Provision of prostate cancer services in Tanzania: perspectives from five tertiary hospitals.

BACKGROUND: Access to quality prostate cancer services remains a global challenge, particularly in Low- and Middle-Income countries. This is often due to weak health systems that struggle to meet the population's needs. The provision of quality health services to patients with prostate cancer requires a comprehensive approach involving multiple stakeholders and structural inputs. However, few studies have comprehensively assessed the relationship between these structural inputs and prostate cancer treatment outcomes. This study, therefore, aimed to determine the availability of selected structural inputs and descriptions of how they influence the provision of quality services to patients with prostate cancer in Tanzania. METHODS: We conducted a cross-sectional study using an explanatory sequential mixed-method approach to collect data from five tertiary hospitals providing cancer services in Tanzania. A validated checklist was used to collect information on available structural inputs for prostate services at tertiary hospitals. A semi-structured interview guide was used to conduct 42 in-depth interviews with 20 healthcare providers, five hospital managers, and 17 patients undergoing treatment for prostate cancer. Descriptive analysis was performed for the quantitative data, and thematic analysis was conducted with the aid of NVivo 14 qualitative software for the interview transcripts. RESULTS: All five assessed tertiary hospitals had inadequate human resources for health to provide prostate cancer services. Only one had 70% of the required HRH, while none had above 40% of the required HRH. Within the hospitals, the skill mix imbalance was severe across cadres. Five themes emerged: inadequate infrastructure, delays in diagnosis, delays in treatment, shortage of human resources for health (HRH), and inefficient organization of prostate cancer services. CONCLUSION: The findings of this study, underscore the major health system deficiencies for the provision of prostate cancer services in tertiary hospitals. With the increased aging population, strong health systems are vital in addressing conditions of old aging, including prostate cancers. Studies on optimization of the available HRH and infrastructure are needed to improve the provision of prostate cancer in tertiary hospitals as an interim solution while long-term measures are needed for improving the HRH availability and conducive infrastructure.

Combination of the PARPi and ARSi in advanced castration resistant prostate cancer: a review of the recent phase III trials.

Tumors with an impaired ability to repair DNA double-strand breaks by homologous recombination, including those with alterations in breast cancer 1 and 2 (BRCA1 and BRCA2) genes, are very sensitive to blocking DNA single-strand repair by inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a synthetic deadly strategy in the treatment of different types of cancer, such as prostate cancer (PCa). The phase 3 PROfound study was the first to lead to olaparib approval in patients with metastatic castration resistant PCa (mCRPC) and BRCA genes mutations. In recent years, the benefit of combination therapy consisted of a PARP inhibitor (PARPi) plus an androgen receptor signalling inhibitor (ARSi), was evaluated as first-line treatment of mCRPC, regardless of the mutational state of genes, participating in the homologous recombination repair (HRR). This review explores the role of PARPi in PCa and analyses the data of latest clinical trials exploring the PARPi-ARSi combinations, and how these results could change our clinical practice.

The role of Fetuin-A and Leucine-rich α-2-glycoprotein in the diagnosis of prostate cancer - a pilot study.

BACKGROUND: Prostate cancer (PC) is one of the most frequently diagnosed non-skin solid cancers and is a leading cause of cancer-related death and the incidence increasing. Early diagnosis of the disease improves the outcomes. There is an urgent need for new biomarkers with greater discriminative precision for diagnosis, risk-stratification and treatment. The aim of our study was to evaluate the diagnostic and prognostic potential of Fetuin-A and LRG1 in patients with PC. METHODS: Serum levels of Fetuin-A and LRG1 were compared in patients with PC (n=46), a control group 1 including young, healthy subjects (n=26) and control group 2 including patients with negative prostate biopsy (n=46). In PC patients, the levels of both biomarkers were compared in subgroups with different tumour characteristics. RESULTS: We demonstrated a statistically significant higher concentrations of Fetuin-A in PC patients compared to control group 2 (439 mg/L vs. 372 mg/L), P<0.001. No statistically significant difference was found between PC patients and control group 1, nor for LRG1 levels between the three groups. In PC patients, higher serum levels of LRG1 were found in M1 patients compared to M0 (98 mg/L vs. 42 mg/L), P=0.059. CONCLUSION: Fetuin-A levels are significantly higher in patients with prostate cancer than in patients without malignancy but LRG1 levels do not differ between patients with PC and controls.

