Prostate Cancer Morbidity Research Articles

Identification and validation of cigarette smoking-related genes in predicting prostate cancer development through bioinformatic analysis and experiments

The morbidity and mortality rates of prostate cancer (PCa) are high among elderly men worldwide. Several factors, such as heredity, obesity, and environment are associated with the occurrence of PCa. Cigarette smoking, which is also an important factor in the development of PCa, can lead to genetic alterations and consequently promote PCa development. However, the smoking-induced genetic alterations in PCa are unclear. This study aimed to identify the potential smoking-related genes associated with PCa development. The smoking-related differentially expressed genes (DEGs) were identified using the Gene Expression Omnibus (GEO) which included lots of PCa datasets. DEGs were subjected to protein–protein interaction (PPI) network analysis to identify the hub genes. The pathways in which these hub genes were enriched were identified. The Cancer Genome Atlas (TCGA) dataset was used to examine the expression of smoking-related genes in PCa samples and estimate their value in predicting tumor progression and prognosis. In total, 110 smoking-related DEGs were got from GSE68135 dataset which included microarray data of PCa patients with smoking or not and 14 smoking-related key genes associated with PCa were identified from PPI network. The expression of the following seven key genes was altered in TCGA PCa patients: EWSR1, SRSF6, COL6A3, FBLN1, DCN, CYP2J2, and PLA2G2A. EWSR1, SRSF6, FBLN1, and CYP2J2 also influenced PCa progression. Additionally, EWSR1 influenced disease-free survival. In the logistic regression model, CYP2J2, which exhibited the highest risk scores, was identified as the risk gene for PCa. We also found one of the smoking-related genes: EWSR1 was truly upregulated in clinical PCa patients and influenced PCa cells invasion and proliferation. This study identified the function of smoking-related genes involved in the progression of PCa.

EphA2 regulates vascular permeability and prostate cancer metastasis via modulation of cell junction protein phosphorylation.

Prostate cancer morbidity and mortality demonstrate a need for more effective targeted therapies. One potential target is EphA2, although paradoxically, pro- and anti-oncogenic effects have been shown to be mediated by EphA2. We demonstrate that unique activating and blocking EphA2-targeting monoclonal antibodies display opposing tumor-suppressive and oncogenic properties in vivo. To further explore this complexity, we performed detailed phosphoproteomic analysis following ligand-induced EphA2 activation. Our analysis identified altered phosphorylation of 73 downstream proteins related to the PI3K/AKT/mTOR and ERK/MAPK pathways, with the majority implicated in cell junction and cytoskeletal organization, cell motility, and tumor metastasis. We demonstrate that the adapter protein SHB is an essential component in mediating the inhibition of the ERK/MAPK pathway in response to EphA2 receptor activation. Furthermore, we identify the adherence junction protein afadin as an EphA2-regulated phosphoprotein which is involved in prostate cancer migration and invasion.

Phytochemicals a Noval Approach as Therapeutic in Prostate Cancer Treatment

Prostate cancer stands as a prominent cause of mortality among men globally. The escalating challenges of resistance, toxicity, and side effects associated with traditional treatments have propelled a shift toward more intensive and aggressive approaches in prostate cancer treatment. The persistent rise in incidence coupled with the inadequacy of conventional therapies in managing advanced prostate cancer necessitates the exploration and development of innovative agents for both the treatment and prevention of this malignancy. The utilization of naturally occurring compounds in chemoprevention has emerged as a promising and cost-effective strategy in recent decades. This approach aims to decrease the incidence and morbidity of prostate cancer (PCa) by inhibiting precancerous events before the onset of clinical disease [28]. Prostate cancer (PCa) presents a substantial opportunity for intervention to prevent or impede its progression. With its high incidence and extended latency, PCa remains an ideal candidate for chemoprevention. Pursuing agents that provide substantial protection against the development of this disease is crucial. The discovery of effective chemopreventive agents could have a considerable impact on disease-related costs, morbidity, and mortality for a significant portion of the population

Racial disparity in prostate cancer: an outlook in genetic and molecular landscape.

