Biochemical Recurrence Of Prostate Cancer Research Articles

SC234 - Optimizing timing and indications for 68Ga-PSMA PET/CT in patients with biochemical recurrent prostate cancer after radical prostatectomy

SC234 - Optimizing timing and indications for 68Ga-PSMA PET/CT in patients with biochemical recurrent prostate cancer after radical prostatectomy

SC95 - The key role of concomitant androgen-deprivation therapy on the efficacy of imaging guided treatments in men with biochemical recurrent prostate cancer after radical prostatectomy and positive 68Ga-PSMA PET/CT scan

SC95 - The key role of concomitant androgen-deprivation therapy on the efficacy of imaging guided treatments in men with biochemical recurrent prostate cancer after radical prostatectomy and positive 68Ga-PSMA PET/CT scan

PSA-Stratified Performance of [18F]DCFPyL PET/CT in Biochemically Recurrent Prostate Cancer Patients under Androgen Deprivation Therapy.

Based on in vitro studies, it is known that androgen deprivation therapy (ADT) increases prostate-specific membrane antigen (PSMA) expression on prostate cancer (PCa) cells. However, ADT also has cytoreductive effects which can decrease lesion size. The present evaluation was conducted to further analyze the influence of ongoing ADT on [18F]DCFPyL positron emission tomography/computed tomography (PET/CT) performance in the setting of biochemically recurrent PCa. We retrospectively evaluated two groups of PCa patients, previously treated with radical intent, who had undergone [18F]DCFPyL PET/CT because of biochemical relapse with a minimum PSA level of 0.4 ng/mL. One group consisted of 95 patients under ADT at the time of the PET examination, and the other consisted of 445 patients not receiving ADT at the time of PET/CT. The uptake characteristics of the cardiac blood pool, liver, parotid glands, and five most active lesions were measured and compared between these two groups. The overall detection rate of [18F]DCFPyL PET/CT in patients under ADT at the time of imaging was significantly higher than patients not under ADT (91.6% vs. 80.4%, p-value = 0.007). However, the PSA-stratified differences in detection rates between patients with and without ADT did not reach statistical significance. Except for the maximal standardized uptake values corrected for lean body mass (SULmax) in the PSA range of 1 to <2 ng/mL, the intensity and volume of [18F]DCFPyL accumulation were higher in patients with ADT compared to the patients without. Statistical significance was attained for the SULmax in PSA range of 0.5 to <1 ng/mL (p-value = 0.0004) and metabolic tumor volume (MTV) in all PSA ranges (p-values of 0.0005 to 0.03). No significant difference was observed for radiotracer uptake in normal organs between the two groups with and without ADT. In this study population with biochemical recurrence of PCa and measurable PSA, ongoing ADT at the time of [18F]DCFPyL PET/CT imaging was associated with higher radiotracer uptake and overall lesion detection rate. This could be due in part to the more aggressive disease phenotype in patients with ongoing ADT.

Antidepressant medication use and prostate cancer recurrence in men with depressive disorders

PurposeWhether treating prostate cancer survivors with a depressive disorder with antidepressants can affect their cancer outcomes is unknown. We evaluated the association between antidepressant use and prostate cancer recurrence, in survivors with comorbid depressive disorders.MethodsWe conducted a longitudinal cohort study of 10,017 men with prostate cancer (stages I–II) diagnosed who also had a comorbid depressive disorder followed a maximum of 22 years, and examined rates of biochemical recurrence by antidepressant medication use. We conducted multivariable Cox models based on time-dependent antidepressant drug use status, and examined the risk of biochemical recurrence by cumulative duration of antidepressant use.ResultsOf these 10,017 survivors, 1842 (18%) experienced biochemical recurrence over 69,500 person-years of follow-up. The prostate cancer biochemical recurrence rate was greater with antidepressant non-use (31.3/1000 person-years) compared to antidepressant use (23.5/1000 person-years). In Cox proportional hazards multivariable adjusted models, non-use of antidepressants was associated with a 34% increased risk of biochemical recurrence compared to antidepressant use (HR = 1.34, 95% CI: 1.24–1.44). Longer use of antidepressants was associated with a lower biochemical recurrence risk (P trend test < 0.001).ConclusionUntreated depressive disorders in prostate cancer patients may be associated with an increased risk of biochemical recurrence.

A seven-gene prognosis model to predict biochemical recurrence for prostate cancer based on the TCGA database.

