A Systematic Review on Artificial Intelligence Evaluating Metastatic Prostatic Cancer and Lymph Nodes on PSMA PET Scans.

Early detection of metastatic prostate cancer (mPCa) is crucial. Whilst the prostate-specific membrane antigen (PSMA) PET scan has high diagnostic accuracy, it suffers from inter-reader variability, and the time-consuming reporting process. This systematic review was registered on PROSPERO (ID CRD42023456044) and aims to evaluate AI's ability to enhance reporting, diagnostics, and predictive capabilities for mPCa on PSMA PET scans. Inclusion criteria covered studies using AI to evaluate mPCa on PSMA PET, excluding non-PSMA tracers. A search was conducted on Medline, Embase, and Scopus from inception to July 2023. After screening 249 studies, 11 remained eligible for inclusion. Due to the heterogeneity of studies, meta-analysis was precluded. The prediction model risk of bias assessment tool (PROBAST) indicated a low overall risk of bias in ten studies, though only one incorporated clinical parameters (such as age, and Gleason score). AI demonstrated a high accuracy (98%) in identifying lymph node involvement and metastatic disease, albeit with sensitivity variation (62-97%). Advantages included distinguishing bone lesions, estimating tumour burden, predicting treatment response, and automating tasks accurately. In conclusion, AI showcases promising capabilities in enhancing the diagnostic potential of PSMA PET scans for mPCa, addressing current limitations in efficiency and variability.

A Systematic Review on Prostate-Specific Membrane Antigen Positron Emission Tomography (PSMA PET) Evaluating Localized Low- to Intermediate-Risk Prostate Cancer: A Tool to Improve Risk Stratification for Active Surveillance?

Active surveillance remains a treatment option for low- to intermediate-risk prostate cancer (PCa) patients. Prostate-specific membrane antigen positron emission tomography and computed tomography (PSMA PET/CT) has emerged as a useful modality to assess intraprostatic lesions. This systematic review aims to evaluate PSMA PET/CT in localized low- to intermediate-risk PCa to determine its role in active surveillance. Following PRISMA guidelines, a search was performed on Medline, Embase, and Scopus. Only studies evaluating PSMA PET/CT in localized low- to intermediate-risk PCa were included. Studies were excluded if patients received previous treatment, or if they included high-risk PCa. The search yielded 335 articles, of which only four publications were suitable for inclusion. One prospective study demonstrated that PSMA PET/CT-targeted biopsy has superior diagnostic accuracy when compared to mpMRI. One prospective and one retrospective study demonstrated MRI occult lesions in 12.3-29% of patients, of which up to 10% may harbor underlying unfavorable pathology. The last retrospective study demonstrated the ability of PSMA PET/CT to predict the volume of Gleason pattern 4 disease. Early evidence demonstrated the utility of PSMA PET/CT as a tool in making AS safer by detecting MRI occult lesions and patients at risk of upgrading of disease.

A Population-based Study Comparing Outcomes for Patients With Metastatic Castrate Resistant Prostate Cancer Treated by Urologists or Medical Oncologists With First Line Abiraterone Acetate or Enzalutamide.

OBJECTIVES: To compare toxicity and all-cause mortality for mCRPC patients receiving first line oral systemic therapy prescribed by medical oncologists and urologists. METHODS: Population-based retrospective cohort study of chemotherapy-naïve men aged ≥66 years treated for mCRPC with first-line abiraterone or enzalutamide based on administrative health data (Ontario, Canada, 2012-2017). Primary outcomes were hospitalizations/ER visits for any cause or treatment-related toxicity during first-line mCRPC treatment. Secondary outcome was all-cause mortality. We calculated hazard ratios (HRs) comparing outcomes for different medical specialties using multivariable Cox proportional hazards models. RESULTS: Among 3405 mCRPC patients, 2407 (70.7%) received abiraterone and 998 (29.3%) received enzalutamide. 1786 (52.5%) patients visited the ER or were hospitalized. Men treated by medical oncologists had an increased risk of hospitalization/ER visits (HR1.16, 95%CI 1.03-1.31; P = .02), toxicity-related visits (HR1.34, 95%CI 1.08-1.69; P = .01), and mortality (HR1.16, 95%CI 1.02-1.33; P = .02) compared to urologists. Limited information was available, beyond PSA adjustment and prior treatment, on patient disease burden. CONCLUSION: We observed fewer hospital visits overall and for treatment-related toxicity for mCRPC patients who were prescribed first line abiraterone or enzalutamide by urologists compared to medical oncologists. These differences may result from higher prostate cancer disease burden in patients managed by medical oncologists, and/or other unmeasured differences in patient management between specialties.

