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Scientific Reports Aug 2023The objective of this study was to compare transperineal (TP) versus transrectal (TR) magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS) fusion prostate...
The objective of this study was to compare transperineal (TP) versus transrectal (TR) magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS) fusion prostate biopsy (PBx). Consecutive men who underwent prostate MRI followed by a systematic biopsy. Additional target biopsies were performed from Prostate Imaging Reporting & Data System (PIRADS) 3-5 lesions. Men who underwent TP PBx were matched 1:2 with a synchronous cohort undergoing TR PBx by PSA, Prostate volume (PV) and PIRADS score. Endpoint of the study was the detection of clinically significant prostate cancer (CSPCa; Grade Group ≥ 2). Univariate and multivariable analyses were performed. Results were considered statistically significant if p < 0.05. Overall, 504 patients met the inclusion criteria. A total of 168 TP PBx were pair-matched to 336 TR PBx patients. Baseline demographics and imaging characteristics were similar between the groups. Per patient, the CSPCa detection was 2.1% vs 6.3% (p = 0.4) for PIRADS 1-2, and 59% vs 60% (p = 0.9) for PIRADS 3-5, on TP vs TR PBx, respectively. Per lesion, the CSPCa detection for PIRADS 3 (21% vs 16%; p = 0.4), PIRADS 4 (51% vs 44%; p = 0.8) and PIRADS 5 (76% vs 84%; p = 0.3) was similar for TP vs TR PBx, respectively. However, the TP PBx showed a longer maximum cancer core length (11 vs 9 mm; p = 0.02) and higher cancer core involvement (83% vs 65%; p < 0.001) than TR PBx. Independent predictors for CSPCa detection were age, PSA, PV, abnormal digital rectal examination findings, and PIRADS 3-5. Our study demonstrated transperineal MRI/TRUS fusion PBx provides similar CSPCa detection, with larger prostate cancer core length and percent of core involvement, than transrectal PBx.
Topics: Male; Humans; Prostate; Prostate-Specific Antigen; Magnetic Resonance Imaging; Image-Guided Biopsy; Prostatic Neoplasms; Magnetic Resonance Spectroscopy
PubMed: 37596374
DOI: 10.1038/s41598-023-40371-7 -
Medical Oncology (Northwood, London,... Aug 2023The prostate cancer tumor microenvironment (TME) is comprised of many cell types that can contribute to and influence tumor progression. Some of the most abundant...
The prostate cancer tumor microenvironment (TME) is comprised of many cell types that can contribute to and influence tumor progression. Some of the most abundant prostate cancer TME cells are macrophages, which can be modeled on a continuous spectrum of M1-like (anti-tumor macrophages) to M2-like (pro-tumor macrophages). A function of M2-like macrophages is efferocytosis, the phagocytosis of apoptotic cells. Based on literature from other models and contexts, efferocytosis further supports the M2-like macrophage phenotype. MerTK is a receptor tyrosine kinase that mediates efferocytosis by binding phosphatidylserine on apoptotic cells. We hypothesize efferocytosis in the prostate cancer TME is a tumor-promoting function of macrophages and that targeting MerTK-mediated efferocytosis will slow prostate cancer growth and promote an anti-tumor immune infiltrate. The aims of this study are to measure efferocytosis of prostate cancer cells by in vitro human M1/M2 macrophage models and assess changes in the M2-like, pro-tumor macrophage phenotype following prostate cancer efferocytosis. Additionally, this study aims to demonstrate that targeting MerTK decreases prostate cancer efferocytosis and promotes an anti-tumor immune infiltrate. We have developed methodology using flow cytometry to quantify efferocytosis of human prostate cancer cells using the LNCaP cell line. We observed that M2 macrophages efferocytose the LNCaP cell line more than M1 macrophages. Following efferocytosis of LNCaP cells by M2 human monocyte-derived macrophages (HMDMs), we observed an increase in the M2-like, pro-tumor phenotype by flow cytometry cell surface marker analysis. By qRT-PCR, flow cytometry, and Western blot, we detected greater MerTK expression in M2 than M1 macrophages. Targeting MerTK with antibody Mer590 decreased LNCaP efferocytosis by M2 HMDMs, establishing the role of MerTK in prostate cancer efferocytosis. In the prostate cancer mouse model hi-myc, Mertk KO increased anti-tumor immune infiltrate including CD8 T cells. These findings support targeting MerTK-mediated efferocytosis as a novel therapy for prostate cancer.
