 index is positively correlated with the P/M ratio (r=0.491, p=0.002).ConclusionP/M ratio is a more ideal parameter than SUVmax as a single parameter in early-stage PCa diagnosis. According to our data, the combination of SUVmax, SUVmean, and P/M ratio as a composite parameter for diagnosis of early stage PCa improves the diagnostic accuracy of 11C-choline PET/CT.

Evaluation of GNMT Gene Expression in Prostate Cancer Tissues using Real-Time PCR

Introduction: Prostate cancer is the second most common cancer and the leading cause of cancer-related deaths worldwide. In the present study, the expression level of glycine N-methyl transferase gene (GNMT) was investigated in prostate cancer tissue. The GNMT enzyme is encoded by the GNMT gene. Increased GNMT gene expression increases the conversion of glycine to sarcosine and results in the elevated levels of sarcosine in blood and urine. Methods: The expression level of GNMT gene in tissue samples of patients with prostate cancer was compared with those with benign prostatic hyperplasia using Real-Time PCR technique. Results: The GNMT gene expression level increased significantly in prostate cancer patients compared with those with benign prostatic hyperplasia (p-value <0.001). In addition, the expression level of GNMT gene was stage-dependent and significant increases were observed in all stages of prostate cancer compared with those with benign prostatic hyperplasia (p-value <0.001). Conclusion: The concentration of sarcosine is controlled by GNMT and it seems that increasing the expression level of GNMT gene increases the level of sarcosine concentration. Thus, it appears that increased levels of GNMT expression occur in the early stages of prostate cancer. Therefore, periodic measurement of GNMT expression levels can detect prostate cancer before it forms a cancer cell and invades other tissues.

Exploration of the Tumor Mutational Burden as a Prognostic Biomarker and Related Hub Gene Identification in Prostate Cancer.

To explore the signature function of the tumor mutational burden (TMB) and potential biomarkers in prostate cancer (PCa), transcriptome profiles, somatic mutation data, and clinicopathologic feature information were downloaded from The Cancer Genome Atlas (TCGA) database. R software package was used to generate a waterfall plot to summarize the specific mutation information and calculate the TMB value of PCa. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to select the hub genes related to the TMB from the ImmPort network to build a risk score (RS) model to evaluate prognostic values and plot Kaplan–Meier (K-M) curves to predict PCa patients survival. The results showed that PCa patients with a high TMB exhibited higher infiltration of CD8+ T cells and CD4+ T cells and better overall survival (OS) than those with a low TMB. The anti-Mullerian hormone (AMH), baculoviral IAP repeat-containing 5 (BIRC5), and opoid receptor kappa 1 (OPRK1) genes were three hub genes and their copy number variation (CNV) was relatively likely to affect the infiltration of immune cells. Moreover, PCa patients with low AMH or BIRC5 expression had a longer survival time and lower cancer recurrence, while elevated AMH or BIRC5 expression favored PCa progression. In contrast, PCa patients with low OPRK1 expression had poorer OS in the early stage of PCa and a higher recurrent rate than those with high expression. Taken together, these results suggest that the TMB may be a promising prognostic biomarker for PCa and that AMH, OPRK1, and BIRC5 are hub genes affecting the TMB; AMH, OPRK1, and BIRC5 could serve as potential immunotherapeutic targets for PCa treatment.

Role of Testosterone Levels on the Combinatorial Effect of Boswellia serrata Extract and Enzalutamide on Androgen Dependent LNCaP Cells and in Patient Derived Cells.

