The potential role of purinergic signaling in cancer therapy: perspectives on anti-CD73 strategies for prostate cancer.

Purines and pyrimidines are signaling molecules in the tumor microenvironment that affect cancer immunity. The purinergic signaling pathways have been shown to play an important role in the development and progression of cancer. CD39 and CD73 are ectonucleotidases responsible for breaking down ATP or ADP into adenosine, which regulates immunosuppression in various types of cancer. These enzymes have been studied as a potential therapeutic target in immunotherapy, and recent research suggests a correlation between ectonucleotidases and clinical outcomes in cancer.Prostate cancer is the most diagnosed cancer in men, after non-melanoma skin tumors, and is the second leading cause of death in men in the world. Despite having long survival periods, patients often receive excessive or insufficient treatment. Within this complex landscape, the adenosine/CD73 pathway plays a crucial role. Therefore, this review aims to highlight new findings on the potential role of purinergic signaling in cancer treatment and emphasizes the importance of anti-CD73 as a pharmacological strategy for prostate cancer therapy.

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.

Chemotactic signaling pathways in prostate cancer: Implications in the tumor microenvironment and as potential therapeutic targets.

Prostate cancer (PCa) stands as a significant global health concern, ranking among the leading causes of cancer deaths in men. While there are several treatment modalities for localized PCa, metastatic castration-resistant PCa (mCRPC) remains incurable. Despite therapeutic advancements showing promise in mCRPC, their impact on overall survival has been limited. This chapter explores the process by which tumors form, reviews our current understanding of PCa progression to mCRPC, and addresses the challenges of boosting anti-tumor immune responses in these tumors. It specifically discusses how chemotactic signaling affects the tumor microenvironment and its role in immune evasion and cancer progression. The chapter further examines the rationale of directly or indirectly targeting these pathways as adjuvant therapies for mCRPC, highlighting recent pre-clinical and clinical studies currently underway. The discussion emphasizes the potential of targeting specific chemokines and chemokine receptors as combination therapies with mainstream treatments for PCa and mCRPC to maximize long-term survival for this deadly disease.

Comprehensive Analysis of Metastatic Prostate Cancer: Real-World Data From the Middle East.

PURPOSE: Metastatic prostate cancer (Pca) is a complex disease with diverse clinical characteristics and outcomes across the geographical distribution. Herein, we present a series of patients from the Middle East, aiming at identifying disease outcomes and prognostic factors specific to this regional context. METHODS AND MATERIALS: This is a retrospective study of patients with metastatic Pca, diagnosed at King Hussein Cancer Center, Jordan, between 2006 and 2018. Survival was estimated using the Kaplan-Meier method and compared using the log-rank test. Factors that significantly affected overall survival (OS) in the univariable analysis were examined in a multivariable Cox regression analysis. RESULTS: A total of 188 patients with metastatic Pca were included in this analysis, of whom 168 (89%) had de novo metastatic disease. The median age at diagnosis was 68 years, 144 (77%) had bone metastasis, 32 (17%) had visceral metastasis, and 126 (67%) had high-volume disease. At a median follow-up of 67 months, the median OS was 44.3 months. The following factors predicted inferior OS in univariable analysis: smoking, normal BMI, high-volume disease, high alkaline phosphatase (ALP), previous local therapy for prostate, and orchiectomy versus medical androgen deprivation therapy (ADT). On multivariable analysis, high-volume disease (hazard ratio [HR], 1.92 [95% CI, 1.17 to 3.13]; P = .0094), high ALP (HR, 2.136 [95% CI, 1.38 to 3.31]; P < .001), and orchiectomy (HR, 2.40 [95% CI, 1.51 to 3.82]; P < .001) emerged as independent factors for inferior OS. CONCLUSION: Metastatic Pca outcomes in our population closely align with the global benchmark. High volume status, elevated ALP, and performance of surgical as opposed to medical ADT emerge as prognostic indicators of poor survival.

The multifaceted role of the stroma in the healthy prostate and prostate cancer.