The incidence rate of prostate cancer is increasing rapidly. This study aims to explore the gene-associated mechanism of prostate cancer biochemical recurrence (BCR) after radical prostatectomy and to construct a biochemical recurrence of prostate cancer prognostic model. The DEseq2 R package was used for the differential expression of mRNA. The ClusterProfiler R package was used to analyze the functional enrichment of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to explore related mechanisms. The Survival, Survminer, and My.stepwise R packages were used to construct the prognostic model to predict the biochemical recurrence-free probability. The RMS R package was used to draw the nomogram. For evaluating the prognostic model, the timeROC R package was used to draw the time-dependent ROC curve (receiver operating characteristic curve). To investigate the association between mRNA and prostate cancer, we performed differential expression analysis on the TCGA (The Cancer Genome Atlas) database. Seven protein-coding genes (VWA5B2, ARC, SOX11, MGAM, FOXN4, PRAME, and MMP26) were picked as independent prognostic genes by regression analysis. Based on their Cox coefficient, a risk score formula was proposed. According to the risk scores, patients were divided into high- and low-risk groups based on the median score. Kaplan-Meier plot curves showed that the low-risk group had a better biochemical recurrence-free probability compared to the high-risk group. The 1-year, 3-year, and 5-year AUCs (areas under the ROC curve) of the model were 77%, 81%, and 86%, respectively. In addition, we built a nomogram based on the result of multivariate Cox regression analysis. Furthermore, we select the GSE46602 dataset as our external validation. The 1-year, 3-year, and 5-year AUCs of BCR-free probability were 83%, 82%, and 80%, respectively. Finally, the levels of seven genes showed a difference between PRAD tissues and adjacent non-tumorous tissues. This study shows that establishing a biochemical recurrence prediction prognostic model comprising seven protein-coding genes is an effective and precise method for predicting the progression of prostate cancer.

Management of Biochemical Recurrence of Prostate Cancer After Curative Treatment: A Focus on Older Patients.

Following a treatment with curative intent, a biochemical recurrence may be diagnosed, often many years after the primary treatment. The consequences of this relapse on survival are very heterogeneous. The expected specific survival at relapse is above 50% at 10 years. Therefore, its management needs to be balanced with the individual life expectancy. The relapse needs to be categorized as either a low- or high-risk category. The latter has to be considered for salvage therapy, provided the individual life expectancy is long enough. It is evaluated through an initial geriatric assessment, starting with the G8 score as well as the mini-Cog. A comprehensive geriatric assessment might be needed based on the G8 score. Patients will then be categorized as either fit, vulnerable, or frail. If a local salvage therapy is considered, the relapse localization might be of interest in some situations. Available salvage therapies in senior adults have nothing special compared to salvage of younger men, except for aggressive local therapy, which might be less well tolerated. The key objective in managing a biochemical recurrence in senior adults is to find the right balance between under- and over-treatment in a shared decision process. In many frail and vulnerable men, a clinically oriented watchful waiting should be preferred, while fit men with an aggressive relapse and a significant life expectancy need an active therapy.

Different predictive values of microvessel density for biochemical recurrence among different PCa populations: A systematic review and meta-analysis.

Several studies have explored the relationship between intratumoral microvessel density (MVD) and the risk of postoperative biochemical recurrence (BCR) in prostate cancer (PCa), although the results are contradictory. Therefore, we conducted a meta-analysis to investigate the effect of MVD on BCR in PCa. We searched PubMed, MEDLINE, Science Direct/Elsevier, the Cochrane Library, CNKI, and EMBase databases from inception through January 2022, with no year or language restrictions, and used NOS guidelines to evaluate the quality of the 19 eligible studies. The derived hazard ratio (HR) and 95% confidence interval (95%CI) were used to assess each endpoint. Data synthesis was performed with RevMan to assess the prognostic value of MVD in PCa and its heterogeneity, while the publication bias was examined using STATA 16.0. Our meta-analysis included 19 articles (4 for T1-2, 6 for T1-3, and 9 for T1-4) on postoperative biochemical recurrence of PCa, among which, 3933 patients were pooled. The predictive ability of intratumoral MVD for different stages of PCa on BCR was T1-2 (HR, 2.46; 95% CI, 1.08-5.58; p= 0.03; I2 = 83%), T1-3 (HR, 2.38, 95% CI, 1.41-4.01; p= 0.001; I2 = 82%), T1-4 (HR, 1.61; 95% CI, 1.19-2.19; p= 0.002; I2 = 61%).The subgroup analyses based on European and immunohistochemical antibody none-factor VII were consistent with primary one. Sensitivity analysis excluding those studies judged to be at high risk of bias in T1-2 showed a HR of 2.99[1.70,5.27] (I2 = 38%, p= 0.0001), demonstrating the robustness of risk estimates of MVD for the assessment of biochemical recurrence. Microvessel density is a predictor of BCR among patients with PCa, and earlier T stage PCa with a stronger MVD is associated with BCR. Further studies are needed to investigate neoangiogenesis in different T stages of PCa and whether MVD will be of benefit to the EAU-recommended tool for biochemical recurrence risk assessment.

