PSA Level Research Articles

Evaluación del valor predictivo negativo de la resonancia magnética multiparamétrica de próstata al combinar su puntuación con parámetros del antígeno prostático específico en pacientes con PSA en zona gris

ObjectiveTo calculate the negative predictive value (NPV) of negative multiparametric prostate magnetic resonance imaging (mpMRI), accepted as no lesions on images, when combined with prostate-specific antigen density (PSAD) and free/total prostate-specific antigen ratio (f/t PSA) in grey zone patients. MethodsOne hundred ninety-one patients with PSA levels between 4-10mg/ml and negative mpMRI were analyzed. The NPV of negative mpMRI was calculated according to a PSAD level of <0.15 ng/ml/ml, f/t PSA ratio of >0.15, and a combination of both. Patients were divided into three risk groups according to these two parameters:•PSAD 0.01-0.07 ng/ml/ml and f/t PSA ratio ≥25 in a low-risk group.•PSAD 0.08-0.15 ng/ml/ml, and f/t PSA ratio 0.15-0.24 in an intermediate-risk group and high-risk group.•PSAD>0.15 ng/ml/ml and f/t PSA ratio <15 in high-risk group, ResultsNPV of negative mpMRI was 92.6% for clinically significant prostate carcinoma (CSPCa). It increased to 97.5% in a low-risk group and decreased to 33.3% for CSPCa in a high-risk group. NPV of negative mpMRI results were so close when combined with PSAD <0.15 ng/ml/ml and f/t PSA>15. Conclusionf/t PSA ratio might also be used to increase the NPV of mpMRI, like PSAD. We advise not to avoid prostate biopsy when PSAD is >0.15 ng/ml/ml and the f/t PSA ratio is <0.15. However, we need randomized controlled studies with more patients to confirm our study.

Role of lymphatic invasion in predicting biochemical recurrence after radical prostatectomy.

Lymphatic invasion in prostate cancer is associated with poor prognosis. However, there is no consensus regarding the clinical and prognostic value of lymphatic invasion. This study aimed to investigate the prognostic value of lymphatic invasion in biochemical recurrence (BCR) and compare the recurrence rates between patients with lymphatic invasion and lymph node metastasis. We retrospectively analyzed 2,207 patients who underwent radical prostatectomy (RP) without pelvic lymph node dissection (PLND) and 742 patients who underwent RP with PLND for clinically localized or locally advanced prostate cancer, between 1993 and 2020, at Seoul National University Hospital. Kaplan-Meier analysis was performed to estimate BCR-free survival (BCRFS) using the log-rank test. The Cox proportional hazards model was used to identify the significant factors for BCR. Propensity score matching was performed with a 1:2 ratio to match age, initial PSA level, pathological T stage, and Gleason score to exclude confounding effects. Of the 2,207 patients who underwent RP without PLND, lymphatic invasion (L1Nx) was observed in 79 (3.5%) individuals. Among the 742 patients who underwent RP with PLND, lymph node metastases were found in 105 patients (14.2%). In patients with lymph node metastasis, lymphatic invasion was observed in 50 patients (47.6%), whereas lymphatic invasion was observed in 53 patients (8.3%) among those without lymph node metastasis. In patients who underwent RP without PLND, Kaplan-Meier analysis showed significantly poorer BCR-free survival in the L1Nx group than in the L0Nx group (p < 0.001). In patients who underwent RP with PLND, the L1N0, L0N1, and L1N1 groups showed significantly worse prognoses than the L0N0 group (p < 0.001). However, there was no significant difference in BCRFS between the L1N0 and lymph node metastasis groups, including the L0N1 and L1N1 groups. After propensity score matching at a 1:2 ratio, the L1Nx group showed significantly poorer outcomes in terms of BCRFS than the L0Nx group (p = 0.05). In addition, the L1N0 group showed a significantly worse prognosis than the L0N0 group after propensity score matching. Lymphatic invasion in radical prostatectomy specimens is an independent prognostic factor, which can complement lymph node status for predicting biochemical recurrence. Considering lymphatic invasion as an adverse pathological finding, similar to lymph node metastasis, adjuvant therapy could be considered in patients with lymphatic invasion.

Direct Patlak Reconstruction of [68Ga]Ga-PSMA PET for the Evaluation of Primary Prostate Cancer Prior Total Prostatectomy: Results of a Pilot Study.