Defining oligometastatic hormone sensitive prostate cancer and clinically significant outcomes: Implications on clinical trials?

PURPOSE: With the current movement toward treating oligometastatic hormone sensitive prostate cancer (OMPC), we design a study with the objective of gathering opinions regarding what would be considered a clinically significant benefit from such treatments. METHODS: Data was collected from physicians of the Society of Urologic Oncology using a self-administered questionnaire using SurveyMonkey. The questionnaire was designed to obtain characteristics on clinical practice of the respondents, definitions used for OMPC and also what would be considered a clinically significant benefit according to the respondents. We present a descriptive analysis of the responses obtained. RESULTS: We obtained 119 responses (response rate of 12.6%) after sending the questionnaire twice with one month apart. Most of them being staff/faculty (89%) practicing in the United States of America (84.87%). Most of the responders referred that a significant proportion of their practice comes from PC patients. Most defined OMPC <3 bone/lymph node metastasis seen with conventional imaging, only 26.9% of the responders used positron emission tomography. Regarding the clinical benefit of metastasis-oriented treatment, a curing rate >10% or an increase in 1 year of androgen deprivation therapy-free survival would make the treatment worthwhile. We present examples of sample size calculations for future clinical trials using these parameters as an expected "clinically-significant" benefit. CONCLUSION: This study shows that most clinicians still support the use of conventional imaging to define OMPC. Our findings show that a curing rate of a minimum of 11% and an androgen deprivation therapy-free survival at 1 year are considered clinically significant and this should be used for estimating the sample size in future clinical trials.

Radical nephrectomy with resection of vena cava thrombus using extracorporeal circulation and deep hypothermic circulatory arrest.

INTRODUCTION: Patients with renal cell carcinoma (RCC) with level 3 or 4 caval thrombus have a poor prognosis, with reported five-year survival rates of 30-40%. The aim of this study was to assess the perioperative morbidity and long-term oncological outcomes for radical nephrectomy with resection of vena cava thrombus using a combined surgical approach, including extracorporeal circulation and deep hypothermic circulatory arrest. METHODS: A retrospective review was performed of the institutional case log to identify all radical nephrectomies with caval thrombus performed from January 2006 to May 2020. RESULTS: Twenty-five patients were identified with level 2 thrombus in one (4%), level 3 thrombus in eight (32%), and level 4 in 16 (64%). The median followup was 20.6 months (range 0.2-133.3). The median age at surgery was 68.4 years (range 44.2-85.5). Twenty-one (84%) patients were symptomatic at presentation. Six (24%) patients had distant metastases at diagnosis. The median circulatory arrest time was 15 minutes (range 6-35). The 30-day grade ≥3 complication rate was 8%. The 30-day mortality rate was 8%. The one-year, two-year, three-year, and five-year recurrence-free survival (RFS) rates were 53%, 18%, 10%, and 10%, respectively. The median time to systemic treatment was 7.7 months (range 1.2-25.7). The one-year, two-year, three-year, and five-year overall survival (OS) rates were 70%, 43%, 36%, and 31%, respectively. CONCLUSIONS: Radical nephrectomy with resection of vena cava thrombus using extracorporeal circulation and deep hypothermic circulatory arrest is associated with some morbidity and mortality but remains a safe and effective strategy for advanced RCC patients who would otherwise be managed palliatively.

Utility of digital rectal examination in a population with prostate cancer treated with active surveillance.