Loss of phosphatase and tensin homolog expression castration-sensitive prostate cancer predicts outcomes in men after prostatectomy.

OBJECTIVES: This study aimed to investigate the potential for using the phosphatase and tensin homolog (PTEN) gene as a prognostic marker in post-prostatectomy patients with castration-sensitive prostate cancer (PCa). METHODS: A total of 180 patients with castration-sensitive PCa who underwent radical prostatectomy at our institution were included in this study. PTEN expression was evaluated using immunohistochemistry, and patients were classified into two groups based on the staining intensity: PTEN-Normal and PTEN-Loss. The association between PTEN expression and biochemical recurrence was analyzed using the Cox proportional hazards model. RESULTS: Patients in the PTEN-Loss group had a higher risk of biochemical recurrence (hazard ratio, 4.642; 95% confidence interval, 2.137-10.083; p < 0.001) and a lower recurrence-free rate compared to the PTEN-Normal group (35% vs. 75%). In addition to clinicopathological factors, such as the serum prostate-specific antigen level, Gleason score, and T stage, evaluation of PTEN expression improved the prediction of biochemical recurrence after prostatectomy (area under the curve, 0.577 vs. 0.688). CONCLUSIONS: Low PTEN expression is a significant predictor of biochemical recurrence in patients with castration-sensitive PCa who have already undergone prostatectomy.

Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer.

BACKGROUNDAndrogen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance.METHODSTo investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line.RESULTSWe confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor (AR) signaling and the increased transcriptional heterogeneity and lineage plasticity during the emergence of ARSI resistance. We further identified amplifications involving a putative enhancer downstream of the AR and transcriptional downregulation of SSTR1, encoding somatostatin receptor 1, in ARSI-resistant tumors. We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation.CONCLUSIONOur findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDINGNational Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute.

The Role of Transurethral BPH Surgeries in Management of Urinary Symptoms in Prostate Cancer Patients, Narrative Review.

PURPOSE OF REVIEW: Prostate cancer and benign prostate hyperplasia (BPH) are two ubiquitous pathologies that may coexist. A significant percentage of patients with different stages of prostate cancer suffer lower urinary tract symptoms (LUTS) due to associated BPH. We aimed to review the literature regarding the role of transurethral surgeries in the management of prostate cancer patients and the different available management options. RECENT FINDINGS: The evidence in literature for the use of BPH surgeries in prostate cancer patients is based mainly on low-quality retrospective studies. In patients on active surveillance, BPH surgeries are beneficial in relieving LUTS without oncological risk and can eliminate the contribution of adenoma to PSA level. In patients with advanced prostate cancer, palliative BPH surgery can relieve LUTS and urinary retention with unclear oncological impact; however some reports depict that the need for BPH surgery in advanced prostate cancer is associated with poorer prognosis. In patients receiving radiotherapy, various studies showed that transurethral resection of prostate (TURP) is associated with increased radiotoxicity despite some recent reports encouraging the use of Holmium Laser Enucleation of the Prostate (HoLEP) to improve urinary symptom scores before radiotherapy. The most commonly reported techniques utilized are TURP, photoselective vaporization of prostate (PVP) and HoLEP. The use of BPH surgery is justified for relieving LUTS in selected prostate cancer patients on active surveillance or in advanced stages, however the use in the pre-radiotherapy settings remains controversial. Future prospective and randomized controlled trials are required for validating the benefits and assessing potential hazards.

Real-world outcomes in patients with metastatic castration-resistant prostate cancer beyond progression after upfront androgen receptor signaling inhibitor.