Co-therapy with herbal extracts along with current clinical drugs is being increasingly recognized as a useful complementary treatment for cancer. The anti-cancer property of the phyto-derivative acetyl-11 keto β boswellic acid (AKBA) has been studied in many cancers, including prostate cancer. However, the whole extract of the gum resin Boswellia serrata (BS) and anti-androgen enzalutamide has not been explored in prostate cancer to date. We hypothesized that the BS extract containing 30% (AKBA) with enzalutamide acted synergistically in the early phase of cancer, especially in LNCaP cells, by inhibiting androgen receptor (AR) and by reducing cell proliferation, and further, that the extract would be superior to the action of the active ingredient AKBA when used alone or in combination with enzalutamide. To test our hypothesis, we treated LNCaP cells with BS extract or AKBA and enzalutamide both individually and in combination to analyze cell viability under different levels of dihydrotestosterone (DHT). The inhibition of androgen receptor (AR) followed by the expression of prostate-specific antigen (PSA) and the efflux mechanism of the cells were analyzed to determine the effect of the combination on the cellular mechanism. Cells derived from prostate cancer patients were also tested with the combination. Only 6 µM enzalutamide along with BS in the range of 4.1 µg/ml to 16.4 µg/ml gave the best synergistic results with nearly 50% cell killing even though standard enzalutamide doses were as high as 48 µM. Cell killing was most effective at intermediate DHT concentrations of approximately 1 nM, which corresponds to normal physiological serum levels of DHT. The Pgp expression level and the androgen receptor expression levels were reduced under the combination treatment; the former helping to minimize drug efflux and the latter by reducing the sensitivity to hormonal changes. Furthermore, the combination reduced the PSA level secreted by the cells. In contrast, AKBA could not achieve the needed synergism for adequate cell killing at equivalent concentrations. The combination of enzalutamide and BS extract containing 30% AKBA because of their synergistic interaction is an attractive therapeutic option for treating early stage (hormone-dependent) prostate cancer and is superior to the use of AKBA alone.

Dosimetric Effects Due to Inter-Observer Variability of Organ Contouring When Utilizing a Knowledge-Based Planning System for Prostate Cancer

Purpose: Radiotherapy is a widely accepted standard of care for early-stage prostate cancer, and it is believed that the plan quality and treatment outcome are associated with contour accuracy of both the target and organs-at-risk (OAR). The purposes of this study are to 1) assess geometric and dosimetric uncertainties due to inter-observer contour variabilities and 2) evaluate the effectiveness of geometric indicators to predict target dosimetry in prostate radiotherapy. Methods: Twenty prostate patients were selected for this retrospective study. Five experienced clinicians created unique structure sets containing prostate, seminal vesicles, bladder, and rectum for each patient. A fully automated script and knowledge-based planning routine were utilized to create standardized and unbiased plans that could be used to evaluate changes in isodose distributions due to inter-observer variability in structure segmentation. Plans were created on a “gold-standard” structure set, as well as on each of the user-defined structure sets. Results: Inter-observer variability of contours during structure segmentation was very low for clearly defined organs such as the bladder but increased for organs without well-defined borders (prostate, seminal vesicles, and rectum). For plans generated with the user-defined structure sets, strong/moderate correlations were observed between the geometric indicators for target structure agreement and target coverage for both low-risk and intermediate-risk patient groups, while OAR indicators showed no correlation to final dosimetry. Conclusions: Target delineation is crucial in order to maintain adequate dosimetric coverage regardless of the associated inter-observer uncertainties in OAR contours that had a limited impact upon final dosimetry.

Application of focused ultrasound in
 oncology: fundamentals and perspectives
 (literature review)

Relevance: The introduction into clinical practice of new
 non-invasive, safe and effective methods of treatment of benign and malignant diseases is an urgent task.
 The purpose was to study literature sources on the experience of using MRI-guided focused ultrasound (MRgFUS)
 method of thermal ablation for its subsequent implementation and use at the East Kazakhstan Region Multidisciplinary
 Center of Oncology and Surgery of Ust-Kamenogorsk.
 Results: The proposed method is based on real-time
 MRI-guided thermal ablation by focused ultrasound. Numerous studies have shown its clinical and economic efficiency,
 safety, and convenience for patients with bone metastases,
 early-stage prostate cancer, and uterine myoma.
 Conclusions: MRgFUS ablation is a modern non-invasive
 technique that expands the ways to treat benign and malignant tumors. In certain cases, it can be a good alternative to
 invasive treatments. MRgFUS ablation can be used in combination with other treatments.

The Predictive Role of Prostate-Specific Antigen Changes Following Transurethral Resection of the Prostate for Patients with Localized Prostate Cancer.