Prostate cancer (PCa) incidence, morbidity, and mortality rates are significantly impacted by racial disparities. Despite innovative therapeutic approaches and advancements in prevention, men of African American (AA) ancestry are at a higher risk of developing PCa and have a more aggressive and metastatic form of the disease at the time of initial PCa diagnosis than other races. Research on PCa has underlined the biological and molecular basis of racial disparity and emphasized the genetic aspect as the fundamental component of racial inequality. Furthermore, the lower enrollment rate, limited access to national-level cancer facilities, and deferred treatment of AA men and other minorities are hurdles in improving the outcomes of PCa patients. This review provides the most up-to-date information on various biological and molecular contributing factors, such as the single nucleotide polymorphisms (SNPs), mutational spectrum, altered chromosomal loci, differential gene expression, transcriptome analysis, epigenetic factors, tumor microenvironment (TME), and immune modulation ofPCa racial disparities. This review also highlights future research avenues to explore the underlying biological factors contributing to PCa disparities, particularly in men of African ancestry.

Disrupting prostate cancer research: Challenge accepted; report from the 2023 Coffey-Holden Prostate Cancer Academy Meeting.

The 2023 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, themed "Disrupting Prostate Cancer Research: Challenge Accepted," was convened at the University of California, Los Angeles, Luskin Conference Center, in Los Angeles, CA, from June 22 to 25, 2023. The 2023 marked the 10th Annual CHPCA Meeting, a discussion-oriented scientific think-tank conference convened annually by the Prostate Cancer Foundation, which centers on innovative and emerging research topics deemed pivotal for advancing critical unmet needs in prostate cancer research and clinical care. The 2023 CHPCA Meeting was attended by 81 academic investigators and included 40 talks across 8 sessions. The central topic areas covered at the meeting included: targeting transcription factor neo-enhancesomes in cancer, AR as a pro-differentiation and oncogenic transcription factor, why few are cured with androgen deprivation therapy and how to change dogma to cure metastatic prostate cancer without castration, reducing prostate cancer morbidity and mortality with genetics, opportunities for radiation to enhance therapeutic benefit in oligometastatic prostate cancer, novel immunotherapeutic approaches, and the new era of artificial intelligence-driven precision medicine. This article provides an overview of the scientific presentations delivered at the 2023 CHPCA Meeting, such that this knowledge can help in facilitating the advancement of prostate cancer research worldwide.

Abstract 4437: Dysregulated lipid metabolism and high-fat diet influences prostate cancer (PCa) progression

Abstract Dysregulation of lipid metabolism is observed during the development and progression of various types of cancer including prostate cancer (PCa). Systemic metabolic changes driven by genetic alterations in conjunction with obesity and a high-fat diet have been demonstrated to induce PCa progression. In this study, we aimed to investigate the impact of high- and low-fat diets on the progression and morbidity of prostate cancer, utilizing inducible genetically engineered mouse models (GEMMs) that mimic different grades of prostate cancer. The mice were initially placed on a standard diet until week 6, after which they were randomly assigned to either a low-fat or high-fat diet. At week 8, the Cre recombinase enzyme was activated to induce the desired phenotype in the GEMMs, effectively mimicking the initiation and progression of prostate cancer. The experimental design allowed us to gain insights into the interplay between dysregulated lipid metabolism, diet, and the pathogenesis of prostate cancer. Two groups of mice were taken for the study, with one group being fed a low-fat diet and the other group being fed a high-fat diet. The mice were maintained on their respective diets for a period of 1, 3, and 5 months. At each endpoint, tissue samples were collected. Samples were taken from the prostate, plasma, and liver tissues. These samples were then subjected to various analyses to investigate the changes occurring at the molecular and cellular level. Blood was collected to determine lipidomic content in response to high and low-fat diet and the relation of tumour progression. Finally, faecal samples were collected throughout the duration of the experiment to perform metagenomic studies. The consumption of a high-fat diet significantly increased the body weight of the mice which corresponded to increased liver weight. Furthermore, we identified that the consumption of a high-fat diet significantly correlated with an increase in prostate weight at 3 and 5 months after initiation. Preliminary metabolomic analysis of the plasma revealed a distinct clustering of samples based on the consumed diet. Metagenomic analyses conducted at 1 and 3 months indicated a visible shift in the composition and diversity of gut microbiota in mice fed either a high- or low-fat diet. In conclusion, our study will shed light on the influence of dietary factors on prostate cancer development, providing valuable information for the development of targeted therapeutic strategies to combat this disease. Citation Format: Saurav Subedi, Federico La Manna, Katja Ovchinnikova, Eugenio Zoni, Nicola Zamboni, Bahtiyar Yilmaz, George N. Thalmann, Marianna Kruithof-de Julio. Dysregulated lipid metabolism and high-fat diet influences prostate cancer (PCa) progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4437.