BACKGROUND: Upfront androgen receptor signaling inhibitor (ARSI) along with androgen deprivation therapy is the current standard of care for metastatic castration-sensitive prostate cancer. However, evidence on second-line therapy after upfront ARSI is scarce. We aimed to evaluate the oncological outcome of ARSI versus docetaxel (DOC) after upfront ARSI therapy in a real-world clinical practice. METHODS: Subjects were metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed within 2 years of upfront ARSI therapy and received ARSI (ARSI group) or DOC (DOC group) as a second-line therapy. Second-line progression-free survival (second-line PFS), and second-line overall survival (second-line OS) were assessed. Propensity score matching (PSM) was used to adjust the clinicopathological features and treatment patterns. RESULTS: A total of 101 mCRPC patients, 68 in the ARSI group, and 33 in the DOC group, were included in this analysis. Median second-line PFS was 6.3 months in the ARSI group and 4.9 months in the DOC group (p = 0.21). Median second-line OS was 25.0 months in the ARSI group and 14.2 months in the DOC group (p = 0.06). Prostate-specific antigen nadir ≤ 0.2 ng/ml during upfront ARSI therapy was significantly associated with improved second-line PFS. After PSM, no significant difference in second-line PFS and second-line OS were observed between the two groups. CONCLUSION: ARSI or DOC has comparable oncologic outcomes in terms of second-line PFS and second-line OS. Further prospective research with longer follow-ups will be needed to identify the optimal treatment after upfront ARSI therapy.

Measurement of PDE5 concentration in human serum: proof-of-concept and validation of methodology in control and prostate cancer patients.

PURPOSE: We aimed to investigate if the type 5 phosphodiesterase (PDE5), an enzyme with cardinal biological functions in sexual and cardiovascular health, can be detected and quantited in human serum. METHODS: Blood samples were collected from control male and female subjects. PDE5 levels were measured by a specific ELISA kit. ROC curves weighted for age and serum levels of PSA (male subjects), or age (female subjects) were used to identify the predictive ability in the detection of PCa. Sensitivity, specificity, PPV and NPV values were determined for cut-off value determined during ROC curve analysis. RESULTS: 41 control male subjects, 18 control female subjects, and 55 consecutive subjects, of which 25 were affected by benign prostatic hypertrophy (BPH) and 30 with histologically confirmed prostate cancer (PCa), were studied. PDE5 serum levels were detectable in all subjects (range: 5 to 65 ng/ml). Analysis by MANCOVA identified a significant difference in serum PDE5 between control subjects or hyperplasia patients and PCa patients. Marginal means of serum PDE5 concentrations showed a significant difference (p < 0.001). The ROC curve demonstrated that PDE5 serum levels can predict men with or without PCa, with 0.806 AUC value (p < 0.0001). Using a 12.705 ng/ml PDE5 serum cut-off yielded sensitivity, specificity, PPV, and NPV of 83.3%, 77.27%, 62.5%, and 91.1% in detecting men with histologically proven PCa, respectively. CONCLUSIONS: We demonstrated, for the first time, that PDE5 levels can be detected in human sera and that PCa patients have significantly higher PDE5 concentration compared to BPH patients or male and female controls. While serum PDE5 level measurement may open new research avenues, the clinical relevance of PDE5 levels in PCa patients deserves further investigation.

The Anti-proliferative Effect of a Novel Glutaminase Inhibitor IN-3 on Prostate Cancer Cells.

Objective: This study aimed to evaluate anti-cancer potential of a novel glutaminase (GLS) inhibitor IN-3 in prostate cancer cells. Methods: The cell viability upon IN-3 treatment was examined using crystal violet staining and IC50 values were calculated for cancer cell lines PC-3 and LNCaP and normal fibroblasts CCD1072sk. The expression levels of GLS isoforms were determined by real-time polymerase chain reaction after IN-3 treatment. The metastatic prostate cancer dataset was downloaded from C-Bioportal and the expressions of GLS isoforms were analyzed. Results: The IC50 values of IN-3 for LNCaP, PC-3 and CCD1072sk were 2.13, 6.14 and 15.39 µM respectively. The dose dependent effect of IN-3 was evident even in low concentration with 1 µM in LNCaP and 2 µM in PC-3 and these anti-proliferative effects of IN-3 were highly significant with p-values lower than 0.0001. The treatment of PC-3 cells with 10 µM IN-3 elevated the expression of kidney type GLS isoform of GLS1 but not GLS2. Comparison of metastatic and localized prostate cancer tissues showed that GLS1 was highly expressed not only in primary but also in metastatic prostate cancer tissues. GLS1 expression was significantly higher than GLS2 expression with p-values lower than 0.001. Conclusions: The GLS inhibitor IN-3 may be a potent anti-cancer agent in prostate cancer by demonstrating its differential effect between cancer and normal cells. Further studies are warranted to elucidate its drug potential in prostate cancer.