Topics: Animals; Mice; Male; Humans; c-Mer Tyrosine Kinase; Prostatic Neoplasms; Phagocytosis; Macrophages; Prostate; Tumor Microenvironment
PubMed: 37644281
DOI: 10.1007/s12032-023-02153-z -
Zeitschrift Fur Medizinische Physik May 2024MR-guided radiotherapy (MRgRT) online plan adaptation accounts for tumor volume changes, interfraction motion and thus allows daily sparing of relevant organs at risk....
BACKGROUND AND PURPOSE
MR-guided radiotherapy (MRgRT) online plan adaptation accounts for tumor volume changes, interfraction motion and thus allows daily sparing of relevant organs at risk. Due to the high interfraction variability of bladder and rectum, patients with tumors in the pelvic region may strongly benefit from adaptive MRgRT. Currently, fast automatic annotation of anatomical structures is not available within the online MRgRT workflow. Therefore, the aim of this study was to train and validate a fast, accurate deep learning model for automatic MRI segmentation at the MR-Linac for future implementation in a clinical MRgRT workflow.
MATERIALS AND METHODS
For a total of 47 patients, T2w MRI data were acquired on a 1.5 T MR-Linac (Unity, Elekta) on five different days. Prostate, seminal vesicles, rectum, anal canal, bladder, penile bulb, body and bony structures were manually annotated. These training data consisting of 232 data sets in total was used for the generation of a deep learning based autocontouring model and validated on 20 unseen T2w-MRIs. For quantitative evaluation the validation set was contoured by a radiation oncologist as gold standard contours (GSC) and compared in MATLAB to the automatic contours (AIC). For the evaluation, dice similarity coefficients (DSC), and 95% Hausdorff distances (95% HD), added path length (APL) and surface DSC (sDSC) were calculated in a caudal-cranial window of ± 4 cm with respect to the prostate ends. For qualitative evaluation, five radiation oncologists scored the AIC on the possible usage within an online adaptive workflow as follows: (1) no modifications needed, (2) minor adjustments needed, (3) major adjustments/ multiple minor adjustments needed, (4) not usable.
RESULTS
The quantitative evaluation revealed a maximum median 95% HD of 6.9 mm for the rectum and minimum median 95% HD of 2.7 mm for the bladder. Maximal and minimal median DSC were detected for bladder with 0.97 and for penile bulb with 0.73, respectively. Using a tolerance level of 3 mm, the highest and lowest sDSC were determined for rectum (0.94) and anal canal (0.68), respectively. Qualitative evaluation resulted in a mean score of 1.2 for AICs over all organs and patients across all expert ratings. For the different autocontoured structures, the highest mean score of 1.0 was observed for anal canal, sacrum, femur left and right, and pelvis left, whereas for prostate the lowest mean score of 2.0 was detected. In total, 80% of the contours were rated be clinically acceptable, 16% to require minor and 4% major adjustments for online adaptive MRgRT.
CONCLUSION
In this study, an AI-based autocontouring was successfully trained for online adaptive MR-guided radiotherapy on the 1.5 T MR-Linac system. The developed model can automatically generate contours accepted by physicians (80%) or only with the need of minor corrections (16%) for the irradiation of primary prostate on the clinically employed sequences.
Topics: Humans; Male; Magnetic Resonance Imaging; Prostatic Neoplasms; Radiotherapy, Image-Guided; Deep Learning; Radiotherapy Planning, Computer-Assisted; Prostate
PubMed: 37263911
DOI: 10.1016/j.zemedi.2023.05.001 -
JAMA Network Open Mar 2024Multiple strategies integrating magnetic resonance imaging (MRI) and clinical data have been proposed to determine the need for a prostate biopsy in men with suspected... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Multiple strategies integrating magnetic resonance imaging (MRI) and clinical data have been proposed to determine the need for a prostate biopsy in men with suspected clinically significant prostate cancer (csPCa) (Gleason score ≥3 + 4). However, inconsistencies across different strategies create challenges for drawing a definitive conclusion.