To investigate the use of kinetic parameters derived from direct Patlak reconstructions of [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) to predict the histological grade of malignancy of the primary tumor of patients with prostate cancer (PCa). Thirteen patients (mean age 66 ± 10 years) with a primary, therapy-naïve PCa (median PSA 9.3 [range: 6.3-130 µg/L]) prior radical prostatectomy, were recruited in this exploratory prospective study. A dynamic whole-body [68Ga]Ga-PSMA-11 PET/CT scan was performed for all patients. Measured quantification parameters included Patlak slope (Ki: absolute rate of tracer consumption) and Patlak intercept (Vb: degree of tracer perfusion in the tumor). Additionally, the mean and maximum standardized uptake values (SUVmean and SUVmax) of the tumor were determined from a static PET 60 min post tracer injection. In every patient, initial PSA (iPSA) values that were also the PSA level at the time of the examination and final histology results with Gleason score (GS) grading were correlated with the quantitative readouts. Collectively, 20 individual malignant prostate lesions were ascertained and histologically graded for GS with ISUP classification. Six lesions were classified as ISUP 5, two as ISUP 4, eight as ISUP 3, and four as ISUP 2. In both static and dynamic PET/CT imaging, the prostate lesions could be visually distinguished from the background. The average values of the SUVmean, slope, and intercept of the background were 2.4 (±0.4), 0.015 1/min (±0.006), and 52% (±12), respectively. These were significantly lower than the corresponding parameters extracted from the prostate lesions (all p < 0.01). No significant differences were found between these values and the various GS and ISUP (all p > 0.05). Spearman correlation coefficient analysis demonstrated a strong correlation between static and dynamic PET/CT parameters (all r ≥ 0.70, p < 0.01). Both GS and ISUP grading revealed only weak correlations with the mean and maximum SUV and tumor-to-background ratio derived from static images and dynamic Patlak slope. The iPSA demonstrated no significant correlation with GS and ISUP grading or with dynamic and static PET parameter values. In this cohort of mainly high-risk PCa, no significant correlation between [68Ga]Ga-PSMA-11 perfusion and consumption and the aggressiveness of the primary tumor was observed. This suggests that the association between SUV values and GS may be more distinctive when distinguishing clinically relevant from clinically non-relevant PCa.

An exploratory study of unexplained concentration of 18F-PSMA-1007 in the bladder for prostate cancer PET/CT imaging.

18F-PSMA-1007 PET/CT imaging is increasingly used for the diagnosis, staging, and efficacy assessment of patients with prostate cancer. Compared with other PSMA tracers, 18F-PSMA-1007 is mainly cleared by the liver and bile and has lower urinary clearance, thus allowing a better assessment of the lesions around the bladder. However, there were some patients who showed an obvious concentration of the 18F-PSMA-1007 in the bladder, which may affect the observation of peripheral lesions, but the mechanism of this change is unknown. The aim of this study was to explore the cause of bladder 18F-PSMA-1007 concentration by assessing the clinical and imaging characteristics of 18F-PSMA-1007 PET/CT scans. A total of 284 patients were included in this retrospective study, and their clinical characteristics such as age, height, weight, Gleason score, metastases, different treatment methods, the level of liver and kidney function, PSA level, and imaging characteristics such as 18F-PSMA-1007 injected activity, the interval between injection to scan, physiological distribution (parotid gland, kidney, liver, spleen, intestine, obturator internus), pathological distribution (prostate lesions, metastases) were collected, and were compared after subgrouping using bladder urine SUVmax. This study showed that the distribution of bladder 18F-PSMA-1007 was not correlated with the above clinical and imaging characteristics, so further studies are needed to find the explanations, and thus to improve the disease assessment of this type of prostate cancer patients.