Simple SummaryA part of localized prostate cancer (PC) was an incidental finding in patients who received transurethral resection of the prostate (TURP) for urinary symptoms. The present study examined whether changes in prostate-specific antigen (PSA) levels after TURP possess a predictive value for localized PC. Our data revealed that patients at intermediate risk who are associated with tumor involvement ≤5% in TURP specimens, PSA_TURP ≤ 4 ng/mL, and ≥68% PSA reduction following TURP might be suitable for conservation management instead of immediate local therapy. Moreover, for patients with no pre-TURP PSA, Gleason score (GS) < 7, and low PSA_TURP could potentially be utilized to select which patients could be considered for conservative management after TURP. The findings suggest the pathologic finding of TURP and changes in PSA could be used as adjuvant markers to guide a risk-adaptive strategy for patients with localized PC.Regarding localized prostate cancer (PC), questions remain regarding which patients are appropriate candidates for conservative management. Some localized PC was an incidental finding in patients who received transurethral resection of the prostate (TURP) for urinary symptoms. It is known that TURP usually affects the level of prostate-specific antigen (PSA). In the present study, we examined whether changes in PSA levels after TURP possess a predictive value for localized PC. We retrospectively reviewed the clinical data of 846 early-stage PC patients who underwent TURP for urinary symptoms upon diagnosis at our hospital. Of 846 patients, 687 had tumor involvement in TURP specimens, and 362 had post-TURP PSA assessment. Our data revealed that, in addition to low GS and PSA levels at diagnosis, ≤5% tumor involvement in TURP specimens, greater PSA reduction (≥68%) following TURP, and post-TURP PSA ≤ 4 were significantly associated with better progression-free survival (PFS). Survival analysis revealed that the addition of prostate-directed local therapy significantly improved PFS in intermediate- and high-risk groups, but not in the low-risk group. Moreover, in the intermediate-risk group, local therapy improved PFS only for patients who were associated with post-TURP PSA > 4 ng/mL or <68% PSA reduction following TURP. We also found that local therapy had no obvious improvement in PFS for those with post-TURP ≤ 4 ng/mL regardless of pre-TURP PSA. In conclusion, conservative management is considered for patients at low or intermediate risk who have greater PSA reduction following TURP and low post-TURP PSA. Therefore, the levels of PSA following TURP might be helpful for risk stratification and the selection of patients for conservative management.

O-glycosylated clusterin as a sensitive marker for diagnosing early stages of prostate cancer.

Prostate-specific antigen (PSA) has been the most popular diagnostic marker for prostate cancer. The frequent occurrence of low PSA values (<10 ng/ml) in patients with highly suspicious prostate cancer, however, has undermined the accuracy of clinical examinations. The aim of this study was to develop a better resolution for diagnosing prostate cancer to overcome the disadvantage of PSA. We focused on the glycosylation status of patients' serum proteins and conducted comprehensive lectin microarray analyses to characterize N- and O-glycans using sera from prostate cancer and benign prostatic diseases. Next, we retrieved candidate serum proteins with characteristic glycan structures using lectin-immobilized beads and identified them by quantitative mass spectrometry using a technique referred to as isobaric tag for relative and absolute quantitation (iTRAQ)labeling. Finally, we constructed a new assay to quantify a candidate glycoprotein with the newly identified glycans. Lectin microarray analyses revealed that sera from patients with prostate cancer had a higher affinity for Jacalin, Amaranthus caudatus (ACA) lectin, and Maclura pomifera (MPA) lectin, compared with that from patients with benign prostatic diseases and normal subjects, suggesting that O-glycosylated proteins are more abundant in sera from patients with prostate cancer. Then, serum glycoproteins preferentially adsorbed onto Jacalin-Agarose as well as biotin-ACA/and biotin-MPA/streptavidin-immobilized magnetic beads were isolated, labeled with iTRAQ, and identified using quantitative mass spectrometry. It was found that the ACA- and MPA-recognizable clusterin was more enriched in patients' sera from prostate cancer compared with those from benign prostatic diseases. Following this discovery, we constructed a Luminex-based assay to quantify O-glycosylated clusterin, in which total serum clusterin was first captured on anti-clusterin antibody-immobilized beads, and then clusterin-associated O-glycans were determined by the pair of biotin-MPA and streptavidin-phycoerythrin. When PSA values registered less than 10 ng/ml, the corresponding serum level of MPA-recognized clusterin determined by this assay was beneficial for distinguishing the patients with prostate cancer from the patients with benign prostatic disease. For PSA values that measure less than 10 ng/ml, the serum O-glycosylated clusterin level can be a complementary indicator for the malignancy of prostate cancer.

An Amplified Fatty Acid-Binding Protein Gene Cluster in Prostate Cancer: Emerging Roles in Lipid Metabolism and Metastasis.