OBJECTIVE
To determine the optimal prostate biopsy decision-making strategy for avoiding unnecessary biopsies and minimizing the risk of missing csPCa by combining MRI Prostate Imaging Reporting & Data System (PI-RADS) and clinical data.
DATA SOURCES
PubMed, Ovid MEDLINE, Embase, Web of Science, and Cochrane Library from inception to July 1, 2022.
STUDY SELECTION
English-language studies that evaluated men with suspected but not confirmed csPCa who underwent MRI PI-RADS followed by prostate biopsy were included. Each study had proposed a biopsy plan by combining PI-RADS and clinical data.
DATA EXTRACTION AND SYNTHESIS
Studies were independently assessed for eligibility for inclusion. Quality of studies was appraised using the Quality Assessment of Diagnostic Accuracy Studies 2 tool and the Newcastle-Ottawa Scale. Mixed-effects meta-analyses and meta-regression models with multimodel inference were performed. Reporting of this study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.
MAIN OUTCOMES AND MEASURES
Independent risk factors of csPCa were determined by performing meta-regression between the rate of csPCa and PI-RADS and clinical parameters. Yields of different biopsy strategies were assessed by performing diagnostic meta-analysis.
RESULTS
The analyses included 72 studies comprising 36 366 patients. Univariable meta-regression showed that PI-RADS 4 (β-coefficient [SE], 7.82 [3.85]; P = .045) and PI-RADS 5 (β-coefficient [SE], 23.18 [4.46]; P < .001) lesions, but not PI-RADS 3 lesions (β-coefficient [SE], -4.08 [3.06]; P = .19), were significantly associated with a higher risk of csPCa. When considered jointly in a multivariable model, prostate-specific antigen density (PSAD) was the only clinical variable significantly associated with csPCa (β-coefficient [SE], 15.50 [5.14]; P < .001) besides PI-RADS 5 (β-coefficient [SE], 9.19 [3.33]; P < .001). Avoiding biopsy in patients with lesions with PI-RADS category of 3 or less and PSAD less than 0.10 (vs <0.15) ng/mL2 resulted in reducing 30% (vs 48%) of unnecessary biopsies (compared with performing biopsy in all suspected patients), with an estimated sensitivity of 97% (vs 95%) and number needed to harm of 17 (vs 15).
CONCLUSIONS AND RELEVANCE
These findings suggest that in patients with suspected csPCa, patient-tailored prostate biopsy decisions based on PI-RADS and PSAD could prevent unnecessary procedures while maintaining high sensitivity.
Topics: Male; Humans; Magnetic Resonance Imaging; Prostatic Neoplasms; Prostate-Specific Antigen; Prostate; Biopsy
PubMed: 38551559
DOI: 10.1001/jamanetworkopen.2024.4258 -
BMC Public Health Sep 2023Prostate cancer (PCa) is the most diagnosed cancer in Australian men, and the number of survivors is growing with advances in diagnosis and treatment. Work participation...
BACKGROUND
Prostate cancer (PCa) is the most diagnosed cancer in Australian men, and the number of survivors is growing with advances in diagnosis and treatment. Work participation following PCa diagnosis and treatment becomes a significant aspect of quality of life and survivorship. Using a qualitative phenomenological approach, we explored the work-related experiences of PCa survivors in Australia.
METHODS
Semi-structured telephone interviews were conducted with 16 men (6 salaried employees, 10 self-employed; 8 diagnosed ≥ 5 years) purposively sampled from a community setting. Interviews were inductively analysed.
RESULTS
Five main themes emerged: motivations to work; treatment decisions and work; the effects of PCa and its treatment on ability to participate in work; being an employee versus being self-employed; and personal agency. PCa and its treatment side-effects were detrimental to men's work capacity and ability, and could persist over an extended period. Most men expressed a strong desire to retain work or return to work. Discussions with healthcare professionals about work-related consequences were largely missing when treatment decisions were made. Self-employed men faced greater challenges than their salaried counterparts due to high financial burden and limited social and business support. Family, workplace and wider community support, and self-care, enhanced men's work participation experiences.
CONCLUSIONS
PCa and its treatment substantially and persistently impacted men's working lives, and their experiences were diverse and multifaceted. Self-employed and long-term PCa survivors face greater challenges and are at high risk of poor work outcomes. A systematic approach and involvement of stakeholders at all levels is required to support ongoing work participation.
