External validation of predictive models of sexual, urinary, bowel and hormonal function after surgery in prostate cancer subjects.

BACKGROUND: In 2020, a research group published five linear longitudinal models, predict Expanded Prostate Cancer Index Composite-26 (EPIC-26) scores post-treatment for radical prostatectomy, external beam radiotherapy and active surveillance collectively in US patients with localized prostate cancer. METHODS: Our study externally validates the five prediction models for patient reported outcomes post-surgery for localised prostate cancer. The models' calibration, fit, variance explained and discrimination (concordance-indices) were assessed. Two Australian validation cohorts 1 and 2 years post-prostatectomy were constructed, consisting of 669 and 439 subjects, respectively (750 in total). Patient reported function in five domains post-prostatectomy: sexual, bowel, hormonal, urinary incontinence and other urinary dysfunction (irritation/obstruction). Domain function was assessed using the EPIC-26 questionnaire. RESULTS: 1 year post-surgery, R2 was highest for the sexual domain (35%, SD = 0.02), lower for the bowel (21%, SD = 0.03) and hormone (15%, SD = 0.03) domains, and close to zero for urinary incontinence (1%, SD = 0.01) and irritation/obstruction (- 5%, SD = 0.04). Calibration slopes for these five models were 1.04 (SD = 0.04), 0.84 (SD = 0.06), 0.85 (SD = 0.06), 1.16 (SD = 0.13) and 0.45 (SD = 0.04), respectively. Calibration-in-the-large values were - 2.2 (SD = 0.6), 2.1 (SD = 0.01), 5.1 (SD = 0.1), 9.6 (SD = 0.9) and 4.0 (SD = 0.2), respectively. Concordance-indices were 0.73, 0.70, 0.70, 0.58 and 0.62, respectively (all had SD = 0.01). Mean absolute error and root mean square error were similar across the validation and development cohorts. The validation measures were largely similar at 2 years post-surgery. CONCLUSIONS: The sexual, bowel and hormone domain models validated well and show promise for accurately predicting patient reported outcomes in a non-US surgical population. The urinary domain models validated poorly and may require recalibration or revision.

Clinical outcomes for men with positive surgical margins after radical prostatectomy-results from the South Australian Prostate Cancer Clinical Outcomes Collaborative community-based registry.

Objective: Positive surgical margins (PSMs) after radical prostatectomy (RP) indicate failure of surgery to completely clear cancer. PSMs confer an increased risk of biochemical recurrence (BCR), but how more robust outcomes are affected is unclear. This study investigated factors associated with PSMs following RP and determined their impact on clinical outcomes (BCR, second treatment [radiotherapy and/or androgen deprivation therapy], and prostate cancer-specific mortality [PCSM]). Methods: The study cohort included men diagnosed with prostate cancer (pT2-3b/N0/M0) between January 1998 and June 2016 who underwent RP from the South Australian Prostate Cancer Clinical Outcomes Collaborative database. Factors associated with risk of PSMs were identified using Poisson regression. The impact of PSMs on clinical outcomes (BCR, second treatment, and PCSM) was assessed using competing risk regression. Results: Of the 2827 eligible participants, 28% had PSMs-10% apical, 6% bladder neck, 17% posterolateral, and 5% at multiple locations. Median follow-up was 9.6 years with 81 deaths from prostate cancer recorded. Likelihood of PSM increased with higher pathological grade and pathological tumor stage, and greater tumour volume, but decreased with increasing surgeon volume (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.88-0.98, per 100 previous prostatectomies). PSMs were associated with increased risk of BCR (adjusted sub-distribution hazard ratio [sHR] 2.5; 95% CI 2.1-3.1) and second treatment (sHR 2.9; 95% CI 2.4-3.5). Risk of BCR was increased similarly for each PSM location, but was higher for multiple margin sites. We found no association between PSMs and PCSM. Conclusion: Our findings support previous research suggesting that PSMs are not independently associated with PCSM despite strong association with BCR. Reducing PSM rates remains an important objective, given the higher likelihood of secondary treatment with associated comorbidities.

Aberrant protein expression of Appl1, Sortilin and Syndecan-1 during the biological progression of prostate cancer.