INTRODUCTION: Digital rectal examination (DRE) is part of the clinical evaluation of men on active surveillance (AS). The purpose of the present study is to analyze the value of DRE as a predictor of upgrading in a population of men with prostate cancer (PCa) treated with AS. METHODS: We used the prostate biopsy (PBx) database from an academic center, including PBx from 2006-2018, and identified 2029 confirmatory biopsies (CxPBx) of men treated with AS, of which 726 men had both diagnostic (initial) and CxPBx information available. We did a descriptive analysis and evaluated sensitivity, specificity, and predictive values of DRE for the detection of clinically significant PCa (csPCa). Multivariable regression analysis was done to identify predictors of csPCa. The primary outcome was to evaluate DRE as a predictor of the presence of csPCa at CxPBx. RESULTS: Among the 2029 patients with a CxPBx, 75% had PCa, and of these, 30.3% had upgrading to International Society of Urologic Pathologists (ISUP) grade ≥2. Thirteen percent of men had a suspicious DRE (done by their treating physician). Sensitivity, specificity, negative and positive predictive values of DRE to detect csPCa were best with a prostate-specific antigen (PSA) <4 ng/ml (27%, 88%, 31%, and 87%, respectively). A suspicious DRE at CxPBx, particularly if the DRE at diagnosis was negative, was a predictor of csPCa (odds ratio [OR] 2.34, p=0.038). The main limitation of our study is the retrospective design and the lack of magnetic resonance imaging. CONCLUSIONS: We believe DRE should still be used as part of AS and can predict the presence of csPCa, even with low PSA values. A suspicious nodule on DRE represents a higher risk of upgrading and should prompt further assessment.

A High Percent Free Prostate Specific Antigen in the Setting of Biochemical Recurrence after Radical Prostatectomy is Associated with Poorer Outcomes: A Validation Study Using Prospectively Collected Biobank Specimens.

PURPOSE: The role of percent free prostate specific antigen (%fPSA) in patients who have undergone radical prostatectomy and subsequently experienced disease relapse is unclear. We previously conducted 2 retrospective studies and found %fPSA 15 or greater in the setting of biochemical recurrence confers more aggressive disease. To validate that finding we used biobank specimens collected prospectively when patients were first diagnosed with biochemical recurrence. MATERIALS AND METHODS: Biobank specimens of patients with undetectable prostate specific antigen after radical prostatectomy and subsequent biochemical recurrence (prostate specific antigen 0.1 ng/ml or greater) were analyzed for %fPSA. Patients were stratified according to the %fPSA cutoff of 15. Univariable and multivariable logistic regression analysis was performed to predict covariates associated with a higher %fPSA. Cox proportional hazard models were performed to evaluate the prognostic effect of %fPSA on androgen deprivation therapy-free survival, metastasis-free survival, castration resistant-free survival and cancer specific survival. RESULTS: A total of 154 men were included in the study, of whom 126 (82%) had %fPSA less than 15 and 28 (18%) had %fPSA 15 or greater. Median followup for %fPSA less than 15 and %fPSA 15 or greater was 75 and 69 months, respectively. Patients with %fPSA 15 or greater had increased hazard of receiving androgen deprivation therapy (43% vs 25%, adjusted HR 2.40, 95% CI 1.12-5.11), metastatic disease (21% vs 7.9%, adjusted HR 4.10, 95% CI 1.11-15.2) and castration resistant prostate cancer (14% vs 4.0%, unadjusted HR 4.14, 95% CI 1.11-15.5) vs %fPSA less than 15, respectively. CONCLUSIONS: Patients with %fPSA 15 or greater were started on androgen deprivation therapy earlier, and they had progression to castration resistant prostate cancer and metastatic stage earlier. %fPSA 15 or greater in the setting of biochemical recurrence after radical prostatectomy is an indicator of a more aggressive disease. Unlike in the diagnostic setting, a higher %fPSA portends a worse clinical outcome.

Photoselective vaporization of the prostate: study outcomes as a function of risk of bias, conflicts of interest, and industrial sponsorship.

PURPOSE: To investigate the outcomes of comparative studies on photoselective vaporization of the prostate (PVP) as a function of risk of bias (RoB), conflicts of interest (COI), and industrial sponsorship (IS). METHODS: We performed a systematic literature search for comparative studies on PVP [randomized controlled trials (RCTs) and non-randomized comparative studies (NRCSs)]. Study selection as well as comprehensive assessment of RoB, COIs, and IS were performed in duplicate. The identified studies were further rated by two independent board-certified urologists as either PVP-favourable or PVP-unfavourable. Descriptive statistics were performed among all identified studies and among the subgroups of studies rated as favourable and unfavourable, respectively. RESULTS: Sixty-five studies qualified for inclusion (25 RTCs and 40 NRCSs) of which 56 (86%) were rated favourable and 9 (14%) unfavourable. A majority of all studies mentioned the absence/presence of potential COIs (78%). In contrast, a sponsorship statement was only found in 29% of the investigations. Studies rated favourable demonstrated a higher percentage of COIs (39% versus 22%). IS was exclusively found among favourable studies. Furthermore, a serious or critical RoB was more often found in favourably rated NRCSs. CONCLUSIONS: COIs and IS seem to be associated with favourable study outcomes in comparative studies on PVP. The transparency of the whole research process from study conception to the dissemination of the results has to be further improved to prevent a harmful effect of COIs and IS on the internal validity of studies.