Protocol of a randomised, controlled trial comparing immediate curative therapy with conservative treatment in men aged ≥75 years with non-metastatic high-risk prostate cancer (SPCG 19/GRand-P).

Older men (aged ≥75 years) with high risk, non-metastatic prostate cancer (PCa) are increasingly treated with curative therapy (surgery or radiotherapy). However, it is unclear if curative therapy prolongs life and improves health-related quality of life (HRQoL) in this age group compared to conservative therapy, which has evolved considerably during the last decade. The Scandinavian Prostate Cancer Group (SPCG) 19/Norwegian Get-Randomized Research Group-Prostate (GRand-P) is a randomised, two-armed, controlled, multicentre, phase III trial carried out at study centres in Norway, Denmark, Finland, and Sweden. The primary endpoints are overall survival and HRQoL (burden of disease scale, European Organisation for the Research and Treatment of Cancer [EORTC] Elderly Cancer patients). Secondary endpoints are PCa-specific survival, metastasis-free survival, role-functioning scale (EORTC quality of life questionnaire 30-item core), urinary irritative/obstructive scale (26-item Expanded Prostate Cancer Index Composite [EPIC-26]), bowel scale (EPIC-26), intervention-free survival, PCa morbidity, use of secondary and tertiary systemic therapies, mean quality-adjusted life-years (QALYs), and mean total healthcare costs. A total of 980 men (aged ≥75 years) with non-metastatic, high-risk PCa will initially be screened with Geriatric 8 (G8) health status screening tool and Mini-COG© brief cognitive test. Participants identified by G8 as 'fit' or 'frail' will be randomised (ratio 1:1) to either immediate curative therapy (radiotherapy or prostatectomy) or conservative therapy (endocrine therapy or observation). Participants who are unable or unwilling to participate in randomisation will be enrolled in a separate observation group. Randomised patients will be followed for 10 years. Ethics approval has been granted in Norway (457593), Denmark (H-22051998), Finland (R23043) and Sweden (Dnr 2023-05296-01). The trial is registered on Clinicaltrials.org (NCT05448547).

A study of Vitamin D and parathyroid hormone levels in patients with prostatic cancer

Background: Vitamin D, a key nutrient in the body, has been linked to a decrease in prostate cancer (PCa) morbidity and mortality rates. The study concluded that any compensation mechanism may no longer be adequate for patients with PCa, and further research is needed to understand the mechanisms underlying the relationship between serum Vitamin D and parathyroid hormone (PTH) homeostasis. The findings will help determine cancer prevalence and trends in India and support public health initiatives to control cancer. Aims and Objectives: The aim is to assess the mean values of Vitamin D and PTH in patients with PCa and also to compare these levels with that of healthy controls (non-PCa). Materials and Methods: One hundred participants in the outpatient department of the Department of Biochemistry were assigned as control subjects, and another 100 participants were participants with PCa. 5 mL of fasting venous blood were drawn into red top vials using a disposable syringe and needle in an aseptic manner. PTH and serum Vitamin D were estimated. Results: When comparing PCa patients to healthy controls, the observed Vitamin D level was significantly lower in the former group. Furthermore, a notable distinction in Vitamin D levels was noted between the two groups. Furthermore, we found that PCa patients had higher PTH values than healthy controls. When we compared the PTH values of the two groups, we found a substantial difference. Conclusion: The authors conclude from the study that with alterations in the study parameters in patients with PCa, any compensation mechanism may become insufficient.

