Prostate-specific antigen testing for prostate cancer: Time to reconsider the approach to screening.

BACKGROUND: Prostate cancer is now the most common cancer in men in Australia. Men should be aware of the potential risk of significant prostate cancer despite the lack of symptoms. Screening for prostate cancer using prostate-specific antigen (PSA) has been controversial. General practice guidelines can be confusing leading to men not being tested for prostate cancer. Reasons cited include overdiagnosis and overtreatment with associated morbidity. OBJECTIVE: This article aims to highlight the current evidence for PSA testing and advocate for updating outdated guidelines and resources. DISCUSSION: Current evidence shows that a risk-stratified approach to PSA screening helps to assess that risk. Recent studies show improved survival rates with early intervention compared with observation/delayed treatment. Imaging, including magnetic resonance imaging and prostate-specific membrane antigen positron emission tomography, have made a significant difference in the management pathway. Biopsy techniques have progressed to minimise sepsis risk. Quality and patient-reported outcomes registry data highlight the increased use of active surveillance in patients with low to intermediate risk of prostate cancer, reducing treatment-associated harms in men with low risk of progression. There have also been improvements in medical therapeutics for advanced disease.

Raman spectroscopy system for real-time diagnosis of clinically significant prostate cancer tissue.

Prostate cancer (PCa) is a significant healthcare problem worldwide. Current diagnosis and treatment methods are limited by a lack of precise in vivo tissue analysis methods. Real-time cancer identification and grading could dramatically improve current protocols. Here, we report the testing of a thin optical probe using Raman spectroscopy (RS) and classification methods to detect and grade PCa accurately in real-time. We present the first clinical trial on fresh ex vivo biopsy cores from an 84 patient cohort. Findings from 2395 spectra measured on 599 biopsy cores show high accuracy for diagnosing and grading PCa. We can detect clinically significant PCa from benign and clinically insignificant PCa with 90% sensitivity and 80.2% specificity. We also demonstrate the ability to differentiate cancer grades with 90% sensitivity and specificity ≥82.8%. This work demonstrates the utility of RS for real-time PCa detection and grading during routine transrectal biopsy appointments.

Multicenter evaluation of neoadjuvant and induction gemcitabine-carboplatin versus gemcitabine-cisplatin followed by radical cystectomy for muscle-invasive bladder cancer.

PURPOSE: Cisplatin-based chemotherapy followed by radical cystectomy (RC) is recommended in patients with muscle-invasive bladder cancer (MIBC). However, up to 50% of patients are cisplatin ineligible. The aim of this study was to compare clinical outcomes after ≥ 3 cycles of preoperative gemcitabine-carboplatin (gem-carbo) versus gemcitabine-cisplatin (gem-cis). METHODS: We identified 1865 patients treated at 19 centers between 2000 and 2013. Patients were included if they had received ≥ 3 cycles of neoadjuvant (cT2-4aN0M0) or induction (cTanyN + M0) gem-carbo or gem-cis followed by RC. RESULTS: We included 747 patients treated with gem-carbo (n = 147) or gem-cis (n = 600). Patients treated with gem-carbo had a higher Charlson Comorbidity Index (p = 0.016) and more clinically node-positive disease (32% versus 20%; p = 0.013). The complete pathological response (pCR; ypT0N0) rate did not significantly differ between gem-carbo and gem-cis (20.7% versus 22.1%; p = 0.73). Chemotherapeutic regimen was not significantly associated with pCR (OR 0.99 [95%CI 0.61-1.59]; p = 0.96), overall survival (OS) (HR 1.20 [95%CI 0.85-1.67]; p = 0.31), or cancer-specific survival (CSS) (HR 1.35 [95%CI 0.93-1.96]; p = 0.11). Median OS of patients treated with gem-carbo and gem-cis was 28.6 months (95%CI 18.1-39.1) and 45.1 months (95%CI 32.7-57.6) (p = 0.18), respectively. Median CSS of patients treated with gem-carbo and gem-cis was 28.8 months (95%CI 9.8-47.8) and 71.0 months (95%CI median not reached) (p = 0.02), respectively. Subanalyses of the neoadjuvant and induction setting did not show significant survival differences. CONCLUSION: Our results show that a subset of cisplatin-ineligible patients with MIBC achieve pCR on gem-carbo and that survival outcomes seem comparable to gem-cis provided patients are able to receive ≥ 3 cycles and undergo RC.