864 Does the PROMIS Trial Deliver What It Promised? Validation in a North West Population

Abstract Aim The PROMIS trial changed the landscape on how men with raised PSA are evaluated. We changed the pathway at a North West hospital, utilising multiparametric MRI (MP-MRI) scans and incorporated additional safety parameters (family history and PSA density) to maintain the advantage of avoiding unnecessary biopsy whilst not missing significant cancers. We present the performance of this pathway. Method We retrospectively reviewed 596 referrals of men with high PSA level between January - December 2021. Variables audited included demographics, PSA level, PSA density, Prostate Imaging-Reporting and Data System (PI-RADS) score on MP-MRI, biopsy results, Gleason score and prognostic grade grouping. Results Of 596 patients, 65.9% of men were aged between 50-75 years. The most common quintile of presenting PSA was 4.00-9.99 (53.2%). Of the 381 patients with non-metastatic prostate cancer who underwent MP-MRI, 38.3% were classed as PI-RAD 1-2, 16% PI-RAD 3 and 45.7% PI-RAD 4-5. Overall, 48.3% of patients did not undergo biopsy. Biopsy rates in PI-RAD 1-5 were 2.3%, 3.9%, 52.5%, 92.5% and 91.5% respectively, the decision made to monitor PSA instead in some cases due to co-morbidities or patient preference. Of 197 biopsies, 79.2% were positive, 87.8% initially classed as PI-RADS 4 or 5. Of the cancers picked up, 82.1% were clinically significant (Gleason score ≥3+4). Conclusions This study shows the pathway incorporating MP-MRI, family history and PSA density enables 48.3% of patients to avoid unnecessary biopsy and therefore overdiagnosis of clinically insignificant cancers. The PROMIS trial delivers what it promised.

Role of mucin glycosylation in the gut microbiota-brain axis of core 3 O-glycan deficient mice

Alterations in intestinal mucin glycosylation have been associated with increased intestinal permeability and sensitivity to inflammation and infection. Here, we used mice lacking core 3-derived O-glycans (C3GnT−/−) to investigate the effect of impaired mucin glycosylation in the gut-brain axis. C3GnT−/− mice showed altered microbial metabolites in the caecum associated with brain function such as dimethylglycine and N-acetyl-l-tyrosine profiles as compared to C3GnT+/+ littermates. In the brain, polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive granule cells showed an aberrant phenotype in the dentate gyrus of C3GnT−/− mice. This was accompanied by a trend towards decreased expression levels of PSA as well as ZO-1 and occludin as compared to C3GnT+/+. Behavioural studies showed a decrease in the recognition memory of C3GnT−/− mice as compared to C3GnT+/+ mice. Combined, these results support the role of mucin O-glycosylation in the gut in potentially influencing brain function which may be facilitated by the passage of microbial metabolites through an impaired gut barrier.

Role of 68Ga-PSMA PET/CT in Initial Staging of Prostate Cancer and Correlation with PSA and Gleason Score

Background Prostate cancer is the second most common male malignancy. Its prognosis depends on the tumor stage as well as its aggressiveness; expressed histopathologically by Gleason scores. Furthermore, optimal patient management depends on the tumor stage. 68Ga PSMA PET/CT has a wide spectrum of uses in prostate malignancy, some of them are comprehensively studied while others are still under investigation. The most widely accepted use is the accurate initial staging of cancer prostate as well as predicting the long-term outcome, with SUVmax being a promising prognostic parameter correlating significantly with other established prognostic parameters, including the Gleason score and the PSA levels. Objective To evaluate the role of 68GA- PSMA PET/CT in initial staging of prostate cancer and correlate with PSA level and Gleason score. Methods A prospective descriptive study over the course of 6 months. It included patients with pathologically proven prostate cancer referred for a PSMA PET/CT scan for initial staging without any treatment or interventions. Results 68Ga-PSMA PET/CT scans of 36 patients were evaluated for local staging (primary prostatic lesions, extra-prostatic spread, and seminal vesicle invasion), regional nodal staging, and metastatic spread (extra-regional lymph nodes, osseous lesions, and visceral lesions). PET/CT findings as well as the SUVmax of the most avid lesions were correlated with PSA level, Gleason scores, as well as Gleason grade risk groups. A statistically significant relationship was found between PSA level and SUVmax of prostatic lesion as well as that of the most avid metastatic regional lymph node, the presence of extra-regional lymph nodal spread, the presence of osseous metastatic lesions, the presence of seminal vesicle invasion, extra-prostatic extension, and the presence of PSMA-avid regional lymph nodal spread. On the other hand, a statistically significant relationship was found between Gleason scores and the presence of regional lymph nodal spread and osseous metastatic lesions. Lastly, a statistically significant relationship was found between Gleason grading risk groups and the presence of regional lymph nodal spread and osseous metastatic lesions. Conclusion 68Ga-PSMA PET/CT is a powerful staging and stratifying tool for the majority of prostate cancer patients, being significantly correlated with PSA level and Gleason scores. However, patients with low PSA scores still pose a dilemma as they showed significantly low PSMA uptake, rendering the use of 68Ga-PSMA PET/CT for staging in such patients controversial. 68Ga-PSMA PET/CT based imaging findings should ideally be supported with histopathological documentation and/or follow-up imaging results in order to confirm the nature of detected lesions and help establish accurate sensitivity and specificity of 68Ga-PSMA PET/CT.