Topics: Male; Humans; Prostate; Cancer Survivors; Quality of Life; Australia; Prostatic Neoplasms; Survivors
PubMed: 37716940
DOI: 10.1186/s12889-023-16706-4 -
Scientific Reports Nov 2023Although hormone therapy is effective for the treatment of prostate cancer (Pca), many patients develop a lethal type of Pca called castration-resistant prostate cancer...
Although hormone therapy is effective for the treatment of prostate cancer (Pca), many patients develop a lethal type of Pca called castration-resistant prostate cancer (CRPC). Dysregulation of DNA damage response (DDR)-related genes leads to Pca progression. Here, we explored DDR-related signals upregulated in CRPC tissues. We analyzed the gene expression profiles in our RNA-sequence (RNA-seq) dataset containing benign prostate, primary Pca, and CRPC samples. We identified six DDR-related genes (Ribonuclease H2 Subunit A (RNASEH2A), replication factor C subunit 2 (RFC2), RFC4, DNA Ligase 1 (LIG1), DNA polymerase D1 (POLD1), and DNA polymerase E4 (POLE4)) that were upregulated in CRPC compared with Pca tissues. By analyzing public databases and validation studies, we focused on RFC2 as a new biomarker. Functional analysis demonstrated that silencing of RFC2 expression inhibited cell proliferation and induced the expression of DNA damage and apoptosis markers in CRPC model cells. Furthermore, immunohistochemical (IHC) analysis revealed that high expression of RFC2 protein correlated with poor prognosis in patients with Pca and increased expression in CRPC tissues compared with localized Pca. Thus, our study suggests that six DDR-related genes would be important for Pca progression. RFC2 could be a useful biomarker associated with poor outcomes of patients with Pca.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Prostate; Cell Proliferation; Biomarkers; DNA-Directed DNA Polymerase; Cell Line, Tumor
PubMed: 37950047
DOI: 10.1038/s41598-023-46651-6 -
Biochimica Et Biophysica Acta. Reviews... Mar 2024Prostate cancer is unique compared to other major cancers due to the presence of multiple primary malignant foci in the majority of patients at the time of diagnosis.... (Review)
Review
Prostate cancer is unique compared to other major cancers due to the presence of multiple primary malignant foci in the majority of patients at the time of diagnosis. Each malignant focus has distinct somatic mutations and gene expression patterns, which represents a challenge for the development of prognostic tests for localized prostate cancer. Additionally, the molecular heterogeneity of advanced prostate cancer has important implications for management, particularly for patients with metastatic and locally recurrent cancer. Studies have shown that prostate cancers with mutations in DNA damage response genes are more sensitive to drugs inhibiting the poly ADP-ribose polymerase (PARP) enzyme. However, testing for such mutations should consider both spatial and temporal heterogeneity. Here, we summarize studies where multiregional genomics and transcriptomics analyses have been performed for primary prostate cancer. We further discuss the vast interfocal heterogeneity and how prognostic biomarkers and a molecular definition of the index tumor should be developed. The concept of focal treatments in prostate cancer has been evolving as a demand from patients and clinicians and is one example where there is a need for defining an index tumor. Here, biomarkers must have proven value for individual malignant foci. The potential discovery and implementation of biomarkers that are agnostic to heterogeneity are also explored as an alternative to multisample testing. Thus, deciding upon whole-organ treatment, such as radical prostatectomy, should depend on information from biomarkers which are informative for the whole organ.
Topics: Male; Humans; Prostatic Neoplasms; Prostate; Mutation; Prostatectomy; Biomarkers
PubMed: 38272101
DOI: 10.1016/j.bbcan.2024.189080 -
Cancer Research Sep 2023In prostate cancer, there is an urgent need for objective prognostic biomarkers that identify the metastatic potential of a tumor at an early stage. While recent...