Salvage radical prostatectomy following focal therapy: functional and oncological outcomes.

OBJECTIVES: To report the oncological and functional outcomes of salvage radical prostatectomy (sRP) after focal therapy (FT). PATIENTS AND METHODS: A retrospective review of all patients who underwent sRP after FT was performed. Clinical and pathological outcomes focussed on surgical complications, oncological, and functional outcomes. RESULTS: In all, 34 patients were identified. The median (interquartile range [IQR]) age was 61 (8.25) years. FT modalities included high-intensity focussed ultrasound (19 patients), laser ablation (13), focal brachytherapy (one) and cryotherapy (one). The median (IQR) time from FT to recurrence was 10.9 (17.6) months. There were no rectal or ureteric injuries. Two (5.9%) patients had iatrogenic cystotomies and four (11.8%) developed bladder neck contractures. The mean (sd) hospital stay was 2.5 (2.1) days. The T-stage was pT2 in 14 (41.2%) patients, pT3a in 16 (47.1%), and pT3b in four (11.8%). In all, 13 (38%) patients had positive surgical margins (PSMs). Six (17.6%) patients received adjuvant radiotherapy (RT). At a mean follow-up of 4.3 years, seven (20.6%) patients developed biochemical recurrence (BCR), and of these, six (17.6%) patients required salvage RT. PSMs were associated with worse BCR-free survival (hazard ratio 6.624, 95% confidence interval 2.243-19.563; P < 0.001). The median (IQR) preoperative International Prostate Symptom Score and International Index of Erectile Function score was 7 (4.5-9.5) and 23.5 (15.75-25) respectively, while in the final follow-up the median (IQR) values were 7 (3.5-11) and 6 (5-12.25), respectively (P = 0.088 and P < 0.001). At last follow-up, 31 (91.2%) patients were continent, two (5.9%) had moderate (>1 pad/day) incontinence, and one (2.9%) required an artificial urinary sphincter. CONCLUSIONS: sRP should be considered as an option for patients who have persistent clinically significant prostate cancer or recurrence after FT. PSMs should be recognised as a risk for recurrent disease after sRP.

An actionable sterol-regulated feedback loop modulates statin sensitivity in prostate cancer.

OBJECTIVE: The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death. METHODS: Deregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography-mass spectrometry. RESULTS: High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells. CONCLUSION: Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents.

The who, when, and why of primary adrenal malignancies: Insights into the epidemiology of a rare clinical entity.

BACKGROUND: Primary malignancies of the adrenal glands are rare. Epidemiologic assessment of primary adrenal malignancies is lacking and has been limited to case reports and series. Population-level data can provide a better understanding of the incidence, distribution, and prognostic factors associated with these rare malignancies. METHODS: The Surveillance, Epidemiology, and End Results database (1973-2013) was queried for all patients who were diagnosed with primary adrenal malignancies, categorized in 5 histologic groups: adrenocortical carcinoma (ACC), pheochromocytoma and paraganglioma (PH), neuroblastoma (NE), non-Hodgkin lymphoma (NHL), and sarcoma (SA). Age-adjusted incidence, distribution trends, and cancer-specific survival (CSS) for each group were analyzed. RESULTS: In total, 4695 patients with primary adrenal malignancies were identified, including 2057 with ACC, 512 with PH, 1863 with NE, 202 with NHL, and 61 with SA. The age-adjusted incidence of all 5 histologic subtypes was rising. Age at presentation differed substantially by histologic group: NE was the most prevalent during the first decade of life, whereas ACC predominated after age 30 years, and NHL outnumbered PH after age 70 years. Patient-specific factors were not associated with advanced disease at the time of presentation. The 5-year CSS rate for each histologic subtype was 38% for ACC, 69% for PH, 64% for NE, 38% for NHL, and 42% for SA. Survival outcomes for patients with ACC, NHL, PH and SA remained unchanged over the 40-year study period. Multimodal therapy was associated with higher CSS in patients with NE. CONCLUSIONS: This first population-level analysis of all primary adrenal malignancies provides important initial data regarding presentation and clinical outcomes. Notably, except for patients with NE, the survival of patients with these rare cancers has not improved over the past 40 years.