Role of Focal HIFU Prostate Ablation in the Management of Unilaterally Diagnosed Low and Intermediate Risk Prostate Cancer

Objective Focal therapy for prostate cancer is gaining a rising evidence about their comparative effectiveness in cancer control with fewer complications to the radical treatment options. The aim of this study is to highlight the effectiveness of the focal therapy treatment on the ISUP group 2 and 3 mainly. Subjects/patients and methods 115 patients with localized prostate cancer who had HIFU in our centre over 10 years were included. PSA levels were recorded routinely follow up MRI and the results of the prostate biopsies after the treatment. Results Patients were followed up after the treatment for 34 months in average. The failure free survival rate was higher in ISUP 2 (85.9%) in comparison to ISUP 3 (82.6%). Different grades of histological recurrence were detected in 24% in these patients, and they were offered different treatments accordingly. The patients had good functional performance after the procedure with IPSS of average 8 in the follow up and about 20% of them having erectile dysfunction with good response on medical treatment. Conclusion HIFU is an eminent treatment for the localized prostate cancer with a comparative oncological to the radical treatment with low functional side effects especially in intermediate risk group.

Application of 18F-PSMA-1007 PET/MR Imaging in Early Biochemical Recurrence of Prostate Cancer: Results of a Prospective Study of 60 Patients with Very Low PSA Levels ≤ 0.5 ng/mL.

Sixty patients with BCR after radical prostatectomy (RP) with PSA ranged 0.1-0.5 ng/mL were enrolled in a prospective study. All patients underwent simultaneous whole-body and pelvic 18F-PSMA-1007 PET/MR. The obtained results were verified by 12-month follow-up. Fifty-three lesions were detected in 45 patients with 75% detection rate. The mean PSA value was 0.31 ng/mL. Of all PSMA-positive foci, 91% were localized in the pelvis, and only 9% of lesions were located in the extrapelvic region. Local recurrences were detected in 29%, PSMA-positive lymph nodes were detected in 64% of patients and bone metastases lesions were detected in 7% of patients. 18F-PSMA-1007 PET/MR seems to be an excellent diagnostic tool in patients with early BCR with very low PSA levels, especially with dt PSA < 6 months. The synergistic effect of combining 18F-PSMA-1007 and whole-body PET/MR with precise multiparametric assessment of pelvic lesions is of particular benefit in early BCR.

Node Oligorecurrence in Prostate Cancer: A Challenge.

Within the oligometastatic state, oligorecurrent lymph node disease in prostate cancer represents an interesting clinical entity characterized by a relatively indolent biology that makes it unique: it can be treated radically, and its treatment is usually associated with a long period of control and excellent survival. Additionally, it is an emergent situation that we are facing more frequently mainly due to (a) the incorporation into clinical practice of the PSMA-PET that provides strikingly increased superior images in comparison to conventional imaging, with higher sensitivity and specificity; (b) the higher detection rates of bone and node disease with extremely low levels of PSA; and (c) the availability of high-precision technology in radiotherapy treatments with the incorporation of stereotaxic body radiotherapy (SBRT) or stereotaxic ablative radiotherapy (SABR) technology that allows the safe administration of high doses of radiation in a very limited number of fractions with low toxicity and excellent tolerance. This approach of new image-guided patient management is compelling for doctors and patients since it can potentially contribute to improving the clinical outcome. In this work, we discuss the available evidence, areas of debate, and potential future directions concerning the utilization of new imaging-guided SBRT for the treatment of nodal recurrence in prostate cancer.

Histomorphological characteristics of prostate specimens analyzed at a referral hospital in Kenya.