Head-to-head comparison of 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI in the detection of biochemical recurrence of prostate cancer: summary of head-to-head comparison studies.

Our meta-analysis aimed to evaluate the diagnostic performance of 68Ga-PSMA-11 PET/CT vs. 68Ga-PSMA-11 PET/MRI for biochemical recurrence of prostate cancer. We searched for relevant articles in PubMed and Embase until February 2022. Studies evaluating head-to-head comparison of 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI in men with prostate cancer biochemical recurrence were included. The quality of each study was assessed using the Quality Assessment of Diagnostic Performance Studies-2 (QUADAS-2) tool. A total of 5 studies with 219 patients were included in the analysis. The pooled overall detection rates of 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI in detecting recurrent PCa after definitive treatment were 0.89 (95% CI: 0.65-1.00), 0.92 (95% CI: 0.77-1.00), while the detection rates were 0.20 (95% CI: 0.05-0.41) and 0.29 (95% CI: 0.10-0.53) in local recurrence, 0.51 (95% CI: 0.33-0.69) and 0.52 (95% CI: 0.44-0.61) in lymph node metastasis, 0.18 (95% CI: 0.07-0.33) and 0.20 (95% CI: 0.09-0.35) in bone metastasis. There was no significant difference between the two imaging modalities in the overall detection rate (P = 0.82). In addition, detection rates were also not significantly different in local recurrence, lymph node metastasis, or bone metastasis (P = 0.54, 1.00, 0.82). 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI seem to have equivalent performance in detecting biochemical recurrence in prostate cancer. However, the results of the meta-analysis were drawn from studies with small samples. Further larger studies in this setting are warranted.

89Zr]Zr-PSMA-617 PET/CT in biochemical recurrence of prostate cancer: first clinical experience from a pilot study including biodistribution and dose estimates

PurposeProstate-specific membrane antigen (PSMA)-targeted PET/CT has become increasingly important in the management of prostate cancer, especially in localization of biochemical recurrence (BCR). PSMA-targeted PET/CT imaging with long-lived radionuclides as 89Zr (T1/2 = 78.4 h) may improve diagnostics by allowing data acquisition on later time points. In this study, we present our first clinical experience including preliminary biodistribution and dosimetry data of [89Zr]Zr-PSMA-617 PET/CT in patients with BCR of prostate cancer.MethodsSeven patients with BCR of prostate cancer who revealed no (n = 4) or undetermined (n = 3) findings on [68Ga]Ga-PSMA-11 PET/CT imaging were referred to [89Zr]Zr-PSMA-617 PET/CT. PET/CT imaging was performed 1 h, 24 h, 48 h, and 72 h post injection (p.i.) of 111 ± 11 MBq [89Zr]Zr-PSMA-617 (mean ± standard deviation). Normal organ distribution and dosimetry were determined. Lesions visually considered as suggestive of prostate cancer were quantitatively analyzed.ResultsIntense physiological uptake was observed in the salivary and lacrimal glands, liver, spleen, kidneys, intestine and urinary tract. The parotid gland received the highest absorbed dose (0.601 ± 0.185 mGy/MBq), followed by the kidneys (0.517 ± 0.125 mGy/MBq). The estimated overall effective dose for the administration of 111 MBq was 10.1 mSv (0.0913 ± 0.0118 mSv/MBq). In 6 patients, and in particular in 3 of 4 patients with negative [68Ga]Ga-PSMA-11 PET/CT, at least one prostate cancer lesion was detected in [89Zr]Zr-PSMA-617 PET/CT imaging at later time points. The majority of tumor lesions were first visible at 24 h p.i. with continuously increasing tumor-to-background ratio over time. All tumor lesions were detectable at 48 h and 72 h p.i.Conclusion[89Zr]Zr-PSMA-617 PET/CT imaging is a promising new diagnostic tool with acceptable radiation exposure for patients with prostate cancer especially when [68Ga]Ga-PSMA-11 PET/CT imaging fails detecting recurrent disease. The long half-life of 89Zr enables late time point imaging (up to 72 h in our study) with increased tracer uptake in tumor lesions and higher tumor-to-background ratios allowing identification of lesions non-visible on [68Ga]Ga-PSMA-11 PET/CT imaging.