Increasing prostate cancer radiosensitivity by miR-7-5p knockdown of anti-apoptotic genes.

Despite the success of radiotherapy for prostate cancer treatment, the recent discovery of radiation resistance prevents it from reaching its full potential. This study aims to use hsa-miR-7-5p for the expression of anti-apoptotic genes. The search for anti-apoptotic genes was carried out through databases. The selected genes included XIAP, MCL1, REL, and BIRC3. Our selection was based on the best miRNA because it has a greater impact on genes. The second step involved transfecting the miRNA into a prostate cancer cell line. Subsequently, radiosensitivity was tested using real-time PCR, clonogenic assay, and annexin V flow cytometry. The highest apoptosis rate in the transfected cells was at 0 Gy in hsa-miR-7-5p (28.88 ± 0.80), plenti III (18.81 ± 0.59), and the control group (4.10 ± 1.52) (P<0.001). Also, its rate was at 4 Gy in hsa-miR-7-5p (36.11 ± 1.93), plenti III (26.42 ± 0.42), and the control group (8.79 ± 2.29) (P<0.001). This study showed a decreasing trend in survival with increasing doses. Suppression of anti-apoptotic genes, including XIAP, MCL1, Birc3, and REL, enhanced radiosensitivity by increasing the expression of hsa-miR-7-5p in the PC3 and LNCaP cell lines. Hsa-miR-7-5p is a miRNA that can suppress the expression of anti-apoptotic genes and thus plays an essential role in the process of cell apoptosis. Targeting genes that are associated with apoptosis could potentially enhance the efficacy of treatments for patients with prostate cancer.

Prostate Cancer-related Events in Patients with Synchronous Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Deprivation Therapy with and Without Concurrent Radiation Therapy to the Prostate; Data from the HORRAD Trial.

BACKGROUND AND OBJECTIVE: A survival benefit was demonstrated for patients with low-volume synchronous metastatic hormone-sensitive prostate cancer (mHSPCa) when local radiotherapy to the prostate was added to androgen deprivation therapy. This study aims to determine the incidence of prostate cancer-related events and treatments in those who received and those who did not receive external beam radiotherapy for mHSPCa. METHODS: The HORRAD trial is a multicentre randomised controlled trial recruiting originally 432 patients with mHSPCa diagnosed between 2004 and 2014. In a second updated analysis, 328 patients were studied retrospectively for local and nonlocal prostate cancer-related events and treatments. Outcome measurements included the incidence and treatment of local (bladder outlet or ureter obstruction, catheterisation, surgical intervention, ureteric stents, and nephrostomy tubes) and nonlocal (blood transfusions, hospitalisations, and treatment for painful bone metastases) events. Differences between groups were compared using crude and adjusted logistic regression, while time to occurrence of local events was assessed with Kaplan-Meier curves and Cox regression analysis. KEY FINDINGS AND LIMITATIONS: A significant difference in the incidence of local events was observed: 30 events in the radiotherapy group versus 50 in the nonradiotherapy group (p = 0.04). Time to occurrence of local interventions was significantly longer in the radiotherapy group (hazard ratio 0.61, 95% confidence interval 0.37-0.99, p = 0.04). The study's limitations include its retrospective nature. CONCLUSIONS AND CLINICAL IMPLICATIONS: Local radiotherapy to the prostate prolongs local event-free survival significantly and reduces local prostate cancer-related interventions in patients with mHSPCa.