Prostate cancer (PC) is an age-related disease and represents, after lung cancer, the second cause of cancer death in males worldwide. Mortality is due to the metastatic disease, which mainly involves the bones, lungs, and liver. In the last 20 years, the incidence of metastatic PC has increased in Western Countries, and a further increase is expected in the near future, due to the population ageing. Current treatment options, including state of the art cancer immunotherapy, need to be more effective to achieve long-term disease control. The most significant anatomical barrier to overcome to improve the effectiveness of current and newly designed drug strategies consists of the prostatic stroma, in particular the fibroblasts and the extracellular matrix, which are the most abundant components of both the normal and tumor prostatic microenvironment. By weaving a complex communication network with the glandular epithelium, the immune cells, the microbiota, the endothelium, and the nerves, in the healthy prostatic microenvironment, the fibroblasts and the extracellular matrix support organ development and homeostasis. However, during inflammation, ageing and prostate tumorigenesis, they undergo dramatic phenotypic and genotypic changes, which impact on tumor growth and progression and on the development of therapy resistance. Here, we focus on the characteristics and functions of the prostate associated fibroblasts and of the extracellular matrix in health and cancer. We emphasize their roles in shaping tumor behavior and the feasibility of manipulating and/or targeting these stromal components to overcome the limitations of current treatments and to improve precision medicine's chances of success.

Demographics, Histopathology, and Treatment Outcomes of Squamous Cell Carcinoma of the Prostate.

BACKGROUND: Squamous cell carcinoma of the prostate (SCCP) is a neoplasm that comprises fewer than 1% of all primary prostate cancer diagnoses. Given its rarity, there is a paucity of data regarding the treatment of this disease. The limited literature points to the potential of local therapy in conjunction with chemotherapy to improve patient mortality. METHODS: Using the National Cancer Initiative's Surveillance, Epidemiology, and End Results (SEER) database, a retrospective review of patients diagnosed with primary SCCP between 2000 and 2018 was performed. Patient demographics, tumor characteristics, and patient outcomes based on treatment modality were analyzed. Univariate and survival analyses were conducted with p < 0.05 indicating statistical significance. RESULTS: A total of 66 patients were identified. Five-year overall survival (5y OS) was 24%; mean and median survival were 2.2 years (1.8, 2.7) and 1.2 years (0.3, 2.1), respectively. Patients with Grade I or Grade II disease had an increased 5y OS of 55% (27%, 83%). In comparison, 5y OS was 13% (-2%, 29%) for patients with Grade III and Grade IV disease (p = 0.017). Analysis of 5y OS based on disease histology revealed patients with papillary SCC had a 5y OS of 50% [9.2%, 91%], compared to 21% [9%, 34%] for patients with SCC, not otherwise specified and 0% for those with lymphoepithelial carcinoma (p = 0.048). Analysis of 5y OS stratified by treatment modality revealed no statistically significant change with any treatment (surgery, radiotherapy, and chemotherapy). No difference in 5y OS was seen between those treated with radical prostatectomy versus external beam radiation therapy. CONCLUSIONS: The literature on SCCP remains sparse; the rarity of this disease limits analysis. While the investigation undertaken in this paper does not find any change in 5y OS regardless of treatment modality, the variation in 5y OS based on histologic classification of SCCP points to a potential route for the future treatment of this disease.

Systemic treatments for advanced prostate cancer: relationship between health insurance plan and treatment costs.

OBJECTIVES: The high costs of cancer care can cause significant harm to patients and society. Prostate cancer, the leading nonskin malignancy in men, is responsible for the second-highest out-of-pocket (OOP) payments among all malignancies. Multiple first-line treatment options exist for metastatic castration-resistant prostate cancer (mCRPC); although their costs vary substantially, comparative effectiveness data are limited. There is little evidence of how gross payments made by insurers and OOP payments made by patients differ by treatment and health plan type and how these payment differences relate to utilization. STUDY DESIGN: Retrospective cohort study. METHODS: We used IBM MarketScan databases from 2013-2019 to identify men with prostate cancer who initiated treatment with 1 of 6 drugs approved for first-line treatment of mCRPC. We calculated and compared gross and OOP payments and drug utilization across drug and insurance plan types. RESULTS: We identified 4298 patients who met our inclusion criteria. Insurer payments varied substantially by first-line therapy but were similar across different health plan types, except for docetaxel. OOP payments for a given first-line therapy, in contrast, varied by health plan type. Utilization of first-line therapies varied by plan type in unadjusted analyses, but not after adjusting for patient characteristics. CONCLUSIONS: The extent to which patient OOP payments for drugs reflect differences in gross payments made by insurers varies across health insurance plan types. However, even though OOP payments for the same treatment differ across plan types, treatment choice is not significantly different across type of health insurance after controlling for patient characteristics.

Heme Oxygenase-1 and Prostate Cancer: Function, Regulation, and Implication in Cancer Therapy.