Deep learning algorithm-based multimodal MRI radiomics and pathomics data improve prediction of bone metastases in primary prostate cancer

PurposeBone metastasis is a significant contributor to morbidity and mortality in advanced prostate cancer, and early diagnosis is challenging due to its insidious onset. The use of machine learning to obtain prognostic information from pathological images has been highlighted. However, there is a limited understanding of the potential of early prediction of bone metastasis through the feature combination method from various sources. This study presents a method of integrating multimodal data to enhance the feasibility of early diagnosis of bone metastasis in prostate cancer.Methods and materialsOverall, 211 patients diagnosed with prostate cancer (PCa) at Gansu Provincial Hospital between January 2017 and February 2023 were included in this study. The patients were randomized (8:2) into a training group (n = 169) and a validation group (n = 42). The region of interest (ROI) were segmented from the three magnetic resonance imaging (MRI) sequences (T2WI, DWI, and ADC), and pathological features were extracted from tissue sections (hematoxylin and eosin [H&E] staining, 10 × 20). A deep learning (DL) model using ResNet 50 was employed to extract deep transfer learning (DTL) features. The least absolute shrinkage and selection operator (LASSO) regression method was utilized for feature selection, feature construction, and reducing feature dimensions. Different machine learning classifiers were used to build predictive models. The performance of the models was evaluated using receiver operating characteristic curves. The net clinical benefit was assessed using decision curve analysis (DCA). The goodness of fit was evaluated using calibration curves. A joint model nomogram was eventually developed by combining clinically independent risk factors.ResultsThe best prediction models based on DTL and pathomics features showed area under the curve (AUC) values of 0.89 (95% confidence interval [CI], 0.799–0.989) and 0.85 (95% CI, 0.714–0.989), respectively. The AUC for the best prediction model based on radiomics features and combining radiomics features, DTL features, and pathomics features were 0.86 (95% CI, 0.735–0.979) and 0.93 (95% CI, 0.854–1.000), respectively. Based on DCA and calibration curves, the model demonstrated good net clinical benefit and fit.ConclusionMultimodal radiomics and pathomics serve as valuable predictors of the risk of bone metastases in patients with primary PCa.

Cellular senescence: A potential mode of circular RNAs regulating prostate cancer

AbstractCellular senescence is a state characterized by permanent cell cycle stoppage, which has long been viewed as a protective mechanism against neoplasia. However, accumulating evidence reveal that cellular senescence variously stimulates tumorigenesis and malignant progression in certain contexts. Senescence‐associated secretory phenotype (SASP) is a crucial feature of senescent cells and the main way they function. Prostate cancer (PCa) is apparently an age‐related tumor with a high prevalence in the elderly. With the aggravation of population aging the morbidity of PCa continues to rise. And with the progress of the disease, most patients eventually develop castration‐resistant PCa (CRPC) or drug resistance, which poses a challenge for the treatment of PCa and aggravates the burden on patients and society. Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs formed by back‐splicing of pre‐mRNAs. Characterized by special covalently closed circular structure, they play important regulatory roles in various tumors. Numerous studies have revealed that circRNAs can regulate PCa and cellular senescence in diverse ways. This review explores a potential mode that circRNAs regulate PCa, reveales a significant mechanism of tumorigenesis and progression for PCa, suggesting a new strategy for PCa research.

Androgen deprivation therapy and cardiovascular morbidity in prostate cancer: a narrative review

Prostate cancer is the most common malignancy in men, mostly affecting older men who harbor an increased prevalence of cardiovascular disease and metabolic syndrome. Androgen deprivation therapy (ADT), the standard therapy for various stages of prostate cancer, further increases the risk for cardiovascular disease and for metabolic syndrome. Therefore, screening for cardiovascular risk factors should be performed prior to the initiation of ADT, and, if necessary, cardiological evaluation and interdisciplinary management should be provided during and after completion of ADT. Moreover, the use of agonadotropin-releasing hormone (GnRH) antagonist may help reduce cardiovascular risk in patients with cardiovascular disease.

Racial disparities in new-onset diabetes mellitus in prostate cancer patients on androgen deprivation therapy: a retrospective analysis of TriNetX data.