Age-Adjusted Reference Values for Prostate Specific Antigen - A Systematic Review and Meta-Analysis.

OBJECTIVES: To systematically evaluates the evidence on ethnic differences in age-adjusted reference values of PSA. MATERIALS AND METHODS: In concordance with the Preferred Reporting Items for Systematic Review and Meta-analysis statement, a review of English articles using Medline, Embase and Cochrane databases, from inception to December 2019 was conducted. Studies that reported the PSA upper reference value as 95th percentile of the cohort distribution, in healthy men aged 40 to 79, were included. Methodological quality was assessed with a modified version of the Agency for Healthcare Research and Quality checklist for cross-sectional studies. RESULTS: Forty-three studies examining 325,514 participants were included in the analysis. These were published between 1993 and 2018. Majority were prospective observational studies and reported the reference values in ten-year age intervals. Only five reports directly compared ethnic differences in PSA values. Due to missing data, six studies were not considered in the quantitative synthesis. For the remainder (37/43), heterogeneity in PSA reference values was considerable (Higgin's index = 99.2%), with age and ethnicity being the sole identified significant contributors. Accordingly, the pooled upper limits for PSA reference values were 2.1, 3.2, 4.9 and 6.5 ng/ml for men in their 40 s, 50 s, 60 s, and 70 s, respectively. CONCLUSION: Moderate quality evidence suggest that upper PSA reference limits increased with age and significant ethnic differences were present.

Ethnic and regional differences in the temporal trends of prostate cancer incidence and mortality in New Zealand.

BACKGROUND: Prostate cancer (Pca) is the most frequently diagnosed cancer in New Zealand (NZ) men and the third leading cause of cancer deaths. Temporal changes in Pca incidence and mortality have not been reported despite changes in the Pca landscape. This study aims to analyse the temporal trends in Pca with focus on ethnic and regional variations. METHODS: The study cohort was identified from the NZ Cancer Registry and the mortality collection databases. Men who were diagnosed with Pca between 2000 and 2018 were included in the incidence analysis. Men who died from Pca between 2000 and 2015 were included in the mortality analysis. Other data collected were ethnicity and geographical information. Pca incidence and mortality were calculated as age-standardized rates using the 2001 World Health Organization population. RESULTS: A total of 58 966 men were diagnosed (incidence: 105.2 per 100 000) and 14 749 men died (mortality: 49.3 per 100 000) from Pca. When compared to European men, Maori and Asian men had significantly lower Pca incidence. Mortality rates demonstrated a steady decline, which was more prominent until 2010. Maori and Pacific men had higher mortality rates when compared to European men. In most recent years, the difference in mortality is decreasing for Maori but increasing for Pacific men. There were no regional differences in mortality. CONCLUSION: Pca incidence in NZ has fluctuated over the last 20 years, while mortality rates have shown to steadily decline. Pca mortality was shown to disproportionately affect Maori and Pacific men.

The impact of the extent and location of positive surgical margins on the risk of biochemical recurrence following radical prostatectomy in men with Gleason 7 prostate cancers.

BACKGROUND: Positive surgical margins (PSM) after radical prostatectomy (RP) have been associated with increased risk of biochemical recurrence (BCR). This is heavily influenced by other clinicopathological factors. This study aims to assess the impact of the extent and location of PSM on BCR following RP for Gleason 7 carcinoma of the prostate (CaP). MATERIALS AND METHODS: All men treated with RP between 2008 and 2017 in our region for localized or locally advanced Gleason 7 CaP, were included. Clinical (age, year, preoperative prostate specific antigen) and pathological (prostate weight, positive or negative surgical margins, International Society of Urological Pathology [ISUP] grade, T stage) data were collected. PSM were subcategorised according to Extent into favourable (unifocal and <3 mm in length) or unfavourable (multifocal or ≥3 mm in length), and Location into apical only or others. The outcome was the risk of BCR which was calculated with univariable and multivariable regression models and reported as hazard ratio (HR) with 95% confidence interval (CI). RESULTS: The cohort constituted of 1433 men. Majority had ISUP 2 (71.2%) or localized (62%) disease. Men with PSM (n = 506) were at greater risk of BCR when compared to those with negative margins (adjusted HR = 1.52, [CI: 1.14-2.04], p = .005). Similar observation was demonstrated for both PSM location subgroups. As for the PSM extent category, only men with unfavourable PSM demonstrated an increase in BCR risk over negative margin (adjusted HR = 1.67, [CI: 1.23-2.28], p = .001). CONCLUSIONS: Within this study settings, PSM were generally associated with increased BCR risk. This, however, was not demonstrated in favourable PSM extent cases. Observation rather than active treatment in these men should be considered.