[Comorbidities after radical prostatectomy : Which subjective health restrictions are relevant for long-term survivors?] / Gesundheitsprobleme nach radikaler Prostatektomie : Welche subjektiven Gesundheitseinschränkungen sind für Langzeitüberlebende relevant?

BACKGROUND: Radical prostatectomy (RP) is one of the most common therapeutic strategies for treating localized prostate cancer (PCa). Currently, the significance of postoperative functional limitations for affected patients in the long-term course, especially in comparison to age-related comorbidities, is unclear. OBJECTIVE: The aim of this study was to quantify the prevalence of subjective health restrictions alongside functional deficits in long-term PCa survivors after RP and their relevance for subjective impairments in everyday life. MATERIALS AND METHODS: Using the German version of the Self-Administered Comorbidity Questionnaire (SCQ-D), 3173 long-term survivors after RP reported their comorbidities in 13 predefined categories and in 3 free-text fields along the dimensions "problem," "treatment," and "impairment". RESULTS: The mean age at survey was 79.5 years (standard deviation, SD ±â€¯6.4), with a mean time since RP of 17.4 years (SD ± 3.7). The three most frequently identified comorbidities/percentage of patients who felt impaired were: hypertension (62.2%/8.5%), back pain (44.1%/54.5%), and osteoarthritis (36.1%/54.1%). The most frequently mentioned additional health problems can be subsumed under the umbrella term "urological problems" (6.1%/72.7%): incontinence (4.8%/74.3%), bladder problems (1.1%/61.8%), and erectile dysfunction (0.5%/47.1%). CONCLUSION: In summary, non-cancer-related comorbidities in the long-term course after RP are often perceived as "problems" but rarely lead to subjective impairment. In contrast, treatment-related urological problems are rarely reported as "problems", but they very often lead to subjective impairment in everyday life.

Multi-marker analysis of circulating tumor cells in localized intermediate/high-risk and metastatic prostate cancer.

Circulating tumor cells (CTCs) are an established prognostic marker in metastatic prostate cancer (PrC) but have received little attention in localized high-risk disease. Peripheral blood was obtained from patients with early intermediate and high-risk PrC (n = 15) at baseline, after radiotherapy, and during follow-up, as well as from metastatic PrC patients (n = 23). CTCs were enriched using the microfluidic Parsortix® technology. CTC-related marker were quantified with qPCR and RNA in-situ hybridization (ISH). Positivity and associations to clinical parameters were assessed using McNemar test, Fisher Exact test or log-rank test. The overall positivity was high in both cohorts (87.0% metastatic vs. 66.7% early at baseline). A high concordance of qPCR and RNA ISH was achieved. In metastatic PrC, PSA and PSMA were prognostic for shorter overall survival. In early PrC patients, an increase of positive transcripts per blood sample was observed from before to after radiation therapy, while a decrease of positive markers was observed during follow-up. CTC analysis using the investigated qPCR marker panel serves as tool for achieving high detection rates of PrC patient samples even in localized disease. RNA ISH offers the advantage of confirming these markers at the single cell level. Employing the clinically relevant marker PSMA, our CTC approach can be used for diagnostic purposes to screen patients profiting from PSMA-directed PET-CT or PSMA-targeted therapy.

Amino polycarboxylic acids-modified abiraterone derivatives as potential injectable anti-prostate cancer agents.

Abiraterone (Abi), an effective cytochrome oxidase P450 C17 (CYP17) inhibitor, inhibits androgen synthesis in testes, adrenal glands, and prostate tumors. However, their low bioavailability and dissolution rate due to their poor solubility and toxic side effects have hindered their clinical applications. In this study, water-soluble and injectable Abi derivatives were developed by introducing amino polycarboxylic acids into Abi, and their antiproliferation effects in vitro, mechanism of action, antitumor activities in vivo, pharmacokinetics, and toxicity were investigated. Compared to Abi, the water-soluble derivative Abi-DTPA exhibited excellent antitumor activity in vitro and in vivo. It decreased cell migration, invasion, and mitochondrial membrane potential. A mechanistic study revealed that it still targeted the CYP17 enzyme and increased the expression levels of apoptosis-related proteins, including cleaved caspase 9, cleaved PARP, and cleaved caspase 3. Abi-DTPA was the main form in the plasma and exhibited lower toxicity after intravenous administration. These findings suggest that Abi-DTPA can be used as a novel injectable anti-prostate cancer agent.