Prostate cancer (PCa) is the most common cancer in men in the US and androgen deprivation therapy (ADT) is the most frequently used systemic therapy for PCa. Data suggest that ADT is associated with an increased risk of new-onset diabetes mellitus (NODM) and cardiovascular complications. As the incidence and mortality of PCa are highest among the African American (AA) population, it is important to evaluate the difference in the incidence of NODM and ischemic heart disease (IHD) between AA men compared to Caucasian men. This is a retrospective cohort study utilizing the TriNetX database to assess NODM and IHD risk, risk difference, and risk ratio (RR) after recent ADT initiation in an AA cohort and a Caucasian cohort of patients with PCa. Propensity score matching (PSM) was performed by age, BMI, and confounding comorbidities. After matching, the cohort included 1159 AA patients and 843 Caucasian patients with NODM after ADT initiation. The IHD cohort included 1269 AA patients and 1248 Caucasian patients. The risk of incidence of NODM is higher among AA men at 11.6% risk compared to Caucasian men at 7.4%. The risk difference is 4.1% (95% CI = 3.4, 4.9) p = 0.000. The RR is 1.56 (95% CI = 1.43, 1.70). In contrast, risk difference and risk ratio of IHD was not significant between AA and Caucasian groups. ADT exposure increases the risk of NODM in men with PCa, especially among AA men compared with Caucasian men. Men receiving ADT should be monitored routinely for signs and symptoms of metabolic syndrome and diabetes. Targeted close monitoring of AA men on ADT would be critical to prevent and treat metabolic complications with potential of reducing disparities in PCa morbidity.

Global Burden of Prostate Cancer and Association with Socioeconomic Status, 1990–2019: A Systematic Analysis from the Global Burden of Disease Study

ImportanceBoth the morbidity and mortality of prostate cancer are increasing worldwide. Updated evaluations of prostate cancer burden and its global, regional and national patterns are essential for formulating effective preventive strategies.ObjectiveTo investigate prostate cancer incidence, mortality, and disability-adjusted life years (DALYs) between 1990 and 2019 to facilitate preventive measures and control planning.MethodsAnnual incident cases, deaths, DALYs, age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and age-standardized DALYs rates (ASDRs) of prostate cancer between 1990 and 2019 were derived from the Global Burden of Diseases study 2019. Percentage changes in incident cases, deaths and DALYs and estimated annual percentage changes (EAPCs) in ASIRs, ASMRs and ASDRs were calculated to quantify temporal trends. Correlations between EAPCs and socio-demographic index (SDI) and universal health coverage index (UHCI) were evaluated by Pearson correlation analyses.ResultsGlobally, the number of incident cases, deaths, and DALYs of prostate cancer increased by 116.11%, 108.94%, and 98.25% from 1990 to 2019, respectively. The ASIR increased by an average of 0.26% (95% CI: 0.14%, 0.37%) per year between 1990 and 2019, while the ASMR and ASDR decreased by an average of – 0.75% (95% CI: – 0.84%, – 0.67%) and – 0.71% (95% CI: – 0.78%, – 0.63%) per year in this period, respectively. Epidemic trends in the burdens of prostate cancer were not uniform throughout different groups of SDI or geography. The burdens of prostate cancer varied across SDI regions, with an increasing trend in ASIR, ASMR, and ASDR in low and low-middle SDI regions between 1990 and 2019. A significant positive correlation between the EAPC in ASIR and UHCI was observed in countries with a UHCI < 70 (ρ = 0.37, p < 0.001).InterpretationProstate cancer remains a major global health burden due to the increase in incident cases, deaths, and DALYs in the past three decades. These increases are likely to continue as the population ages, which indicates a potential talent gap in the trained healthcare workforce. The diversity of prostate cancer development models implies the importance of specific local strategies tailored for each country’s risk factor profile. Prevention, early detection and more effective treatment strategies for prostate cancer are essential.