Prostate cancer (PC) is a significant cause of mortality in men worldwide, hence the need for a comprehensive understanding of the molecular mechanisms underlying its progression and resistance to treatment. Heme oxygenase-1 (HO-1), an inducible enzyme involved in heme catabolism, has emerged as a critical player in cancer biology, including PC. This review explores the multifaceted role of HO-1 in PC, encompassing its function, regulation, and implications in cancer therapy. HO-1 influences cell proliferation, anti-apoptotic pathways, angiogenesis, and the tumor microenvironment, thereby influencing tumor growth and metastasis. HO-1 has also been associated with therapy resistance, affecting response to standard treatments. Moreover, HO-1 plays a significant role in immune modulation, affecting the tumor immune microenvironment and potentially influencing therapy outcomes. Understanding the intricate balance of HO-1 in PC is vital for developing effective therapeutic strategies. This review further explores the potential of targeting HO-1 as a therapeutic approach, highlighting challenges and opportunities. Additionally, clinical implications are discussed, focusing on the prognostic value of HO-1 expression and the development of novel combined therapies to augment PC sensitivity to standard treatment strategies. Ultimately, unraveling the complexities of HO-1 in PC biology will provide critical insights into personalized treatment approaches for PC patients.

Prostate-Specific Membrane Antigen Biology and Pathophysiology in Prostate Carcinoma, an Update: Potential Implications for Targeted Imaging and Therapy.

Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, was shown to be expressed 100-1000 fold higher in prostate adenocarcinoma as compared to normal prostate epithelium. Given the enzymatic function of PSMA with the presence of an internalization triggering motif, various Glu-urea-Lys-based inhibitors have been developed and, amongst others, radiolabeled with positron emitters for targeted positron emission tomography imaging such as 68Ga-PSMA-HBED-CC Glu-urea-Lys(Ahx) as well as with beta and alpha-emitting radioisotopes for targeted therapy, e.g., 177Lu-PSMA-617. In this paper, we review and discuss the potential implications for targeted imaging and therapy of altered PSMA-glycosylation, of PSMA-driven activation of the P13K/Akt/mTOR, of the evolution over time and the relationship with androgen signaling and changes in DNA methylation of PSMA, and of androgen deprivation therapy (ADT) in prostate carcinoma.

Prostate cancer temporal and regional trends in Brazil.

Objectives: The Brazilian Unified Health System (Sistema Único de Saúde-SUS) is the universal public healthcare system of Brazil that maintains a nationwide database of its patients. Our primary objective was to analyze regional and temporal trends, while our secondary goal was to establish correlations between states' health economy status and their prostate cancer (PCa) epidemiology. Methods: We analyzed Brazil's nationwide data on prostate cancer (PCa) incidence, mortality, and care gathered between 2013 and 2021 by the Information Technology Department of SUS (DATA-SUS), updated monthly using the International Classification of Diseases (ICD-10) code. Results: In the period, 273,933 new cases of PCa and 135,336 PCa deaths were reported in men aged 50 years or over in Brazil. The median annual PCa-specific incidence rate (PCSIR) ranged from 14.7 in the Southeast to 6.9 in the North region and the median annual PCa-specific mortality rate (PCSMR) ranged from 7.7 in the Northeast to 6.0 in the South region (per 10,000 men >50). The median annual mortality to incidence ratio (MIR) was highest in the North (0.88) and lowest in the Southeast region (0.44). There were significant regional differences in PCa treatment rates (per new cases); the Midwest region had the highest median annual surgery rate (0.63) while the North region had the highest median annual systemic therapy rate (0.75) and the lowest radiation therapy rate (0.06). Temporal analysis of the data showed significant change in annual rate trends after the year 2018 for PCSIR (coefficient [ß] = +3.66, p < 0.001), any treatment (ß = -0.06, p = 0.016), surgery ([SR] ß = +0.05, p = 0.017) radiation therapy ([RTR] ß = -0.06, p = 0.005) and systemic therapy ([STR] ß = -0.10, p = 0.002). After the 2020 pandemic, annual PCSIR decreased (ß = -2.15, p = 0.002) but annual PCSMR, MIR, and treatment rates remained stable. Correlation studies showed that the PCSIR was strongly negatively correlated with STR (p < 0.001) and positively correlated with RTR (p = 0.004). MIR was positively correlated with STR (p < 0.001) and negatively correlated with the number of robotic surgical systems per million population (p = 0.003). Conclusion: Our data shows that PCa care is dependent on the region and is likely influenced by access to treatment options. Furthermore, changes after the year 2018 underscore the influence of international guidelines on Brazilian clinicians' decision-making especially concerning population screening which in turn affected incidence and treatment rates. Limitation of our study includes limited patient-related information and data on private practices as well as an unknown impact of traveling patients.

MR-guided Focused Ultrasound Focal Therapy for Prostate Cancer.