Combining PSA and PET features to select candidates for salvage lymph node dissection in recurrent prostate cancer.

To evaluate the relationship between pre-operative PSA value, 68Ga-prostate-specific-membrane-antigen (PSMA) PET performance and oncologic outcomes after salvage lymph node dissection (sLND) for biochemical recurrent prostate cancer (PCa). The study included 164 patients diagnosed with ≤2 pelvic lymph-node recurrence(s) of PCa documented on 68Ga-PSMA PET scan and treated with pelvic ± retroperitoneal sLND at 11 high-volume centres between 2012 and 2019. Pathologic findings were correlated to PSA values at time of sLND, categorized in early (<0.5ng/ml), low (0.5-0.99 ng/ml), moderate (1-1.5ng/ml) and high (>1.5ng/ml). Clinical recurrence (CR)-free survival after sLND was calculated using multivariable analyses and plotted over pre-operative PSA value. Median [interquartile range (IQR)] PSA at sLND was 1.1 (0.6, 2.0) ng/ml, and 131 (80%) patients had one positive spot at PET scan. All patients received pelvic sLND, whereas 91 (55%) men received also retroperitoneal dissection. Median (IQR) number of node removed was 15 (6, 28). The rate of positive pathology increased as a function of pre-operative PSA value, with highest rates for patients with pre-operative PSA >1.5ng/ml (pelvic-only sLNDs: 84%; pelvic + retroperitoneal sLNDs: 90%). After sLND, PSA ≤0.3ng/ml was detected in 67 (41%) men. On multivariable analyses, pre-operative PSA was associated with PSA response (p< 0.0001). There were 51 CRs after sLND. After adjusting for confounders, we found a significant, non-linear relationship between PSA level at sLND and the 12-month CR-free survival (p< 0.0001), with the highest probability of freedom from CR for patients who received sLND at PSA level ≥1ng/ml. In case of PET-detected nodal recurrences amenable to sLND, salvage surgery was associated with the highest short-term oncologic outcomes when performed in men with PSA ≥1ng/ml. Awaiting confirmatory data from prospective trials, these findings may help physicians to optimize the timing for 68Ga-PSMA PET in biochemical recurrent PCa.

Clinical Applications of PSMA PET Examination in Patients with Prostate Cancer.

Simple SummaryThe prostate specific membrane antigens, abbreviated as PSMAs, are type II membrane proteins that are highly ex-pressed on the surface of malignant prostate tissue in prostate cancer (PCa), particularly in aggressive, andro-gen-deprived, metastatic, and hormone-refractory PCa. Today, radionuclides that bind to these PSMA peptides are widely available for diagnostic and therapeutic purposes to specifically image and target prostate tumor cells at molec-ular level. In this descriptive review, we aimed to emphasize the usefulness of PSMA positron emission tomography (PET) examination in the management of patients with various stages of PCa. In addition, we outlined the main pitfalls and limitations of this scan to avoid misinterpretation of the results and to improve the decision making process in rela-tion to the patient’s further treatment. We concluded that PSMA PET examination in primary PCa patients has an es-sential role in the high-risk group. It is the new imaging standard in patients with in biochemical recurrence PCa and plays an important role in treatment decision. Furthermore, PSMA PET scan is a gold standard for the evaluation of PSMA targeted therapies in patients having progress of the disease. Future prospective studies, particularly on the im-pact of PSMA PET on therapy stratification, may further strengthen the role of PSMA in the treatment of PCa patients. With the progressive aging of the population in industrially developed countries, as well as advances in diagnostic and biopsy techniques and improvements in patient awareness, the incidence of prostate cancer (PCa) is continuously increasing worldwide. Therefore, PCa is currently considered as the second leading cause of tumor-related death. Early detection of the tumor and its metastasis is essential, as the rate of disease recurrence is high and occurs in 27% to 53% of all patients who underwent curative therapy with radical prostatectomy or local radiotherapy. In this regard, the prostate specific membrane antigens, abbreviated as PSMAs, are type II membrane proteins that are highly expressed on the surface of malignant prostate tissue in PCa, particularly in aggressive, androgen-deprived, metastatic, and hormone-refractory PCa, and they are inversely associated with the androgen level. Up to 95% of adenocarcinomas of the prostate express PSMA receptors on their surface. Today, radionuclides that bind to these PSMA peptides are widely accepted for diagnostic and therapeutic purposes to specifically image and target prostate tumor cells at the molecular level, a process referred to as targeted theranostics. Numerous studies have demonstrated that the integration of these peptides into diagnostic and therapeutic procedures plays a critical role in the primary staging and treatment decisions of especially high-risk PCa, expands therapeutic options for patients with advanced stage of prostate tumor, and prolongs patients’ survival rate. In this review article, we intend to briefly spotlight the latest clinical utilization of the PSMA-targeted radioligand PET imaging modality in patients with different stages of PCa. Furthermore, limitations and pitfalls of this diagnostic technique are presented.