Disparity in public funding of therapies for metastatic castrate-resistant prostate cancer across Canadian provinces.

INTRODUCTION: Treatment using abiraterone acetate plus prednisone, enzalutamide, cabazitaxel, and radium-223 (Ra-223) improves overall survival (OS) and quality of life for patients with metastatic castrate-resistant prostate cancer (mCRPC). Despite their proven benefits, access to these therapies is not equal across Canada. METHODS: We describe provincial differences in access to approved mCRPC therapies. Data sources include the pan-Canadian Oncology Drug Review database, provincial cancer care resources, and correspondence with pharmaceutical companies. RESULTS: Both androgen receptor-axis-targeted therapies (ARATs), abiraterone acetate plus prednisone and enzalutamide, are funded by provinces in the pre-and post-chemotherapy setting, however, sequential ARAT use is not funded. "Sandwich" therapy, where one ARAT is used pre-chemotherapy and a second is used upon progression on chemotherapy, is funded in six provinces: Ontario (ON), Alberta, New Brunswick, Prince Edward Island (PEI), Nova Scotia (NS), and Newfoundland and Labrador. Ra-223 is funded in five provinces: ON, Quebec (QC), British Columbia (BC), Saskatchewan, and Manitoba to varying degrees; ON allows Ra-223 either pre- or post-chemo (not both); QC allows Ra-223 post-chemo unless chemo is not tolerated; BC allows Ra-223 if other life-prolonging mCRPC therapies have been received or ineligible. Cabazitaxel is funded in all provinces post-docetaxel, except QC and PEI. Cabazitaxel is not funded as fist-line treatment for mCPRC or in combination with other agents. In ON, BC, QC, and PEI, cabazitaxel is not funded after progression on an ARAT in the post-chemotherapy setting. CONCLUSIONS: While all provinces have access to docetaxel and ARATs, sandwiching sequential ARATs with docetaxel is funded only in select provinces. Ra-223 and cabazitaxel access is not ubiquitous across Canada. Such inequalities in access to life-prolonging therapies could lead to disparities in survival and quality of life among patients with mCRPC. Further research should quantify interprovincial variation in outcomes and cost that may result from variable access.

Preoperative core biopsy of soft tissue tumours facilitates their surgical management: a 10-year update.

BACKGROUND: Soft tissue sarcomas (STS) are rare. More often than not, the possibility of STS is not considered preoperatively and the lesions are enucleated. Enucleation (excisional biopsy) is inappropriate for sarcomas as it compromises the planning of definitive surgery and radiotherapy. Incisional biopsy has been regarded as the biopsy of choice by some, but it has a high rate of wound complications. The aims of the study were (i) to assess the current accuracy of core biopsy in the diagnosis of STS; (ii) to assess whether preoperative core biopsy facilitates the surgical management of soft tissue tumours; and (iii) to evaluate whether there has been an increase in the use of core biopsy before referral. METHODS: Patients with soft tissue tumours managed by a surgeon with a special interest in soft STS from 1994 to 2007 were reviewed from data collected in a database prospectively. The accuracy of core biopsy in the diagnosis of soft tissue tumours and planning of definitive surgery were assessed. RESULTS: Ninety-four patients with 98 lesions were reviewed. Sixty-eight lesions had core biopsy. The overall sensitivity of core biopsy in diagnosing soft tissue tumours was 83.6%. It has a sensitivity of 91.3% and specificity of 100% for malignant STS. For patients who had core biopsy, 95% had one-stage surgery; those who had no core biopsy, only 45% had one-stage surgery (P value <0.001). CONCLUSIONS: Core biopsy is accurate in the diagnosis of soft tissue tumours. It is safe and does not have the complications of open biopsy. It enables most patients to have one-stage surgery.