Background: Global shift to high energy foods is important risk factor for new variants of prostate cancer. Some prostate tumors have an indolent course while others have an aggressive course; therefore, knowledge of tumor subtypes can help in clinical decision-making based on the patient profile. Methods: The main aim of the study was to determine the histomorphological characteristics of prostate specimens analyzed at regional referral hospital. The study was a crosssectional retrospective study. The target specimens in this study consisted of prostate specimens that had prostate specific antigen level and were analyzed and reported between 2017 and 2022 at Jaramogi Odinga Oginga teaching and referral hospital, Kisumu Kenya. Results: Prostate color was not reported in eight reports. Of the 72 specimens observed, 50 (69.4%) were reported to be white, 12 (16.7%) were reported to be tan/white, 9 (12.5%) were tan brown, and 1 (1.4%) was tan grey. There was significant variation (p=0.001) in prostate specimen color. Of the 80 specimens, 47 (58.75%) had coarse surface, 16(20.00%) nodulated surfaces and 17 (21.25%) shrunken surfaces. There was variation in prostate surfaces (p&lt;0.00001, X2=23.275). Majority of specimens 55 (68.8%) measured between 0-29 mm, 12 (15%) measured 30-59 mm, 7 (8.8%) measured 60-89, 3 (3.8%) measured 90-119, 2 (2.5%) measured &gt;150 mm and 1 (1.3%) measured 120-149 mm. There was no significant difference in the prostate biopsy sizes in comparison to the mean (p=0.984, t=0.020, 95% CI). The majority 20 (25%), of specimens had prostate cancer 15 (18.75%) had atypical findings, and 2 (2.5%) had high-grade proliferative intraepithelial neoplasia. The microscopic features of the groups did not differ significantly (F2, 34 = 1.469, p = 0.244). There is positive correlation between Gleason scores and Prostate specific antigen levels (p = 0.004, r = 0.474). Conclusion: There is variation of specimen color in prostate specimen with prostate cancer implying that advanced prostate disease causes changes in prostate color. Atypical prostate findings are common in age 50-59 which may suggest that targeted prevention and intervention should focus on this age group. Higher Gleason scores are likely to be observed in patients with higher PSA levels among patients being evaluated for prostate tumors.

Zoledronic Acid Prevents Bone Resorption Caused by the Combination of Radium-223, Abiraterone Acetate, and Prednisone in an Intratibial Prostate Cancer Mouse Model.

An increased risk of non-pathological fractures in patients with prostate cancer and bone metastases has been associated with combination treatment with radium-223, abiraterone, and prednisone/prednisolone in the absence of bone-protecting agents. Here, we investigated possible mechanisms leading to this outcome using an intratibial LNCaP model mimicking prostate cancer bone metastases. Male NOD.scid mice were inoculated intratibially with LNCaP prostate cancer cells and treated with vehicle, radium-223, abiraterone, prednisone, zoledronic acid, or their combinations for 28 days. Serum TRACP 5b and PSA levels were measured. Bone structure, quality, and formation rate of non-tumor-bearing and tumor-bearing tibiae were analyzed by microCT, 3-point bending assay, and dynamic histomorphometry, respectively. Radium-223 incorporation into bone was also measured. Radium-223/abiraterone/prednisone combination treatment induced a transient increase in bone resorption indicated by elevated TRACP 5b levels, which was inhibited by concurrent treatment with zoledronic acid. Furthermore, radium-223/abiraterone/prednisone combination reduced periosteal and trabecular new bone formation and the number of osteoblasts, but bone structure or biomechanical quality were not affected. The abiraterone/prednisone treatment decreased radium-223 incorporation into tumor-bearing bone, possibly explaining the lack of additional antitumor efficacy. In conclusion, radium-223/abiraterone/prednisone combination increased bone resorption, which may have been one of the mechanisms leading to an increased fracture risk in patients with mCRPC.

Detection of Biochemically Recurrent Prostate Cancer with [18F]DCFPyL PET/CT: An Updated Systematic Review and Meta-Analysis with a Focus on Correlations with Serum Prostate-Specific Antigen Parameters.