Effect of hormonal therapy on 18F-fluciclovine PET/CT in the detection of prostate cancer recurrence, localization of metastatic disease, and correlation with prostate-specific antigen.

18F-Fluciclovine, is a positron emission tomography (PET) radiotracer approved for the localization of sites of prostate cancer recurrence in men with a rising prostate-specific antigen (PSA) after definitive treatment. To explore the impact of androgen deprivation therapy (ADT) on the performance of 18F-fluciclovine, we conducted a retrospective analysis to compare the 18F-fluciclovine PET/CT positivity rate in patients receiving ADT at the time of the scan with the rate achieved in patients not receiving ADT. A retrospective review of data from patients who underwent18F-fluciclovine PET/CT for biochemical recurrence of prostate cancer between December 2016 to March 2020 was performed.The cohort was divided into an ADT group (patient reportedly on ADT) anda non-ADT group (not currently receiving ADT). Patients with unknown ADT status or undetectable/unknown PSA were excluded. For each group, the number of positive18F-fluciclovine PET/CT scans (positivity rate) was evaluated for thewhole body, prostate/bed, and extraprostatic regions and rates were correlated with PSA. The Fisher's Exact test was applied to establish the significancebetween the ADT and non-ADT positivity groups. Mantel-Haenszel trend test was performed to assess linearity between the positivity rate and PSA level. In 320 patients, the status of ADT was known. At the time of the18F-fluciclovine scan,68/320 (21%) patients were on ADT, while 252/320 (79%) were not. The median Gleason score was 8 (range of 6-10) in the ADT group vs. 7 (range of 6-10) in the non-ADT group (P < 0.001). Overall, positivity rates demonstrated no statistical significance between the ADT and non-ADT groups; Positivity rates (ADT vs. non-ADT) were 82% (56/68) vs. 82% (206/252) for the whole body, 57% (39/68) vs. 60% (152/252) for prostate/bed, and 60% (41/68) vs. 53% (133/252) for extraprostatic regions (P > 0.05). A positive linear correlation was noted between PSA and each group's positivity rate (P < 0.01). However, no significant difference was observed between ADT and non-ADT groups at different PSA levels (P > 0.05). Detection of prostate cancer recurrence with 18F-fluciclovine PET/CT is not significantly influenced by ADT, suggesting that localization of disease in patients with detectable PSA who are receiving ADT is feasible with 18F-fluciclovine.

Construction of miRNA-mRNA network and a nomogram model of prognostic analysis for prostate cancer.

BackgroundDysregulated genetic factors correlate with carcinoma progression. However, the hub miRNAs-mRNAs related to biochemical recurrence in prostate cancer remain unclear. We aim to identify potential miRNA-mRNA regulatory network and hub genes in prostate cancer.MethodsDatasets of gene expression microarray were downloaded from Gene Expression Omnibus (GEO) database for Robust Rank Aggregation (RRA), targeted gene prediction, gene function and signal pathway enrichment analyses, miRNA-mRNA regulatory network construction, core network screening, as well as validation and survival analysis were carried out by using exogenous data.ResultsProstate cancer-related differentially expressed genes were mostly related to actin filament regulation. Moreover, the cGMP-PKG signaling pathway might play a role in prostate cancer progression. As the core of microRNAs, hsa-miR-106b-5p, hsa-miR-17-5p and hsa-miR-183-5p were matched to hub genes (such as TMEM100, FRMD6, NBL1 and STARD4). The expression levels of hub genes in prostate cancer tissues were significantly lower than normal and closely related to prognosis of patients. The ridge regression model was applied to establish a risk score system. Both risk score and Gleason were used to establish a nomogram. Nomogram predicted the area under the [receiver operating characteristic (ROC)] curve (AUC) of biochemical recurrence at 1-, 3-, and 5-year of 0.713, 0.732 and 0.753, respectively.ConclusionsHub genes were closely related to prostate cancer development and progression, which might become biomarkers for diagnosis and prognosis. This novel nomogram established could be applied to clinical prediction.