Space curvature-inspired nanoplasmonic sensor for breast cancer extracellular vesicle fingerprinting and machine learning classification.

Extracellular vesicles (EVs) are micro and nanoscale lipid-enclosed packages that have shown potential as liquid biopsy targets for cancer because their structure and contents reflect their cell of origin. However, progress towards the clinical applications of EVs has been hindered due to the low abundance of disease-specific EVs compared to EVs from healthy cells; such applications thus require highly sensitive and adaptable characterization tools. To address this obstacle, we designed and fabricated a novel space curvature-inspired surfaced-enhanced Raman spectroscopy (SERS) substrate and tested its capabilities using bioreactor-produced and size exclusion chromatography-purified breast cancer EVs of three different subtypes. Our findings demonstrate the platform's ability to effectively fingerprint and efficiently classify, for the first time, three distinct subtypes of breast cancer EVs following the application of machine learning algorithms on the acquired spectra. This platform and characterization approach will enhance the viability of EVs and nanoplasmonic sensors towards clinical utility for breast cancer and many other applications to improve human health.

Association of age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer.

PURPOSE: To assess the association of patient age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: We analyzed data from 1105 patients with MIBC. Patients age was evaluated as continuous variable and stratified in quartiles. Pathologic objective response (pOR; ypT0-Ta-Tis-T1N0) and pathologic complete response (pCR; ypT0N0), as well survival outcomes were assessed. We used data of 395 patients from The Cancer Genome Atlas (TCGA) to investigate the prevalence of TCGA molecular subtypes and DNA damage repair (DDR) gene alterations according to patient age. RESULTS: pOR was achieved in 40% of patients. There was no difference in distribution of pOR or pCR between age quartiles. On univariable logistic regression analysis, patient age was not associated with pOR or pCR when evaluated as continuous variables or stratified in quartiles (all p > 0.3). Median follow-up was 18 months (IQR 6-37). On Cox regression and competing risk regression analyses, age was not associated with survival outcomes (all p > 0.05). In the TCGA cohort, patient with age ≤ 60 years has 7% less DDR gene mutations (p = 0.59). We found higher age distribution in patients with luminal (p < 0.001) and luminal infiltrated (p = 0.002) compared to those with luminal papillary subtype. CONCLUSIONS: While younger patients may have less mutational tumor burden, our analysis failed to show an association of age with response to preoperative chemotherapy or survival outcomes. Therefore, the use of preoperative chemotherapy should be considered regardless of patient age.

Predictors of success following extracorporeal shock-wave lithotripsy in a contemporary cohort.

OBJECTIVES: The objectives of this study are to determine the predictors of success following extracorporeal shock-wave lithotripsy (ESWL) in a contemporary cohort at a high-volume stone center. METHODS: We conducted a retrospective review all patients who underwent an elective ESWL within our institution over a 24-month period (January 2014 to December 2015). Data on patient demographics, stone variables, and inpatient treatment outcomes were evaluated.The presence of residual stone fragments larger than 4 mm on follow-up imaging was considered to be treatment failure. Using this threshold, clinically relevant variables between the treatment success and failure groups were identified. Multivariable logistic regression analyses (MVA) of clinically relevant variables were used to determine the independent factors predicting ESWL success. RESULTS: Of 446 study eligible patients, 421 patients had complete follow-up data and were included in the analysis. Treatment was successful in 72.2% of patients in this study. Stone size, number of shocks delivered, and maximum treatment intensity were statistically different in the two groups. In a MVA where stone size, location, density, presence of ureteric stent, skin-stone distance (SSD), number of shocks, and maximum shock intensity were included, only stone size of <10 mm (odds ratio [OR] 3.4 [95% confidence interval [CI]: 1.98-5.84]) and SSD <15 cm (OR: 0.133, [95% CI: 0.027-0.65]) were the independent predictor of ESWL success. CONCLUSION: We have demonstrated "real world" outcomes with high-volume use of ESWL. In our experience that with diligent patient selection, ESWL remains an effective tool for the management of upper tract calculi.