Simple SummaryProstate cancer is the second most common cancer in men. In many cases, prostate cancer grows very slowly and remains confined to the prostate. These localized cancers can usually be cured. However, prostate cancer can also metastasize to other organs of the body, which often results in death of the patient. We found that a cluster of genes involved in accumulation and utilization of fats exists in multiple copies and is expressed at much higher levels in metastatic prostate cancer compared to localized disease. These genes, called fatty acid-binding protein (or FABP) genes, individually and collectively, promote properties associated with prostate cancer metastasis. We propose that levels of these FABP genes may serve as an indicator of prostate cancer aggressiveness, and that inhibiting the action of FABP genes may provide a new approach to prevent and/or treat metastatic prostate cancer.Treatment for early stage and localized prostate cancer (PCa) is highly effective. Patient survival, however, drops dramatically upon metastasis due to drug resistance and cancer recurrence. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. It is therefore crucial to decipher the key genetic alterations and relevant molecular pathways driving PCa metastatic progression so that predictive biomarkers and precise therapeutic targets can be developed. Through PCa cohort analysis, we found that a fatty acid-binding protein (FABP) gene cluster (containing five FABP family members) is preferentially amplified and overexpressed in metastatic PCa. All five FABP genes reside on chromosome 8 at 8q21.13, a chromosomal region frequently amplified in PCa. There is emerging evidence that these FABPs promote metastasis through distinct biological actions and molecular pathways. In this review, we discuss how these FABPs may serve as drivers/promoters for PCa metastatic transformation using patient cohort analysis combined with a review of the literature.

Gonadotropin-Releasing Hormone Receptors in Prostate Cancer: Molecular Aspects and Biological Functions.

Pituitary Gonadotropin-Releasing Hormone receptors (GnRH-R) mediate the activity of the hypothalamic decapeptide GnRH, thus playing a key role in the regulation of the reproductive axis. Early-stage prostate cancer (PCa) is dependent on serum androgen levels, and androgen-deprivation therapy (ADT), based on GnRH agonists and antagonists, represents the standard therapeutic approach for PCa patients. Unfortunately, the tumor often progresses towards the more aggressive castration-resistant prostate cancer (CRPC) stage. GnRH receptors are also expressed in CRPC tissues, where their binding to both GnRH agonists and antagonists is associated with significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic effects, mediated by the Gαi/cAMP signaling cascade. GnRH agonists and antagonists are now considered as an effective therapeutic strategy for CRPC patients with many clinical trials demonstrating that the combined use of these drugs with standard therapies (i.e., docetaxel, enzalutamide, abiraterone) significantly improves disease-free survival. In this context, GnRH-based bioconjugates (cytotoxic drugs covalently linked to a GnRH-based decapeptide) have been recently developed. The rationale of this treatment is that the GnRH peptide selectively binds to its receptors, delivering the cytotoxic drug to CRPC cells while sparing nontumor cells. Some of these compounds have already entered clinical trials.

Graphene-based Electrochemical Biosensor for Impedimetric Detection of miRNAs as Potential Cancer Biomarkers

MicroRNAs (miRNAs) have shown great potential to be used as biomarkers for the screening and clinical diagnosis of cancer. In this study, an electrochemical biosensor based on graphene-modified glassy carbon electrode was developed for the detection of miRNA-21, a well-known biomarker for the early stage of prostate cancer. A novel molecular tethering agent was used for immobilization of single-stranded probe DNA onto the electrode surface. Different parameters related to biosensor fabrication and experimental conditions were optimized to obtain the highest biosensor response. Electrochemical impedance spectroscopy was employed to achieve a sensitive and label-free detection method for miRNA-21 through measuring the change in charge-transfer resistance (Rct) before and after hybridization. Under the optimal conditions, the biosensor showed a linear impedimetric response between ΔRct and logarithm of miRNA-21 concentration ranging from 10−14 to 10−8 M with a correlation coefficient of 0.972 and a detection limit of 3 fM. The selectivity of the biosensor was examined against non-complementary miRNA-141. The biosensor showed acceptable reproducibility, regeneration ability and stability as well as remarkable response (recoveries 90%–116%) in real plasma samples. The results indicated that the proposed biosensor could be used as a promising alternative to conventional methods in early clinical and point-of-care cancer diagnosis.