A Detailed Evaluation of the Effect of Prostate-specific Antigen–based Screening on Morbidity and Mortality of Prostate Cancer: 21-year Follow-up Results of the Rotterdam Section of the European Randomised Study of Screening for Prostate Cancer

BackgroundConsidering the long natural history of prostate cancer (PCa), long-term results of the European Randomised Study of Screening for PCa (ERSPC) are crucial. ObjectiveTo provide an update on the effect of prostate-specific antigen (PSA)-based screening on PCa-specific mortality (PCSM), metastatic disease, and overdiagnosis in the Dutch arm of the ERSPC. Design, setting, and participantsBetween 1993 and 2000, a total of 42376 men, aged 55–74 yr, were randomised to a screening or a control arm. The main analysis was performed with men aged 55–69 yr (n = 34831). Men in the screening arm were offered PSA-based screening with an interval of 4 yr. Outcome measurements and statistical analysisIntention-to-screen analyses with Poisson regression were used to calculate rate ratios (RRs) of PCSM and metastatic PCa. Results and limitationsAfter a median follow-up of 21 yr, the RR of PCSM was 0.73 (95% confidence interval [CI]: 0.61–0.88) favouring screening. The numbers of men needed to invite (NNI) and needed to diagnose (NND) to prevent one PCa death were 246 and 14, respectively. For metastatic PCa, the RR was 0.67 (95% CI: 0.58–0.78) favouring screening. The NNI and NND to prevent one metastasis were 121 and 7, respectively. No statistical difference in PCSM (RR of 1.18 [95% CI: 0.87–1.62]) was observed in men aged ≥70 yr at the time of randomisation. In the screening arm, higher rates of PCSM and metastatic disease were observed in men who were screened only once and in a selected group of men above the screening age cut-off of 74 yr. ConclusionsThe current analysis illustrates that with a follow-up of 21 yr, both absolute metastasis and mortality reduction continue to increase, resulting in a more favourable harm-benefit ratio than demonstrated previously. These data do not support starting screening at the age of 70–74 yr and show that repeated screening is essential. Patient summaryProstate-specific antigen–based prostate cancer screening reduces metastasis and mortality. Longer follow-up shows fewer invitations and diagnoses needed to prevent one death, a positive note towards the issue of overdiagnosis.

Disaggregating the effects of daytime and nighttime light exposures on obesity, overweight, prostate and breast cancer morbidity worldwide

ABSTRACT Hormone-dependent cancers and overweight/obesity are not necessarily linked but might have similar underlying causes, such as circadian disruption, lack of physical activity, and unhealthy nutrition. Several empirical studies also attribute the rise in these types of morbidity to vitamin D deficiency, linked in turn to insufficient sunlight exposure. Other studies place an emphasis on melatonin (MLT) hormone suppression, associated with artificial light at night (ALAN) exposure. Yet no studies, carried out to date, have attempted to determine which of these environmental risk factors is associated stronger with the morbidity types in question. In this study, we aim to narrow this knowledge gap by analyzing data available for 100+ countries worldwide, while controlling ALAN and solar radiation exposure estimates by several potential confounders, such as GDPpc, GINI inequality index and unhealthy food consumption. As the study reveals, all the morbidity types under analysis are significantly and positively associated with ALAN exposure estimates (p < 0.05), while solar radiation appears to be significantly associated with prostate cancer rates only (p < 0.05), but not with breast cancer or overweight/obesity rates (p > 0.1). To the best of our knowledge, this study is the first that separates the effects of ALAN and daylight exposures on the abovementioned types of morbidity.

The impact of life expectancy on cost-effectiveness of treatment options for clinically localized prostate cancer.

Life expectancy (LE) impacts effectiveness and morbidity of prostate cancer (CaP) treatment, but its impact on cost-effectiveness is unknown. We sought to evaluate the impact of LE on the cost-effectiveness of radical prostatectomy (RP), radiation therapy (RT), and active surveillance (AS) for clinically localized disease. We created a Markov model to calculate incremental cost-effectiveness ratios (ICERs) for RP, RT, and AS over a 20-year time horizon from a Medicare payer perspective for low- and intermediate-risk CaP. Mortality outcomes varied by tumor risk and PCCI score, a validated proxy for LE. We performed 1,000 Monte Carlo simulations with 1-way sensitivity analyses of PCCI within each tumor risk subgroup to compare cost/quality-adjusted life years (QALYs) between treatments. AS dominated RP and RT for low- and intermediate-risk disease in men with LE ≤10 years (PCCI ≥7 and ≥9, respectively). However, AS failed to dominate RP and RT for men with longer LE. For men with low-risk cancer and LE>10 years (PCCI 0-6), AS had the greatest effectiveness, but failed to dominate due to higher cost relative to RP. For men with intermediate-risk cancer with LE>10 years, AS failed to dominate due to higher cost relative to RP (PCCI 0-8) and lower effectiveness relative to RT (PCCI 0-3). The range of QALYs between RP, RT, and AS varied <13% (range: 0%-12.9%) while costs varied up to 521% (range 0.5%-521%) across PCCI scores. LE strongly modulates the cost of CaP treatments. This results in AS dominating RP and RT in men with LE ≤10 years. However, in men with longer LE, AS fails to dominate primarily due to its high cumulative costs, underscoring the need for risk-adjusted AS protocols.