[18F]DCFPyL is increasingly used for prostate-specific membrane antigen (PSMA) mediated imaging of men with biochemically recurrent prostate cancer (BRPCa). In this meta-analysis, which is updated with the addition of multiple new studies, including the definitive phase III CONDOR trial, we discuss the detection efficiency of [18F]DCFPyL in BRPCa patients. PubMed was searched on 29 September 2022. Studies evaluating the diagnostic performance of [18F]DCFPyL among patients with BRPCa were included. The overall pooled detection rate with a 95% confidence interval (95% CI) was calculated among all included studies and stratified among patients with PSA ≥ 2 vs. <2 ng/mL and with PSA ≥ 0.5 vs. <0.5 ng/mL. The association of detection efficiency with pooled PSA doubling time from two studies was calculated. Seventeen manuscripts, including 2252 patients, met the inclusion criteria and were used for data extraction. A previous meta-analysis reported that the pooled detection rate was 0.81 (95% CI: 0.77-0.85), while our study showed a pooled overall detection rate of 0.73 (95% CI: 0.66-0.79). An increased proportion of positive scans were found in patients with PSA ≥ 2 vs. <2 ng/mL and PSA ≥ 0.5 vs. <0.5 ng/mL. No significant difference was found in detection efficiency between those with PSA doubling time ≥ 12 vs. <12 months. Detection efficiency is statistically related to serum PSA levels but not to PSA doubling time based on available data. The detection efficiency of [18F]DCFPyL in men with BRPCa has trended down since a previous meta-analysis, which may reflect increasingly stringent inclusion criteria for studies over time.

Exploratory analysis of 64CuCl2 PET-CT imaging in carcinoma prostate and its comparison with 68Ga-PSMA-11 and 18F-FDG PET-CT.

Exploratory analysis of 64CuCl2 PET-CT imaging in patients of carcinoma prostate and its head-to-head comparison with 68Ga-PSMA-11 and 18F-FDG PET-CT. In this prospective study, 50 patients of biopsy-proven carcinoma prostate belonging to the entire spectrum of disease were evaluated, out of which 21 patients were for initial staging and 29 were for restaging/response evaluation. Both 64CuCl2 (early and delayed) and 68Ga-PSMA-11 PET-CT were undertaken in all patients and 18F-FDG PET-CT was done in patients whenever possible. All scans were done within a period of 2 weeks, without any interim therapeutic intervention. 64CuCl2 PET-CT was acquired at 1 and 3 h. We evaluated the physiological uptake of 64CuCl2, correlated the uptake in primary with disease parameters like Gleason score and serum PSA levels, and compared the detection rates for primary and metastatic disease with 68Ga-PSMA-11 and 18F-FDG PET-CT. The detection rates of primary disease were same for both 64CuCl2 and 68Ga-PSMA-11 PET-CT and both agents performed similarly in detecting extra-prostatic disease. There was no statistically significant correlation observed between the uptake of 64CuCl2 in the primary lesion with disease parameters. With regard to the evaluation of metastatic disease, the detection rate of 64CuCl2 PET-CT was 86% for lymph nodes, 77.3% for skeletal metastases and 80.6% for soft tissue metastases while 68Ga-PSMA-11 PET-CT performed better with detection rates were 98%, 99% and 85.4%, respectively. In 17 patients where 18F-FDG PET-CT was available, 64CuCl2 PET-CT detected more metastatic disease than 18F-FDG PET-CT. 64CuCl2 PET-CT did not show any additional advantage over 68Ga-PSMA-11 PET-CT in evaluation of local disease or for the assessment of metastatic disease. When compared to 68Ga-PSMA-11 PET-CT, the absence of urinary bladder and ureteric activity allows better contrast for evaluating local disease, but it does not translate into increased disease detection.

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

A pilot study of an organised population-based testing programme for prostate cancer.