Prostate cancer outcomes disparities: Population survival analysis in an ethnically diverse nation.

BACKGROUND: Prostate cancer represents a significant health burden on New Zealand men. There are increasing concerns regarding inequities in prostate cancer morbidity and mortality among the different ethnic groups in New Zealand. This study aims to assess ethnic differences in survival outcomes among men newly diagnosed with prostate cancer. MATERIALS AND METHODS: The analyzed cohort included 42,563 men, 40 years or older, diagnosed with prostate cancer from January 1st, 2000 to January 1st, 2016. Overall and cancer-specific survivals were estimated for the main ethnic groups in New Zealand namely: Maori (indigenous), Pacific, Asian, and European. Hazard ratio (HR) of death from prostate cancer was calculated with Fine-Gray competing risk regression, while adjusting for age, socioeconomic deprivation, year of cancer diagnosis, residential status, presence of urology service, and cancer grade at diagnosis. RESULTS: Among all ethnic groups, Maori participants consistently had worst survival outcomes. At 15-year follow-up, the overall cumulative survival probabilities were 39.8%, 43.6%, 63.3%, and 46.5%, for Maori, Pacific, Asian and European men, respectively. In the same order, cancer-specific survivals were 62.7%, 64.3%, 79.8% and 72.0%. Maori men had 43% higher risk of dying from prostate cancer when compared to Europeans. This persisted following adjustments in the multivariable model (adjusted HR = 1.44, [95% CI: 1.29-1.61], P< 0.001). Conversely, differences in sociodemographic and cancer characteristics between Pacific and European men could explain the higher mortality risk in the former group (adjusted HR = 1.00, [95% CI: 0.84-1.19], P= 0.990). CONCLUSIONS: Significant ethnic disparities in prostate cancer survival outcomes are currently present in New Zealand. Several explanations have been proposed to account for this observation including differences in comorbidities, healthcare access and cancer grade at diagnosis.

Age-adjusted reference values for prostate-specific antigen in a multi-ethnic population.

OBJECTIVE: To establish age-adjusted reference values for prostate-specific antigen in an ethnically diverse population. METHODS: Between 2009 and 2017, data were collected from all men aged 40-79 years, who had a prostate-specific antigen test in the northern region of New Zealand, where the prostate-specific antigen testing service is provided by a single community laboratory and using the same assay analyzer. Men known to have prostate cancer, who developed prostate cancer during the study period, who were treated with finasteride, or who had prostate-specific antigen levels above 20 ng/mL were excluded. Age-adjusted prostate-specific antigen reference values were calculated for each of the main ethnic groups in the country including: Maori (indigenous), Pacific, Asian and European. For every 5-year age interval, the 95th percentile of the log prostate-specific antigen distribution was used to define the upper limit of normal. RESULTS: The study cohort included 215 132 apparently healthy men, with a median age and prostate-specific antigen concentration of 59 years and 0.9 ng/mL, respectively. Prostate-specific antigen levels for the entire cohort increased with age (Pearson correlation = 0.362, P < 0.001). This relationship was most prominent in Pacific men. Similarly, the upper reference limit for the entire cohort increased with age, from 1.60 ng/mL for men aged 40-44 years to 7.61 ng/mL for those aged 75-79 years. Significant ethnic differences were present within each interval, which was most apparent in the older age groups. CONCLUSION: Ethnic differences in age-adjusted prostate-specific antigen reference values are present in New Zealand. These need to be considered when prostate-specific antigen results are being interpreted in clinical practice.

Ethnic and socio-economic disparities in prostate cancer screening: lessons from New Zealand.