99mTc-Labelled Low Molecular Weight Inhibitors of Prostate-Specific Membrane Antigen

High morbidity and mortality rates of prostate cancer (PCa) determine the requirement of looking for new methods of its early diagnosis. Methods of nuclear medicine have a special place in addressing this problem as they allow functional, metabolic and other processes imaging in body, which occur during the cancer development. This approach supposes the use of radiopharmaceuticals (RP), which are capable of selective binding to a specific biological target, for example, prostate-specific membrane antigen (PSMA), which is known to be overexpressed in PCa. Current development of new radiotracers for PCa imaging is focused on low molecular weight PSMA inhibitors due to their high specific binding to PSMA and rapid urinary excretion. Technetium-99m remains the appropriate radionuclide for diagnostic studies due to its optimal nuclear properties, ease of production and versatile coordination chemistry. Therefore, single-photon emission computed tomography (SPECT) imaging with 99mTc-PSMA radioligands can be a cost effective alternative to PET with 68Ga- or 18F-labeled RP. The aim of this review is to summarize and analyze currently available data on 99mTc-labeled low molecular weight PSMA inhibitors for metastatic PCa imaging.

Abstract B039: Adipocyte regulation of ER stress and mTOR signaling in bone-metastatic PCa: The role of stearoyl-CoA desaturase

Abstract Bone metastatic disease is correlated with increased morbidity and mortality in prostate cancer (PCa) patients. Current treatments for bone-metastatic PCa are palliative, and new targets for therapy are desperately needed for this presently incurable disease. Various studies have determined that the supportive nature of the bone marrow (BM) niche and crosstalk between the bone-resident cells and the tumor lead to increased tumor cell survival and escape from therapy. Specifically, studies from our lab highlighted the critical role of bone marrow adipose tissue and its expansion due to obesity or age in PCa progression and chemoresistance in bone. Bone marrow adipocytes are metabolically active cells that, through secretion of lipids and adipokines, have the potential to affect the neighboring cells, including the tumor cells that have disseminated into the BM niche. We have shown previously that interaction with marrow adipocytes promotes lipid uptake by PCa cells, modulates their metabolic phenotype, and activates pro-survival signaling and ER/oxidative stress pathways; however, the molecular mechanisms behind the tumor-promoting effects of adipocytes are not understood. The main objective of this study was to investigate the molecular mechanisms underlying lipid-induced stress during tumor cell-adipocyte crosstalk and its functional relationship to tumor growth and progression in bone. Our preliminary data showed that adipocyte-tumor cell crosstalk increases lipid peroxidation in PCa cells, which coincides with augmented expression of ER stress markers and activation of mTOR signaling. We also observed that PCa cells under adipocyte exposure had augmented gene expression of stearoyl-CoA desaturase (SCD), an ER-resident enzyme responsible for the conversion of saturated fatty acids (SFA) to monounsaturated fatty acids (MUFA). We, therefore, hypothesized that SCD is a metabolic regulator that protects metastatic PCa cells against lipid-induced toxicity and ER stress and promotes tumor survival via activation of mTOR signaling. Here, we show that the inhibition of mTORC1 by Everolimus (EVO) decreases the gene expression of ER stress markers in PCa cells exposed to adipocytes. We also demonstrate that adipocyte-mediated induction of ER stress coincides with an increase in active mTOR signaling in PCa cells, indicating possible bidirectional crosstalk between ER stress and mTOR pathways. Notably, inhibition of SCD in PCa cells grown in Transwell co-culture with adipocytes by either siRNA or the small molecule inhibitor CAY10566 leads to reduced mTOR signaling and an increase in lipid peroxidation in PCa cells. SCD inhibition also increases the gene and protein expression of ER stress markers, specifically XBP1 (S) and ATF4, suggesting apoptosis induction. Collectively, our results place SCD as a mediator of ER stress-mTOR crosstalk and a promoter of tumor survival and suggest that targeting SCD activity might be a viable approach to rewire tumor metabolism, and inhibit metastatic progression in bone and sensitize PCa tumors to therapy. Citation Format: Alexis Wilson, Mackenzie Herroon, Shane Mecca, Laimar Garmo, Izabela Podgorski. Adipocyte regulation of ER stress and mTOR signaling in bone-metastatic PCa: The role of stearoyl-CoA desaturase [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B039.