To determine the feasibility of a digitally automated population-based programme for organised prostate cancer testing (OPT) in Southern Sweden. A pilot project for a regional OPT was conducted between September 2020 and February 2021, inviting 999 randomly selected men aged 50, 56, or 62 years. Risk stratification was based on prostate-specific antigen (PSA) level, PSA density (PSAD), and bi-parametric prostate magnetic resonance imaging (MRI). Men with a PSA level of 3-99 ng/mL had an MRI, and men with elevated PSA level (≥3 ng/mL) had a urological check-up, including a digital rectal examination and transrectal ultrasonography (TRUS). Indications for targeted and/or systematic transrectal prostate biopsies were suspicious lesions on MRI (Prostate Imaging-Reporting and Data System [PI-RADS] 4-5) and/or PSAD > 0.15 ng/mL/mL. Additional indications for prostate biopsies were palpable tumours, PSA ratio < 0.1, or cancer suspicion on TRUS. Patient selection, mail correspondence, data collection, and algorithm processing were performed by an automated digital management system. Feasibility is reported descriptively. A total of 418 men had a PSA test (42%), with increasing participation rates by age (50 years, 38%; 56 years, 44%; and 62 years, 45%). Among these, 35 men (8%) had elevated PSA levels (≥3 ng/mL: one of 139, aged 50 years; 10/143, aged 56 years; and 24/146, aged 62 years). On MRI, 16 men (48%) had a negative scan (PI-RADS < 3), seven men (21%) had PI-RADS 3, nine men (27%) had PI-RADS 4, and one man (3%) had PI-RADS 5. All men with PI-RADS 4 or 5 underwent prostate biopsies, as well as two men with PI-RADS 3 due to PSAD > 0.15 ng/mL/mL or a suspicious finding on TRUS. Prostate cancer was diagnosed in 10 men. Six men underwent active treatment, whereas four men were assigned to active surveillance. Our OPT model is feasible from an operational point of view, but due to the limited scale of this study no conclusions can be made regarding the efficacy of the diagnostic model or outcome.

The role of localised prostate cancer treatment in renal transplant patients: A systematic review.

To systematically review and critically appraise all treatment options for localised prostate cancer in renal transplant candidates and recipients. A systematic review was conducted adhering to PRISMA guidelines. Searches were performed in the Cochrane Library, Embase, Medline, the Transplant Library and Trip database for studies published up to September 2022. Risk of bias was assessed with the Cochrane Risk of Bias in Non-Randomised Studies of Interventions for non-randomised studies tool. A total of 60 studies were identified describing 525 patients. The majority of studies were either retrospective non-randomised comparative or case series/reports of poor quality. The vast majority of studies were focussed on prostate cancer after renal transplantation. Overall, 410 (78%) patients underwent surgery, 93 (18%) patients underwent radiation therapy or brachytherapy, one patient underwent focal therapy (high-intensity frequency ultrasound) and 21 patients were placed on active surveillance. The mean age was 61 years old, the mean PSA level at diagnosis was 9.6ng/mL and the mean follow-up time was 31 months. The majority of patients had low-risk disease with 261 patients having Gleason 6 prostate cancer (50%), followed by 220 Gleason 7 patients (42%). All prostate cancer mortality cases were in high-risk prostate cancer (≥Gleason 8). The cancer-specific survival results were similar between surgery and radiotherapy at 1 and 3years. Localised prostate cancer treatment in renal transplant patients should be risk stratified. Surgery and radiation treatment for localised prostate cancer in renal transplant patients appear equally efficacious. Given the limitations of this study, future research should concentrate on developing a multicentre RCT with long-term registry follow-up.

Mid-term oncologic outcomes of radical prostatectomy in lymph node metastatic prostate cancer patients.

Lymph node invasion (LNI) has been reported in 10-15% of pelvic lymph node dissection during radical prostatectomy (RP). The objective of this study was to describe the mid-term oncological outcomes in prostate cancer (PCa) patients with metastatic lymph node. We conducted a retrospective study at two French referral centers including consecutive cN0 PCa patients who underwent RP and extended pelvic lymph node dissection and had lymph node metastases on final pathological analysis (pN1) between January 2000 and May 2020. Follow-up was per institution, which generally included a PSA level measurement every 3 to 12 months for 5 years and annually thereafter. A total of 123 patients were included: two (1.6%) low-risk, 64 (52%) intermediate-risk and 57 (46.4%) high-risk PCa according to the D'Amico risk classification. The median number of nodes removed and metastatic nodes per patient was 15 (IQR 11-22) and 1 (IQR 1-2), respectively. Adverse pathological features, i.e., ≥pT3a stage, ISUP grade ≥3, and positive surgical margins were reported in 113 (91.9%), 103 (83.7%), and 73 (59%) of cases, respectively. Postoperative treatment was administered in 104 patients, including radiotherapy alone (n=6), androgen deprivation therapy alone (n=27) or combination with androgen deprivation therapy and radiotherapy (n=71). The mean follow-up was 42.7 months. The estimated 3-year biochemical-free survival, clinical recurrence-free survival, and cancer-specific survival was 66% and 85% and 98.8%, respectively. In Cox regression analysis, the number of metastatic nodes was associated with clinical recurrence (P=0.04) and a persistently elevated PSA with biochemical recurrence (P<0.001). The management of lymph node metastatic PCa patients is challenging. Risk stratification of node-positive patients, based on postoperative PSA levels and pathologic features being identified, should help physicians determine which patient would best benefit from multimodal treatment.