PSMA as a Target for Advanced Prostate Cancer: A Systematic Review

ObjectiveProstate-specific membrane antigen (PSMA) is a cell-surface protein widely expressed on most prostate cancer cells that has rapidly emerging clinical utility in the realm of prostate cancer. This systematic review aims to evaluate the efficacy as well as cost-effectiveness of PSMA in the roles of diagnosis and treatment in prostate cancer management.BackgroundThe use of PSMA in the initial staging of patients, early detection of recurrence, and response monitoring are critical to improving prostate cancer treatment. We performed a systematic review of the role of Gallium-68 (68Ga)-PSMA in the initial detection of prostate cancer and detection of biochemical recurrence (BCR) as well as the role of Lutium-177 (177Lu)-PSMA in theranostics. We also investigated the cost-effectiveness of both ligands in comparison to the current standard of care.MethodsIn February 2022 we performed a systematic and comprehensive review of the existing literature. We identified and screened articles published from 1983 up to January 2022 through PubMed. Only 1 study was included prior to 2011. We included articles that investigated the efficacy or cost-effectiveness of PSMA in prostate cancer detection and therapy. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRSIMA) guidelines eligible articles were selected, and relevant information was extracted from the original articles.ResultsA total of 26 articles were included in the analysis of this systematic review. These studies were heterogeneous and were comprised of five prospective studies including 336 patients, three retrospective analyses including 540 patients, one phase III trial, one survival analysis, one randomized control trial, three systematic reviews, three meta-analyses, two in-vivo studies, three reviews, and four cost analyses.ConclusionThe diagnostic and therapeutic role of PSMA appears more efficacious and potentially less expensive than the standard treatment for patients with BCR of prostate cancer. Current evidence suggests PSMA will also fill an unmet need in initial diagnostics of prostate cancer and ligand therapy. However, a consensus has not yet been reached on cost-effectiveness of PSMA and further prospective studies are needed.

LTBP2 inhibits prostate cancer progression and metastasis via the PI3K/AKT signaling pathway.

Biochemical recurrence (BCR) is a cause of concern in advanced prostate cancer (PCa). Thus, novel diagnostic biomarkers are required to improve clinical care. However, research on PCa immunotherapy is also scarce. Hence, the present study aimed to explore promising BCR-related diagnostic biomarkers, and their expression pattern, prognostic value, immune response effects, biological functions, and possible molecular mechanisms were evaluated. GEO datasets (GSE46602, GSE70768, and GSE116918) were downloaded and merged as the training cohort, and differential expression analysis was performed. Lasso regression and SVM-RFE algorithm, as well as PPI analysis and MCODE algorithm, were then applied to filter BCR-related biomarker genes. The CIBERSORT and estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) methods were used to calculate the fractions of tumor-infiltrating immune cells. GO/DO enrichment analyses were used to identify the biological functions. The expression of latent transforming growth factor β-binding protein 2 (LTBP2) was determined by RT-qPCR and western blotting. The role of LTBP2 in PCa was determined by CCK-8, Transwell, and the potential mechanism was investigated by KEGG and GSEA and confirmed by western blotting. In total, 44 BCR-related differentially expressed genes (DEGs) in the training cohort were screened. LTBP2 was found to be a diagnostic biomarker of BCR in PCa and was associated with CD4+ T-cell infiltration and response to anti-PD-1/PD-L1 immunotherapy. Subsequently, using the ESTIMATE algorithm, it was identified that LTBP2 was associated with the tumor microenvironment and could be a predictor of the clinical benefit of immune checkpoint blockade. Finally, the expression and biological function of LTBP2 were evaluated via cellular experiments. The results showed that LTBP2 was downregulated in PCa cells and inhibited PCa proliferation and metastasis via the PI3K/AKT signaling pathway in vitro. In conclusion, LTBP2 was a promising diagnostic biomarker of BCR of PCa and had an important role in CD4+ T-cell recruitment. Moreover, it was associated with immunotherapy in patients with PCa who developed BCR, and it inhibited PCa proliferation and metastasis via the PI3K/AKT signaling pathway in vitro.