OBJECTIVES: To investigate the presence of ethnic and socio-economic disparities in prostate cancer (PCa) screening and identify its impact on cancer outcomes. MATERIALS AND METHODS: From January 2008 to December 2017, all men in the Northern region of New Zealand who had a prostate-specific antigen (PSA) test performed in the community were identified from the electronic laboratory reports database. Asymptomatic men, with no known diagnosis of PCa, were included. Variables collected were age, ethnicity, social deprivation, medical therapy, PSA test information and cancer data. Disparities were investigated by comparing the frequency of PSA testing, proportions of men screened, and rates of cancer detection, between Maori (indigenous) and non-Maori ethnic groups. RESULTS: The study cohort included 248 491 men, who each received approximately 3.45 PSA tests over the 10-year study period. Maori men were less likely to be tested compared to non-Maori men (25.4% vs 46.1% of the total aged-matched region population; P < 0.001). Moreover, they received less frequent PSA testing irrespective of their deprivation status (mean difference of 0.97 PSA tests per person; P < 0.001). The higher testing frequency in non-Maori men was associated with increased PCa diagnosis rates. Nevertheless, cancers detected in Maori men were 73% more likely to be of high grade (Gleason 8 or above), compared to those in non-Maori men. CONCLUSION: There were significant ethnic disparities in PCa screening rates in the Northern region of New Zealand. Maori men, regardless of other demographic factors, were disproportionately affected. The difference in the rates of screening by ethnicity had influenced the incidence and clinical significance of the diagnosed cancers.

Prostate cancer screening in New Zealand: lessons from the past to shape the future in the light of changing evidence.

Prostate cancer represents a significant health burden worldwide. The cancer incidence had substantially increased since the introduction of prostate specific antigen (PSA) in cancer screening. This had led to considerable debates among health professionals and epidemiologists, since PSA as a screening tool seemed to be far from perfect. In New Zealand, the controversy was quite prominent in the last three decades, with some advocating the benefits of screening, while others concerned regarding the risk of harms. With the absence of an organised screening programme and the appropriate monitoring and quality assurance procedures, the effects of the PSA testing debate had undoubtedly caused a variability in the opportunistic prostate cancer screening practices in the community. This, in addition to the recent rapid advancements in prostate cancer imaging, and updated results from randomised trials, have made it mandatory to question the validity of continuing with the current approach to prostate cancer screening. However, high-quality local data on these aspects had been lacking, which represents an ongoing challenge to developing robust and sound health policies.

Impact of sex on response to neoadjuvant chemotherapy in patients with bladder cancer.

OBJECTIVE: To assess the effect of patient's sex on response to neoadjuvant chemotherapy (NAC) in patients with clinically nonmetastatic muscle-invasive bladder cancer (MIBC). METHODS: Complete pathologic response, defined as ypT0N0 at radical cystectomy, and downstaging were evaluated using sex-adjusted univariable and multivariable logistic regression modeling. We used interaction terms to account for age of menopause and smoking status. The association of sex with overall survival and cancer-specific survival was evaluated using Cox regression analyses. RESULTS: A total of 1,031 patients were included in the analysis, 227 (22%) of whom were female. Female patients had a higher rate of extravesical disease extension (P = 0.01). After the administration of NAC, ypT stage was equally distributed between sexes (P = 0.39). On multivariable logistic regression analyses, there was no difference between the sexes or age of menopause with regards to ypT0N0 rates or downstaging (all P > 0.5). On Cox regression analyses, sex was associated with neither overall survival (hazard ratio 1.04, 95% confidence interval 0.75-1.45, P = 0.81) nor cancer-specific survival (hazard ratio 1.06, 95% confidence interval 0.71-1.58, P = 0.77). CONCLUSION: Our study generates the hypothesis that NAC equalizes the preoperative disparity in pathologic stage between males and females suggesting a possible differential response between sexes. This might be the explanation underlying the comparable survival outcomes between sexes despite females presenting with more advanced tumor stage.

Opportunistic prostate cancer screening: A population-based analysis.