Predictive factors associated with differential pathologic response to neoadjuvant chemohormonal therapy in high-risk localized prostate cancer

To explore the clinical parameters and molecular biomarkers that can predict differential pathologic response to neoadjuvant chemohormonal therapy (NCHT) in prostate cancer (CaP).A total of 128 patients with primary high-risk localized CaP who had received NCHT followed by radical prostatectomy (RP) were included. Androgen receptor (AR), AR splice variant-7 (AR-V7) and Ki-67 staining were evaluated in prostate biopsy specimens by immunohistochemistry. The pathologic response to NCHT in whole mount RP specimens was measured based on the reduction degree of tumor volume and cellularity compared to the paired pretreatment needle biopsy, and divided into 5 tier grades (Grades 0-4). Patients with Grades 2 to 4 (the reduction degree more than 30%) were defined as having a favorable response. Logistic regression was performed to explore the predictive factors associated with a favorable pathologic response. The predictive accuracy was evaluated by receiver operating characteristic (ROC) curve and area under the ROC curve (AUC).Ninety-seven patients (75.78%) had a favorable response to NCHT. Logistic regression showed that the preoperative PSA level, low AR expression and high Ki-67 expression in biopsy specimens were associated with a favorable pathologic response (P < 0.05). Furthermore, the AUC of the preoperative PSA level, AR and Ki-67 were 0.625, 0.624 and 0.723, respectively. Subgroup analysis revealed that the rate of favorable pathologic response to NCHT was 88.5% in patients with ARlowKi-67high, which was higher than patients with ARlowKi-67low, ARhighKi-67low, and ARhighKi-67high (88.5% vs. 73.9%, 72.9%, and 70.9%, all P < 0.05).A lower preoperative PSA level was an independent predictive factor for a favorable pathologic response. Moreover, the expression status of AR and Ki-67 in biopsy specimens were associated with differential pathologic response to NCHT, and AR low/Ki-67 high was also associated with favorable response but warrants further evaluation in this patient subgroup and future trial clinical trial design.

Primary Total Prostate Cryoablation for Localized High-Risk Prostate Cancer: 10-Year Outcomes and Nomograms.

The role of prostate cryoablation was still uncertain for patients with high-risk prostate cancer (PC). This study was designed to investigate 10-year disease-free survival and establish a nomogram in localized high-risk PC patients. Between October 2008 and December 2020, 191 patients with high-risk PC who received primary total prostate cryoablation (PTPC) were enrolled. The primary endpoint was biochemical recurrence (BCR), defined using Phoenix criteria. The performance of pre-operative and peri-operative nomograms was determined using the Harrell concordance index (C-index). Among the cohort, the median age and PSA levels at diagnosis were 71 years and 12.3 ng/mL, respectively. Gleason sum 8-10, stage ≥ T3a, and PSA > 20 ng/mL were noted in 27.2%, 74.4%, and 26.2% of patients, respectively. During the median follow-up duration of 120.4 months, BCR-free rates at 1, 3, 5, and 10 years were 92.6%, 76.6%, 66.7%, and 50.8%, respectively. The metastasis-free, cancer-specific, and overall survival rates were 89.5%, 97.4%, and 90.5% at 10 years, respectively. The variables in the pre-operative nomogram for BCR contained PSA at diagnosis, clinical stage, and Gleason score (C-index: 0.73, 95% CI, 0.67-0.79). The variables in the peri-operative nomogram for BCR included PSA at diagnosis, Gleason score, number of cryoprobes used, and PSA nadir (C-index: 0.83, 95% CI, 0.78-0.88). In conclusion, total prostate cryoablation appears to be an effective treatment option for selected men with high-risk PC. A pre-operative nomogram can help select patients suitable for cryoablation. A peri-operative nomogram signifies the importance of the ample use of cryoprobes and helps identify patients who may need early salvage treatment.