Best Approaches and Updates for Prostate Cancer Biochemical Recurrence.

Biochemical recurrence develops in almost one-third of men with prostate cancer after treatment with local therapy. There are numerous options for management, including surveillance, salvage radiation, androgen deprivation therapy (ADT), and clinical trials. This article reviews the current approaches to radiation therapy, ADT, and molecular imaging in men with biochemically recurrent prostate cancer. First, radiation therapy, including selection of field, dose, and use of concurrent antiandrogen therapy, is reviewed. Next, molecular imaging is addressed, including prostate-specific membrane antigen PET imaging and its increased sensitivity in identifying sites of disease. Finally, the factors associated with starting ADT are explored, and the data supporting intermittent over continuous ADT are reviewed. Lastly, the use of prostate-specific membrane antigen PET imaging and its potential role influencing therapy are discussed.

RETRACTED: Association of PSA density and Gleason score of the positive surgical margin with biochemical recurrence in prostate cancer; a historical cohort study.

This study aimed to investigate the association between PSA Density and Gleason score of the positive margin after radical prostatectomy with biochemical recurrence in patients with prostate cancer. In this retrospective cohort study, patients with prostate cancer referred to Hasheminejad Hospital in Tehran during 2009-2019, who underwent radical prostatectomy were assessed to enter the study. Patients were selected by the convenience sampling method. The follow-up period was determined as at least 1 year after radical prostatectomy to determine biochemical recurrence. PSA Density (PSAD) and the Gleason score of surgical specimen and positive surgical margins (PSM) were evaluated and their association with biochemical recurrences was investigated. One hundred and three patients entered the study. The overall biochemical recurrence rate was 48.5% with a mean follow-up of 24 months (12-42 months) and an average time to biochemical recurrence of 18 months (16-20 months). BCR-free survival rates of patients divided based on to the PSAD cut-off point (0.205 ng/ml/cc) were significantly different using the log-rank test (p = 0.008) (85.7%, 57.1%, and 14.3% for values ⩽0.205 ng/ml/cc vs 55.8%, 20.9%, and 0% for values ˃0.205 ng/ml/cc, respectively for 1-, 2- and 3-year survival). In addition, Cox regression showed that the Gleason score of PSM, the Gleason score of the surgical specimen, and the PSAD predicted biochemical recurrence to most extent, respectively. PSAD and PSM Gleason score were strong predictors of biochemical recurrence after radical prostatectomy and their use along with other common indicators including tumor grade and stage and PSA level can increase the accuracy of risk assessment in patients with prostate cancer.

Construction and validation of N6-methyladenosine long non-coding RNAs signature of prognostic value for early biochemical recurrence of prostate cancer.

Early biochemical recurrence (eBCR) indicated a high risk for potential recurrence and metastasis in prostate cancer. The N6-methyladenosine (m6A) methylation modification played an important role in prostate cancer progression. This study aimed to develop a m6A lncRNA signature to accurately predict eBCR in prostate cancer. Pearson correlation analysis was first conducted to explore m6A lncRNAs and univariate Cox regression analysis was further performed to identify m6A lncRNAs of prognostic roles for predicting eBCR in prostate cancer. The m6A lncRNA signature was constructed by least absolute shrinkage and selection operator analysis (LASSO) in training cohort and further validated in test cohort. Furthermore, half maximal inhibitory concentration (IC50) values were utilized to explore potential effective drugs for high-risk group in this study. Five hundred and thirty-eighth m6A lncRNAs were searched out through Pearson correlation analysis and 25 out of 538 m6A lncRNAs were identified to pose prediction roles for eBCR in prostate cancers. An m6A lncRNA signature including 5 lncRNAs was successfully built in training cohort. The high-risk group derived from m6A lncRNA signature could efficiently predict eBCR occurrence in both training (p < 0.001) and test cohort (p = 0.002). ROC analysis also confirmed that lncRNA signature in this study posed more accurate prediction roles for eBCR occurrence when compared with PSA, TNM stages and Gleason scores. Drug sensitivity analysis further discovered that various drugs could be potentially utilized to treat high-risk samples in this study. The m6A lncRNA signature in this study could be utilized to efficiently predict eBCR occurrence, various clinical characteristic and immune microenvironment for prostate cancer.

Ga-68-PSMA-11 PET/CT in Patients with Biochemical Recurrence of Prostate Cancer after Primary Treatment with Curative Intent-Impact of Delayed Imaging.