Prostate cancer (PCa) is a prevalent malignancy in men, and the management of localized disease has evolved significantly in recent years. Focal therapy, wherein the biopsy confirmed site of tumor with margins is treated leaving the remaining gland intact, has emerged as a promising strategy for treating localized clinically significant PCa, minimizing side effects associated with radical therapies. We present the technical aspects, a summary of the most relevant evidence to date on the performance and safety of this technique, and the characteristic MR imaging findings during treatment, in the early posttreatment period and in the long term.

Immunoliposome-based targeted delivery of the CRISPR/Cas9gRNA-IL30 complex inhibits prostate cancer and prolongs survival.

The development of selective and nontoxic immunotherapy targeting prostate cancer (PC) is challenging. Interleukin (IL)30 plays immunoinhibitory and oncogenic roles in PC, and its tumor-specific suppression may have significant clinical implications. CRISPR/Cas9-mediated IL30 gene deletion in PC xenografts using anti-PSCA antibody-driven lipid nanocomplexes (Cas9gRNA-hIL30-PSCA NxPs) revealed significant genome editing efficiency and circulation stability without off-target effects or organ toxicity. Biweekly intravenous administration of Cas9gRNA-hIL30-PSCA NxPs to PC-bearing mice inhibited tumor growth and metastasis and improved survival. Mechanistically, Cas9gRNA-hIL30-PSCA NxPs suppressed ANGPTL 1/2/4, IL1ß, CCL2, CXCL1/6, SERPINE1-F1, EFNB2, PLG, PF4, VEGFA, VEGFD, ANG, TGFß1, EGF and HGF expression in human PC cells while upregulated CDH1, DKK3 and PTEN expression, leading to low proliferation and extensive ischemic necrosis. In the syngeneic PC model, IL30-targeting immunoliposomes downregulated NFKB1 expression and prevented intratumoral influx of CD11b+Gr-1+MDCs, Foxp3+Tregs, and NKp46+RORγt+ILC3, and prolonged host survival by inhibiting tumor progression. This study serves as a proof of principle that immunoliposome-based targeted delivery of Cas9gRNA-IL30 represent a potentially safe and effective strategy for PC treatment.

Tailoring language for genitourinary function in patients with newly diagnosed prostate cancer to facilitate discussions in diverse populations and overcome health literacy barriers.

BACKGROUND: Poor comprehension of prostate cancer (PCa) medical terms can create barriers to PCa treatment discussions. The authors measured comprehension of PCa terms and its relationship to health literacy in a group of Black men who were newly diagnosed with PCa. They examined whether tailoring communication with alternative colloquial words would be helpful and acceptable. METHODS: Patients were recruited from urology clinics (N = 152). After they met with their providers to discuss PCa treatment options, they participated in an educational supplement delivered as a structured interview. The supplement tailored PCa treatment information by allowing men to choose between colloquial and medical terms for genitourinary (GU) function. Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine, and comprehension of common PCa terms was assessed using published methods. Pearson correlation was used to estimate the association between health literacy and comprehension of PCa terms. Spearman rank correlation (r) was used to assess the relation between the total number of medical terms preferred (range, 0-10) and Rapid Estimate of Adult Literacy in Medicine scores (range, 0-66). RESULTS: Most patients (62%) had low health literacy, which was strongly correlated with their understanding of PCa terms (r = 0.526; p < .001). Poor comprehension of many PCa terms established the need to use alternative language for GU function (only 20% knew the word incontinence). There was a statistically significant positive association between the number of medical terms preferred and health literacy (r = 0.358; p < .001). A majority of patients (91%) preferred a mixture of medical and colloquial terms. CONCLUSIONS: Tailoring communications with colloquial terms for GU function was preferred by most patients regardless of health literacy.

Identification of cancer stem cell-related genes through single cells and machine learning for predicting prostate cancer prognosis and immunotherapy.

Background: Cancer stem cells (CSCs) are a subset of cells within tumors that possess the unique ability to self-renew and give rise to diverse tumor cells. These cells are crucial in driving tumor metastasis, recurrence, and resistance to treatment. The objective of this study was to pinpoint the essential regulatory genes associated with CSCs in prostate adenocarcinoma (PRAD) and assess their potential significance in the diagnosis, prognosis, and immunotherapy of patients with PRAD. Method: The study utilized single-cell analysis techniques to identify stem cell-related genes and evaluate their significance in relation to patient prognosis and immunotherapy in PRAD through cluster analysis. By utilizing diverse datasets and employing various machine learning methods for clustering, diagnostic models for PRAD were developed and validated. The random forest algorithm pinpointed HSPE1 as the most crucial prognostic gene among the stem cell-related genes. Furthermore, the study delved into the association between HSPE1 and immune infiltration, and employed molecular docking to investigate the relationship between HSPE1 and its associated compounds. Immunofluorescence staining analysis of 60 PRAD tissue samples confirmed the expression of HSPE1 and its correlation with patient prognosis in PRAD. Result: This study identified 15 crucial stem cell-related genes through single-cell analysis, highlighting their importance in diagnosing, prognosticating, and potentially treating PRAD patients. HSPE1 was specifically linked to PRAD prognosis and response to immunotherapy, with experimental data supporting its upregulation in PRAD and association with poorer prognosis. Conclusion: Overall, our findings underscore the significant role of stem cell-related genes in PRAD and unveil HSPE1 as a novel target related to stem cell.