Diagnosis and assessment of patients with prostate cancer is dependent on accurate interpretation and grading of histopathology. However, morphology does not necessarily reflect the complex biological changes occurring in prostate cancer disease progression, and current biomarkers have demonstrated limited clinical utility in patient assessment. This study aimed to develop biomarkers that accurately define prostate cancer biology by distinguishing specific pathological features that enable reliable interpretation of pathology for accurate Gleason grading of patients. Online gene expression databases were interrogated and a pathogenic pathway for prostate cancer was identified. The protein expression of key genes in the pathway, including adaptor protein containing a pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (Appl1), Sortilin and Syndecan-1, was examined by immunohistochemistry (IHC) in a pilot study of 29 patients with prostate cancer, using monoclonal antibodies designed against unique epitopes. Appl1, Sortilin, and Syndecan-1 expression was first assessed in a tissue microarray cohort of 112 patient samples, demonstrating that the monoclonal antibodies clearly illustrate gland morphologies. To determine the impact of a novel IHC-assisted interpretation (the utility of Appl1, Sortilin, and Syndecan-1 labelling as a panel) of Gleason grading, versus standard haematoxylin and eosin (H&E) Gleason grade assignment, a radical prostatectomy sample cohort comprising 114 patients was assessed. In comparison to H&E, the utility of the biomarker panel reduced subjectivity in interpretation of prostate cancer tissue morphology and improved the reliability of pathology assessment, resulting in Gleason grade redistribution for 41% of patient samples. Importantly, for equivocal IHC-assisted labelling and H&E staining results, the cancer morphology interpretation could be more accurately applied upon re-review of the H&E tissue sections. This study addresses a key issue in the field of prostate cancer pathology by presenting a novel combination of three biomarkers and has the potential to transform clinical pathology practice by standardising the interpretation of the tissue morphology.

Variation in patient reported outcomes following radical prostatectomy: A bi-national registry-based study.

BACKGROUND AND OBJECTIVE: Radical prostatectomy (RP) is a common and widely used treatment for localized prostate cancer. Sequela following RP may include urinary incontinence and sexual dysfunction, outcomes which are recorded within a bi-national Prostate Cancer Outcomes Registry. The objective was to report population-wide urinary incontinence and sexual function outcomes recorded at 12 months following RP; and to quantify and explore factors associated with variation in outcome. MATERIALS AND METHODS: The Prostate Cancer Outcomes Registry of Australia and New Zealand (PCOR-ANZ) was used for this study. Participants were treated with radical prostatectomy between 2016 and 2020. Domain summary scores for urinary incontinence and sexual function from the EPIC-26 instrument were the main outcomes, taken at 12 months following surgery (6-18 months). "Major" urinary and sexual function bother were also assessed. Variation in outcomes was investigated using linear and logistic multivariable regression models adjusted for covariates: age, socioeconomic status, PSA at diagnosis, surgical technique, surgical specimen grade group, margin status, and clinician surgical volume. RESULTS AND CONCLUSIONS: The analytic cohort included 13,083 men with the mean urinary incontinence domain score being 76/100 (SD = 25) with 9.2% reporting major bother. For sexual function, the mean score was 29/100 (SD = 26) with 46% reporting major bother. Of the examined variables, age at surgery and surgical volume category were most predictive of function, with disparities exceeding minimally important differences, though large variation was observed between urologists within volume categories. There is considerable variation in 12-month postprostatectomy functional outcomes. Variation is explained by both patient and clinician factors, though some confounders are unmeasured in this cohort.

Development of Indicators to Assess Quality of Care for Prostate Cancer.

BACKGROUND: The development, monitoring, and reporting of indicator measures that describe standard of care provide the gold standard for assessing quality of care and patient outcomes. Although indicator measures have been reported, little evidence of their use in measuring and benchmarking performance is available. A standard set, defining numerator, denominator, and risk adjustments, will enable global benchmarking of quality of care. OBJECTIVE: To develop a set of indicators to enable assessment and reporting of quality of care for men with localised prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: Candidate indicators were identified from the literature. An international panel was invited to participate in a modified Delphi process. Teleconferences were held before and after each voting round to provide instruction and to review results. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Panellists were asked to rate each proposed indicator on a Likert scale of 1-9 in a two-round iterative process. Calculations required to report on the endorsed indicators were evaluated and modified to reflect the data capture of the Prostate Cancer Outcomes Registry-Australia and New Zealand (PCOR-ANZ). RESULTS AND LIMITATIONS: A total of 97 candidate indicators were identified, of which 12 were endorsed. The set includes indicators covering pre-, intra-, and post-treatment of PCa care, within the limits of the data captured by PCOR-ANZ. CONCLUSIONS: The 12 endorsed quality measures enable international benchmarking on the quality of care of men with localised PCa. Reporting on these indicators enhances safety and efficacy of treatment, reduces variation in care, and can improve patient outcomes. PATIENT SUMMARY: PCa has the highest incidence of all cancers in men. Early diagnosis and relatively high survival rates mean issues of quality of care and best possible health outcomes for patients are important. This paper identifies 12 important measurable quality indicators in PCa care.

Optimum Tools for Predicting Clinical Outcomes in Prostate Cancer Patients Undergoing Radical Prostatectomy: A Systematic Review of Prognostic Accuracy and Validity.