Advances in prostate cancer treatment: Radionuclide therapy for prostate cancer.

The optimal treatment of metastatic castration-resistant prostate cancer (mCRPC) continues to be challenging, given the multitude of life prolonging treatment options. Radionuclide therapy delivers concentrated doses of radiation via ionizing particles chelated to ligands or antibody-based molecules with specific tumor targets and is approved for patients with treatment resistant mCRPC. Variations of radionuclide therapies within the continuum of prostate cancer treatment are being investigated. Landmark phase III clinical trials of beta-emitting 177Lu-PSMA radionuclide therapy have demonstrated the utility of 177Lu-PSMA in the treatment of mCRPC. Further research into alpha-emitting radionuclide therapy and vectors may provide alternative treatments for patients with treatment resistant mCRPC. As radionuclide therapy treatment options evolve, assessing appropriate patient selection for radionuclide therapy is important and may be facilitated by advances in imaging and blood-based biomarkers. Exploration of other approved life prolonging therapies in combination with radionuclide therapy has shown increasing interest as a potential method of combatting radionuclide therapy resistance. In this chapter, we review various types of radionuclide therapies for mCRPC, patient selection for radionuclide therapy from outcome predictions, ongoing clinical trials of radiopharmaceuticals for treatment of prostate cancer, and the resistance mechanisms and challenges to radionuclide therapy.

Intensification Approaches and Treatment Sequencing in Metastatic Castration-resistant Prostate Cancer: A Systematic Review.

BACKGROUND AND OBJECTIVE: Recently, research on treatment intensification has gathered momentum, and three novel therapy combinations were approved for metastatic castration-resistant prostate cancer (mCRPC). This systematic review summarizes the current and emerging evidence around intensified strategies for mCRPC and provides guidance for an ideal therapeutic sequencing. METHODS: Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines were followed to perform this review. PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials.gov, and major international societies' online proceedings were searched comprehensively until May 15, 2024, for terms related to treatment intensification and sequencing for mCRPC. KEY FINDINGS AND LIMITATIONS: Overall, 28 clinical trials and 24 ongoing studies of intensification treatments were included in this review. Algorithms of optimal sequencing of approved treatments for mCRPC were outlined according to the use of androgen receptor pathway inhibitors (ARPIs) with or without docetaxel for earlier disease states. In first line, poly(ADP-ribose) polymerase inhibitor + ARPI combinations improve radiographical progression-free survival (rPFS), particularly for those with BRCA1/2 alterations. The AKT inhibitor combination of ipatasertib + abiraterone extends rPFS in those with PTEN loss or PIK3CA/AKT1/PTEN alterations. In those with two or more risk factors for early progression on enzalutamide, radionuclide 177-Lu-PSMA-617 + enzalutamide prolongs progression-free survival. Ongoing research of intensified approaches for mCRPC, and available and potential predictive and prognostic biomarkers are discussed. CONCLUSIONS AND CLINICAL IMPLICATIONS: Recent approvals and ongoing investigations of single agents and intensification approaches will keep transforming the mCRPC treatment landscape. Improvement of patient profiling applying recognized genomic, molecular, and clinical predictive and prognostic indicators is fundamental to optimize sequential use of available therapies.

Risk of Biochemical Recurrence and Metastasis in Prostate Cancer Patients Treated with Radical Prostatectomy After a 10-year Disease-free Interval.