BACKGROUND: Prostate specific antigen (PSA) utilization in population-based prostate cancer (CaP) screening, has been a controversial area for decades. Current recommendation in our region is for an opportunistic approach to screening, with estimated low prevalence of such practice in the community. However, our clinical observations suggested that the extent is beyond what might be expected from an opportunistic screening practice. This study aims to estimate the current prevalence and the extent of opportunistic CaP screening, and investigate the contemporary patterns of PSA testing in a large population. METHODS: From 2008 to 2017, all men in the Northern cancer network of New Zealand, who had a screening PSA test performed in a community laboratory were identified. The study variables were accessed from multiple prospectively maintained databases. These included: Age, Ethnicity, Region, Social deprivation, Medical therapy, CaP history, Gleason score, and PSA test information (results and date). Population estimations were obtained from customized an updated national census data. RESULTS: The study cohort constituted 311,725 men, with 1,208,214 PSA tests performed, in the ten-year period. The mean age at first test was 55.2 years and each man received approximately 4 PSA tests. The prevalence of opportunistic CaP PSA screening in men aged 40 to 79 years, was 87% of the region population. In the 50 to 69-year age group, 65% of men in the region had been receiving regular 2-yearly, screening PSA tests. Men who had 3 or more PSA tests, were more likely to be diagnosed with CaP (Odds ratio [OR] 1.85, P < 0.001). CONCLUSIONS: PSA based CaP screening, is a highly prevalent practice in the NZ community. This raises concerns regarding the quality of the individual counseling process and the adequacy of resources allocated to accommodate for such practice.

The prognostic value of the neutrophil-to-lymphocyte ratio in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy.

INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) is an attractive marker because it is derived from routine bloodwork. NLR has shown promise as a prognostic factor in muscle invasive bladder cancer (MIBC) but its value in patients receiving neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is not yet established. Since NLR is related to an oncogenic environment and poor antitumor host response, we hypothesized that a high NLR would be associated with a poor response to NAC and would remain a poor prognostic indicator in patients receiving NAC. METHODS: A retrospective analysis was performed on patients with nonmetastatic MIBC (cT2-4aN0M0) who received NAC prior to RC between 2000 and 2013 at 1 of 19 centers across Europe and North America. The pre-NAC NLR was used to split patients into a low (NLR ≤ 3) and high (NLR > 3) group. Demographic and clinical parameters were compared between the groups using Student's t test, chi-squared, or Fisher's exact test. Putative risk factors for disease-specific and overall survival were analyzed using Cox regression, while predictors of response to NAC (defined as absence of MIBC in RC specimen) were investigated using logistic regression. RESULTS: Data were available for 340 patients (199 NLR ≤ 3, 141 NLR > 3). Other than age and rate of lymphovascular invasion, demographic and pretreatment characteristics did not differ significantly. More patients in the NLR > 3 group had residual MIBC after NAC than the NLR ≤ 3 group (70.8% vs. 58.3%, P = 0.049). NLR was the only significant predictor of response (odds ratio: 0.36, P = 0.003) in logistic regression. NLR was a significant risk factor for both disease-specific (hazard ratio (HR): 2.4, P = 0.006) and overall survival (HR:1.8, P = 0.02). CONCLUSION: NLR > 3 was associated with a decreased response to NAC and shorter disease-specific and overall survival. This suggests that NLR is a simple tool that can aid in MIBC risk stratification in clinical practice.

Prostate specific membrane antigen: the role in salvage lymph node dissection and radio-ligand therapy.

INTRODUCTION: Prostate-specific membrane antigen (PSMA) is a receptor highly expressed on the membranes of prostate cancer (PCa) cells and provides a new opportunity for imaging and targeted therapy in metastatic prostate cancer. The use of radio-labelled peptides with high affinity for PSMA-receptor allows for localization of oligo-metastasis to guide salvage lymph node (LN) dissection, and effective delivery of radionuclide therapy to PCa cells. This review discusses the current statistics of PSMA-guided salvage lymph-node dissection. EVIDENCE ACQUISITION: A non-systematic literature search of the Medline, Embase, and Scopus databases was performed in December 2017 using medical subject headings and free-text protocol. EVIDENCE SYNTHESIS: The properties of PSMA has enabled the timely detection of oligometastatic disease, potentially altering oncological outcomes of men with PCa. The utility of PSMA in directing sLND has been proven to have an impact in achieving modest biochemical response which is generally not durable. CONCLUSIONS: Larger randomized controlled trials are needed to validate the current findings, determine treatment protocols, and weigh up its benefits and determine its standing amongst the current management strategies for PCa.