UNLABELLED
In prostate cancer, there is an urgent need for objective prognostic biomarkers that identify the metastatic potential of a tumor at an early stage. While recent analyses indicated TP53 mutations as candidate biomarkers, molecular profiling in a clinical setting is complicated by tumor heterogeneity. Deep learning models that predict the spatial presence of TP53 mutations in whole slide images (WSI) offer the potential to mitigate this issue. To assess the potential of WSIs as proxies for spatially resolved profiling and as biomarkers for aggressive disease, we developed TiDo, a deep learning model that achieves state-of-the-art performance in predicting TP53 mutations from WSIs of primary prostate tumors. In an independent multifocal cohort, the model showed successful generalization at both the patient and lesion level. Analysis of model predictions revealed that false positive (FP) predictions could at least partially be explained by TP53 deletions, suggesting that some FP carry an alteration that leads to the same histological phenotype as TP53 mutations. Comparative expression and histologic cell type analyses identified a TP53-like cellular phenotype triggered by expression of pathways affecting stromal composition. Together, these findings indicate that WSI-based models might not be able to perfectly predict the spatial presence of individual TP53 mutations but they have the potential to elucidate the prognosis of a tumor by depicting a downstream phenotype associated with aggressive disease biomarkers.
SIGNIFICANCE
Deep learning models predicting TP53 mutations from whole slide images of prostate cancer capture histologic phenotypes associated with stromal composition, lymph node metastasis, and biochemical recurrence, indicating their potential as in silico prognostic biomarkers. See related commentary by Bordeleau, p. 2809.
Topics: Male; Humans; Mutation; Prostatic Neoplasms; Prognosis; Prostate; Phenotype; Tumor Suppressor Protein p53
PubMed: 37352385
DOI: 10.1158/0008-5472.CAN-22-3113 -
International Journal of Molecular... Nov 2023Prostate cancer stands as one of the most prevalent malignancies afflicting men worldwide. The tumor microenvironment plays a pivotal role in tumor progression,... (Review)
Review
Prostate cancer stands as one of the most prevalent malignancies afflicting men worldwide. The tumor microenvironment plays a pivotal role in tumor progression, comprising various cell types including endothelial cells, tumor-associated fibroblasts, and macrophages. Recent accumulating evidence underscores the indispensable contribution of endothelial cells to prostate cancer development. Both endothelial cells and tumor cells release a multitude of factors that instigate angiogenesis, metastasis, and even drug resistance in prostate cancer. These factors serve as regulators within the tumor microenvironment and represent potential therapeutic targets for managing prostate cancer. In this review, we provide an overview of the crucial functions of endothelial cells in angiogenesis, metastasis, and drug resistance, and their prospective therapeutic applications in combating this disease.
Topics: Male; Humans; Endothelial Cells; Prostatic Neoplasms; Prostate; Cancer-Associated Fibroblasts; Tumor Microenvironment
PubMed: 38069225
DOI: 10.3390/ijms242316893 -
Seminars in Nuclear Medicine Jan 2024Prostate-specific membrane antigen PET/CT for primary staging of prostate cancer is becoming increasingly popular due to simultaneous assessment of whole-body disease... (Review)
Review
Prostate-specific membrane antigen PET/CT for primary staging of prostate cancer is becoming increasingly popular due to simultaneous assessment of whole-body disease burden, with superior sensitivity and specificity for detecting metastases compared to conventional imaging. PSMA PET in combination with multiparametric MRI (mpMRI) improves the sensitivity of assessment of extra-prostatic extension and seminal vesicle invasion compared to mpMRI alone, and may serve as a second line modality for image-guided biopsy in selected patients with negative mpMRI and/or negative primary biopsies. The superior diagnostic accuracy of PSMA PET/CT affects clinical decision-making with a change of clinical management in one-fourth of patients compared to conventional imaging. However, at present, the effect of implementing PSMA PET/CT for primary staging on patient outcomes is not clear, and prospective studies are warranted. There are several PSMA tracers with similar performance and minor individual pharmacokinetic differences such as higher rate of unspecific bone uptake with 18F-PSMA-1007, but on the other hand, lower urinary excretion, which could give an advantage in the detection of local recurrence. Proper training of the reporting physicians and knowledge of the pitfalls of the specific PSMA tracer used is of utmost importance for high-quality reading. We aim to provide an overview of the current literature and an update on the status of PSMA PET/CT for primary staging of prostate cancer.
Topics: Male; Humans; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes; Prostatic Neoplasms; Prostate; Multiparametric Magnetic Resonance Imaging; Neoplasm Staging
PubMed: 37487824
DOI: 10.1053/j.semnuclmed.2023.07.001