BACKGROUND AND OBJECTIVE: Prostate-specific antigen (PSA) testing is used to follow up prostate cancer (PCa) patients treated with radical prostatectomy (RP). Research on PSA thresholds for identifying PCa patients with biochemical recurrence (BCR) who are at a higher risk of progression yielded inconclusive results. This study aims to investigate the risk of late BCR in PCa patients treated with RP and long postoperative (120 mo) undetectable PSA follow-up, and to identify prognostic factors for late BCR within this patient cohort. METHODS: PCa patients treated with curative RP (1992-2012) and free of BCR during the first 120 mo following RP were retrospectively identified within five European tertiary centers; BCR was defined as two consecutive PSA values of ≥0.2 ng/ml. Kaplan-Meier and Cox regression models tested for an association between BCR and patient or tumor characteristics. KEY FINDINGS AND LIMITATIONS: The study cohort consisted of 4639 patients, of whom 243 (5.2%) developed BCR at a medium follow-up of 147 mo. Of those with BCR, 23 (9.5%) subsequently developed metastatic progression. In Kaplan-Meier models, BCR-free survival differed according to advanced tumor status. In multivariable Cox regression models, pT stage (pT3a: hazard ratio [HR]: 1.46; pT3b: HR: 2.42), pathological Gleason score (pGS 3 + 4: HR: 1.71; pGS ≥4 + 3: HR: 2.47), surgical margin (R1/Rx: HR: 1.72), and pNx stage (pNx: HR: 0.72) represented independent predictors for BCR (all p < 0.05). Conversely, age, PSA at diagnosis, and year of surgery failed to achieve independent predictor status for BCR. CONCLUSIONS AND CLINICAL IMPLICATIONS: Among PCa patients with an uneventful follow-up of at least 10 yr after RP, still one in 20 patients subsequently develop late BCR. Nevertheless, late BCR and subsequent progression to metastasis (0.3%) rates in patients with pT2 stage and pGS ≤3 + 4 were strikingly low, implicating that abandoning follow-up beyond an uneventful period of 10 yr is justifiable within this cohort of patients. PATIENT SUMMARY: In this study, prostate cancer patients treated with a radical prostatectomy and at least 10 yr of uneventful prostate-specific antigen testing were identified within five European centers. Relying on these patients, the rate of subsequent late biochemical recurrence was calculated and risk factors were identified for biochemical recurrence following 10 yr of uneventful prostate-specific antigen testing.

Identification and validation of diagnostic and prognostic biomarkers in prostate cancer based on WGCNA.

BACKGROUND: Prostate cancer (PCa) represents a significant health challenge for men, and the advancement of the disease often results in a grave prognosis for patients. Therefore, the identification of biomarkers associated with the diagnosis and prognosis of PCa holds paramount importance in patient health management. METHODS: The datasets pertaining to PCa were retrieved from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was conducted to investigate the modules specifically associated with the diagnosis of PCa. The hub genes were identified using the LASSO regression analysis. The expression levels of these hub genes were further validated by qRT-PCR experiments. Receiver operating characteristic (ROC) curves and nomograms were employed as evaluative measures for assessing the diagnostic value. RESULTS: The blue module identified by WGCNA exhibited a strong association with PCa. Six hub genes (SLC14A1, COL4A6, MYOF, FLRT3, KRT15, and LAMB3) were identified by LASSO regression analysis. Further verification confirmed that these six genes were significantly downregulated in tumor tissues and cells. The six hub genes and the nomogram demonstrated substantial diagnostic value, with area under the curve (AUC) values ranging from 0.754 to 0.961. Moreover, patients with low expression levels of these six genes exhibited elevated T/N pathological stage and Gleason score, implying a more advanced disease state. Meanwhile, their progression-free survival (PFS) was observed to be potentially poorer. Finally, a significant association could be observed between the expression of these genes and the dysregulation of immune cells, along with drug sensitivity. CONCLUSIONS: In summary, our study identified six hub genes, namely SLC14A1, COL4A6, MYOF, FLRT3, KRT15, and LAMB3, which can be utilized to establish a diagnostic model for PCa. The discovery may offer potential molecular targets for clinical diagnosis and treatment of PCa.