TRENDS IN PROSTATE CANCER DIAGNOSIS DURING THE COVID-19 PANDEMIC: SINGLE-INSTITUTION EXPERIENCE.

The aim of this study was to compare the number of biopsy and surgical procedures on prostate, as well as the number of newly diagnosed, histologically confirmed cases of prostate cancer during the COVID-19 pandemic at Zagreb University Hospital Center (UHC). We retrospectively collected and processed a total of 1344 histopathologic findings of the prostate at the Zagreb UHC. Our results show that during the COVID-19 pandemic, there was a statistically significant decrease in the absolute number of biopsy and surgical procedures on prostate at Zagreb UHC, and so was the number of newly diagnosed, histologically confirmed cases of prostate cancer. During the observed time of the pandemic (March 19, 2020 to December 31, 2020), there was a 37.5% decrease in the absolute number of newly diagnosed prostate cancer cases compared to the same period of the previous year (March 19, 2019 to December 31, 2019). To our knowledge, this is the first study of this kind that is based on the number of prostate cancer diagnoses in Croatia. By observing the early period of the pandemic, our results provide important guidelines for monitoring and understanding the long-term consequences of the pandemic on the prostate cancer morbidity and mortality.

PROSTATE CANCER EPIDEMIOLOGY IN THE EAST KAZAKHSTAN REGION, 2010-2019

Relevance: From 2010 to 2019, prostate cancer morbidity increased, and prostate cancer mortality decreased in Kazakhstan. The peak incidence was observed in patients aged 70 years and older. The East Kazakhstan region had higher morbidity and mortality from prostate cancer than the national average.&#x0D; The study aimed to: assess the indicators of prostate cancer epidemiology in the East Kazakhstan region from 2010 to 2019.&#x0D; Methods: The study calculated prostate cancer incidence, mortality, one-year and five-year survival, and early detection from 2010 to 2019. The statistical significance was assessed by the one-factor linear regression method. Intensive epidemiological indicators were calculated per 100 000 male population.&#x0D; Results: The prostate cancer incidence in East Kazakhstan increased from 2010 to 2019, while the mortality rate increased slightly. There was a statistically significant upward trend for morbidity (p=0.009) and a statistically insignificant trend for mortality (p=0.900).&#x0D; The one-year survival with prostate cancer tended to decrease. However, the trend of one-year survival rates had no statistical significance (p=0.202).&#x0D; The five-year survival rate of patients with prostate cancer in the East Kazakhstan region during the study period tended to decrease. However, the trend in the five-year survival rates of patients with prostate cancer in the East Kazakhstan region had no statistical significance (p=0.826).&#x0D; Early detection of prostate cancer in the early stages remained sustainable in the range of 72.7-77.4. In 2019, this indicator decreased to 63.2%.&#x0D; The share of prostate cancer cases detected at stage III tended to increase. The proportion of prostate cancer cases detected at stage IV tended to decrease during the study period.&#x0D; Conclusion: The prostate cancer epidemiological rates in East Kazakhstan were unstable in the study period. The incidence tended to increase; the mortality rate fluctuated within small limits and remained sustainable. The one-year survival rate tended to decrease. The five-year survival rate was slightly increasing. There was an increase in the detection of prostate cancer at stage III, while the detection at stage IV tended to decrease. Early detection of prostate cancer has decreased with an increase in detection at stage III. The proportion of prostate cancer cases detected at stage IV in the study period tended to decrease.