The economic burden of prostate cancer in Iran: a cross-sectional cost-of-illness study.

OBJECTIVE: This study aims to assess the economic burden of prostate cancer in Iran by analyzing direct medical costs, direct non-medical costs, and indirect costs. We conducted a cross-sectional cost-of-illness study in Khorramabad, located in western Iran, during 2023, using a prevalence-based, bottom-up approach. Data were collected from 285 prostate cancer patients using questionnaires, interviews, and patient records. RESULTS: Our study estimated the economic burden of prostate cancer at $744,990. Direct medical costs accounted for 63.50% of this, totaling $153,330, with therapy being the largest component. Direct non-medical costs were $62,130, and indirect costs from productivity losses were $209,760. The calculated overall cost per patient was $2,614.88. Extrapolating from the 2021 Global Burden of Disease data, which reported approximately 83,000 prostate cancer patients in Iran, the national economic burden is estimated at $217,034,040. This substantial burden highlights the need for improved insurance coverage and early detection. The findings suggest that policymakers and healthcare providers in Iran should develop standardized cost analysis methods and enhance financial protection to alleviate economic strain and improve healthcare outcomes and sustainability.

A costing and health-related quality of life study of high intensity focused ultrasound in primary treatment of localized low or intermediate risk prostate cancer in Ontario.

INTRODUCTION: Prostate cancer is the third leading cause of death from cancer among Canadian men. High intensity focused ultrasound (HIFU) is a novel approach for primary treatment of localized prostate cancer. Little is known, however, about its costs. We aimed to collect the direct costs and health-related quality of life (HRQoL) data of HIFU in primary treatment of localized low and intermediate risk prostate cancer in Ontario. MATERIALS AND METHODS: We collected direct costs and HRQoL data of 20 patients with localized low or intermediate risk prostate cancer who received whole-gland HIFU at a privately owned clinic in Ontario. We compared the direct costs of HIFU, open radical prostatectomy (ORP), robot assisted radical prostatectomy (RARP), and external beam radiation therapy (RT) in primary treatment of localized low and intermediate risk prostate cancer. RESULTS: The average direct costs of HIFU, ORP, RARP, and RT per case in 2023 are $14,886.78, $14,192.26, $21,794.55, and $17,377.51, respectively. The median and interquartile range (IQR) of the study participants' age and HRQoL data prior to the HIFU procedure were 64.5 (11.25) years, 94.5 (8.65), 38.5 (4), 6.0 (4.46), and 22.5 (8.32), respectively. CONCLUSION: Our healthcare payer's perspective costing study revealed median direct costs per case of HIFU and favorable HRQoL outcomes compared to other treatment options for primary treatment of localized low and intermediate risk prostate cancer in Ontario. A health economic model is warranted to analyze the cost-effectiveness of HIFU compared to other treatment options in primary treatment of localized low and intermediate risk prostate cancer.

Molecular mechanisms and targeted therapy for the metastasis of prostate cancer to the bones (Review).

The incidence of prostate cancer (PCa) is increasing, making it one of the prevalent malignancies among men. Metastasis of PCa to the bones poses the greatest danger to patients, potentially resulting in treatment ineffectiveness and mortality. At present, the management of patients with bone metastasis focuses primarily on providing palliative care. Research has indicated that the spread of PCa to the bones occurs through the participation of numerous molecules and their respective pathways. Gaining knowledge regarding the molecular processes involved in bone metastasis may result in the development of innovative and well­tolerated therapies, ultimately enhancing the quality of life and prognosis of patients. The present article provides the latest overview of the molecular mechanisms involved in the formation of bone metastatic tumors from PCa. Additionally, the clinical outcomes of targeted drug therapies for bone metastasis are thoroughly analyzed. Finally, the benefits and difficulties of targeted therapy for bone metastasis of PCa are discussed, aiming to offer fresh perspectives for treatment.