Network pharmacology, molecular docking, and in vitro study on Aspilia pluriseta against prostate cancer.

BACKGROUND: Current prostate cancer treatments are associated with life-threatening side effects, prompting the search for effective and safer alternatives. Aspilia pluriseta Schweinf. ex Engl. has previously shown anticancer activity in lung and liver cancer cell lines. This study investigated its potential for prostate cancer. METHODS: A crude extract of A. pluriseta root was prepared using dichloromethane/methanol (1:1 v/v) and partitioned into hexane, ethyl acetate, and water fractions. The MTT assay was used to assess the antiproliferative activity of the fractions. The active fractions were tested at 6.25-200 µg/ml on human prostate cancer DU-145 cells and non-cancerous Vero E6 cells. Qualitative phytochemical and gas chromatography-mass spectrometry (GC-MS) analyses were conducted to identify chemical compounds. Network pharmacology was employed to predict molecular targets and modes of action of the identified chemical compounds, with subsequent validation through molecular docking and real-time PCR. RESULTS: Active extracts included crude dichloromethane/methanol, hexane, and ethyl acetate fractions, inhibiting DU-145 cell proliferation with IC50 values of 16.94, 20.06, and 24.14 µg/ml, respectively. Selectivity indices were determined to be 6.04 (crude), 3.62 (hexane), and 6.68 (ethyl acetate). Identified phytochemicals comprised phenols, terpenoids, flavonoids, tannins, sterols, and saponins. GC-MS analysis revealed seventy-nine (79) compounds, with seven (7) meeting ideal drug candidate parameters; their hub gene targets included MAPK3, MAPK1, IL6, TP53, ESR1, PTGS2, MMP9, MDM2, AR, and MAP2K1, implicating regulation of PI3K/Akt, MAPK, and p53 signaling pathways as potential modes of action. Core compounds such as 1-heneicosanol, lanosterol, andrographolide, and retinoic acid exhibited strong binding activities, particularly lanosterol with MAPK21 (-9.7 kcal/mol), ESR1 (-8.9 kcal/mol), and MAPK3 (-8.8 kcal/mol). Treatment with A. pluriseta downregulated AR expression and upregulated p53, while also downregulating CDK1 and BCL-2 and upregulating caspase-3. CONCLUSIONS: A. pluriseta extracts inhibited DU-145 cell growth without causing cellular toxicity, suggesting great potential for development as an anti-prostate cancer agent. However, further in vitro and in vivo experiments are recommended.

Causal relationship between folic acid and prostate cancer risk: Insights from Mendelian randomization analysis.

OBJECTIVE: Folic acid is a commonly used dietary supplement of trace element, but it may increase the risk of prostate cancer (PCa). The aim of this study was to investigate the causal relationship between PCa and folic acid supplementation, as well as dietary folate equivalents, using Mendelian randomization (MR) analysis. METHODS: The Genome-Wide Association Study (GWAS) data of folic acid supplementation and dietary folate equivalents were selected from UK Biobank. Meta-analysis of GWASs of PCa was obtained from PCa Association Group to Investigate Cancer-Associated Alterations in the Genome consortium. MR analysis was performed with inverse variance weighted (IVW) method, MR-Egger regression, simple mode, weighted median, and weighted mode analysis. Heterogeneity and horizontal pleiotropy tests and reverse MR analysis were conducted to assess the robustness and reliability of the causal inference. RESULTS: Six single nucleotide polymorphisms (SNPs) associated with folic acid supplementation and five SNPs associated with dietary folate equivalents were identified as instrumental variables. Genetically predicted folic acid supplementation was associated with an increased risk of PCa (OR 1.200, p < 0.001, by IVW method), and there was no evidence of heterogeneity, horizontal pleiotropy, or significant reverse causality (all p > 0.05). In contrast, dietary folate equivalents showed no significant correlation with PCa (p > 0.05 for all five MR methods). CONCLUSION: This study demonstrated an association between increased risk of PCa and folic acid supplementation, but not with dietary folate equivalents. These findings have implications for public health interventions and personalized preventive strategies for PCa.