: BackgroundThe presence of prostate-specific membrane antigen (PSMA) on prostate cancer cells and its metastases allows its use in diagnostics using PET/CT. The aim of this study was to evaluate the usefulness of delayed phase images in the Ga-68-PSMA-11 PET/CT. Methods: 108 patients with prostate cancer (median age: 68.5 years, range: 49–83) were referred for Ga-68-PSMA-11 PET/CT due to biochemical relapse (PSA (prostate-specific antigen) (3.2 ± 5.4 ng/mL). Examinations were performed at 60 min, with an additional delayed phase of the pelvis region at 120–180 min. Results: The Ga-68-PSMA-11 PET/CT showed lesions in 86/108 (80%) patients; detection rate depending on the PSA level: 0.2 < PSA < 0.5 ng/mL vs. 0.5 ≤ PSA < 1.0 ng/mL vs. 1.0 ≤ PSA < 2.0 ng/mL vs. PSA ≥ 2.0 ng/mL was 56% (standard vs. delay: 56 vs. 56%) vs. 60% (52 vs. 60%) vs. 87% (83 vs. 87%) vs. 82% (77 vs. 82%) of patients, respectively. The delayed phase had an impact on the treatment in 14/86 patients (16%) (p < 0.05): 7 pts increased uptake was seen only after 60 min, which was interpreted as physiological or inflammatory accumulation; the delayed image showed increased accumulation in 7 patients only: 4 in regional lymph nodes, 1 in local recurrence, and 2 patients with local recurrence showed additional foci. Conclusions: Delayed phase of Ga-68-PSMA-11 PET/CT has an impact on treatment management in 16% of patients.

18F-PSMA-11 Versus 68Ga-PSMA-11 Positron Emission Tomography/Computed Tomography for Staging and Biochemical Recurrence of Prostate Cancer: A Prospective Double-blind Randomised Cross-over Trial

BackgroundFluorine-18 (18F)-labelled prostate-specific membrane antigen (PSMA) offers several advantages over gallium-68 (68Ga) in terms of costs, yield, transport/distribution, and image resolution. ObjectiveThis trial investigates the new radiotracer 18F-PSMA-11 via a prospective, intraindividual crossover design. The trial was powered for noninferiority of 18F-PSMA-11 over 68Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) in terms of the number of positive PET scans. Secondary endpoints were as follows: (1) superiority of 18F-PSMA-11 over 68Ga-PSMA-11 with respect to the number of positive PET scans, the total number of suspicious prostate cancer lesions, and the miPSMA expression score of corresponding lesions; (2) correlation of the PET/CT images with available follow-up data for 18F-PSMA-11 and 68Ga-PSMA-11; and (3) assessment of the interobserver variability. Design, setting, and participantsProstate cancer patients (primary or biochemical recurrence) were randomised in a double-blind crossover design whereby each patient received both 18F-PSMA-11 and 68Ga-PSMA-11 PET/CT. Outcome measurements and statistical analysisAll scans were reviewed and scored by three independent experienced nuclear physicians following the proposed guideline for the interpretation of PSMA-ligand PET/CT, as described by Eiber et al. Results and limitationsIn total, 82 patients were included for scan analyses. The primary endpoint was met: per patient, the proportions of positive scans rated by the three readers were 67%/67%, 65%/65%, and 73%/70% for 18F-PSMA-11/68Ga-PSMA-11 PET/CT. The miPSMA expression score was higher for 18F-PSMA-11 than for 68Ga-PSMA-11 for the reference reader. Follow-up data showed identical estimated sensitivity for both the 18F-PSMA-11 and the 68Ga-PSMA-11 scan (0.92, 0.83, and 0.92 for the three readers). A fair to good agreement among readers (at patient level) was obtained, which was demonstrated by a Light’s kappa value of 0.59 for both tracers. ConclusionsThe tracer 18F-PSMA-11 is noninferior to68Ga-PSMA-11. Superiority of 18F-PSMA-11 was limited to the miPSMA expression score, given by the reference reader. Inter-rater agreement was fair to good, and equal for both radiotracers. Patient summaryIn this study, we compared two radiotracers: 18F-PSMA-11 and 68Ga-PSMA-11. We proved that 18F-PSMA-11 is not inferior to 68Ga-PSMA-11 for detecting prostate cancer and thus can be used as an alternative. Possible superiority of this tracer should be further investigated in specific subpopulations.