Prostate cancer is a heterogeneous disease whose therapies frequently have adverse effects. Informed patient counseling regarding likely clinical outcomes is therefore important. In this systematic review we aimed to identify all external validations of tools that are used to predict clinical outcomes in patients undergoing radical prostatectomy and evaluate which are optimum for clinical implementation. PubMed and EMBASE were searched from 2007 to 2016. Search terms related to the inclusion criteria were: prostate cancer, clinical outcomes, radical prostatectomy, and prognosis. Titles and abstracts were screened and relevant studies were advanced to full-text review. Reference lists were reviewed for further studies. The Centre for Evidence Based Medicine prognostic tool was used for critical appraisal. Seventy-three studies externally validated 13 pre- and 41 postoperative tools for the prediction of biochemical recurrence (BCR), aggressive BCR, metastasis, and prostate cancer-specific mortality (PCSM). Recommendations for clinical implementation were made on the basis of accuracy, cohort sizes, and consistency. The accuracy of recommended tools ranged from 68% to 79% and 72% to 92% among the largest validation cohorts for pre- and postoperative tools. For preoperative prognosis we recommended the Cancer of the Prostate Risk Assessment (CAPRA) and Stephenson nomograms for BCR, the CAPRA nomogram for aggressive BCR as well as metastasis, and the D'Amico criteria for PCSM. For postoperative prognosis we recommended the CAPRA-Surgery (CAPRA-S), Stephenson, Kattan, Duke prostate cancer (DPC), and the Suardi nomograms for the prediction of BCR, the DPC nomogram for aggressive BCR, the CAPRA-S and Eggener nomograms for metastasis, and the Eggener nomogram for PCSM. Use of these tools should help clinicians deliver accurate, evidence-based counseling to patients undergoing prostatectomy.

Tools for Predicting Clinical and Patient-reported Outcomes in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Systematic Review of Prognostic Accuracy and Validity.

Androgen deprivation therapy (ADT) can result in a range of adverse symptoms that reduce patients' quality of life. Careful patient counseling on the likely clinical outcomes and adverse effects is therefore vital. The present systematic review was undertaken to identify and characterize all the tools used for the prediction of clinical and patient-reported outcome measures (PROMs) in patients with prostate cancer undergoing ADT. PubMed and EMBASE were systematically searched from 2007 to 2016. Search terms related to the inclusion criteria were: prostate cancer, clinical outcomes, PROMs, ADT, and prognosis. Titles and abstracts were reviewed to find relevant studies, which were advanced to full-text review. The reference lists were screened for additional studies. The Centre for Evidence Based Medicine critical appraisal of prognostic studies tool was applied. The search strategy identified 8755 studies. Of the 8755 studies, 22 on clinical outcomes were identified. However, no studies of PROMs were found. Nine tools could be used to predict clinical outcomes in treatment-naive patients and 10 in patients with recurrence. The Japan Cancer of the Prostate Risk Assessment (J-CAPRA) nomogram was the best performing and validated tool for the prediction of clinical outcomes in treatment-naive patients, and the Chi and Shamash prognostic indexes have been validated for use in patients with castration-resistant disease in different clinical contexts. Using the J-CAPRA nomogram should help clinicians deliver accurate, evidence-based counseling to patients undergoing primary ADT. A strong need exists for primary studies that derive and validate tools for the prediction of PROMs in patients undergoing ADT under any circumstance because these are currently absent from the literature.

Development of an International Prostate Cancer Outcomes Registry.

OBJECTIVES: To establish a Prostate Cancer Outcomes Registry-Australia and New Zealand (PCOR-ANZ) for monitoring outcomes of prostate cancer treatment and care, in a cost-effective manner. MATERIALS AND METHODS: Stakeholders were recruited based on their interest, importance in achieving the monitoring and reporting of clinical practice and patient outcomes, and in amalgamation of existing registries. Each participating jurisdiction is responsible for local governance, site recruitment, data collection, and data transfer into the PCOR-ANZ. To establish each local registry, hospitals and clinicians within a jurisdiction were approached to voluntarily contribute to the registry following relevant ethical approval. Patient contact occurs following notification of prostate cancer through a hospital or pathology report, or from a cancer registry. Patient registration is based on an opt-out model. The PCOR-ANZ is a secure web-based registry adhering to ISO 27001 standards. Based on a standardised minimum data set, information on demographics, diagnosis, treatment, outcomes, and patient reported quality of life, are collected. RESULTS: Eight of nine jurisdictions have agreed to contribute to the PCOR-ANZ. Each jurisdiction has commenced implementation of necessary infrastructure to support rapid rollout. PCOR-ANZ has defined a minimum data set for collection, to enable analysis of key quality indicators that will aid in assessing clinical practice and patient focused outcomes. CONCLUSION: PCOR-ANZ will provide a useful resource of risk-adjusted evidence-based data to clinicians, hospitals, and decision makers on prostate cancer clinical practice.

Prostate-specific antigen (PSA) rate of decline post external beam radiotherapy predicts prostate cancer death.

BACKGROUND AND PURPOSE: To assess the association between PSA velocity (PSAV) in the first 24 months after external beam radiotherapy (EBRT) and prostate cancer-specific mortality (PCSM) and all cause mortality. MATERIALS AND METHODS: All eligible patients in the South Australian (SA) Prostate Cancer Clinical Outcomes registry were followed. 848 Patients treated by definitive EBRT with more than one PSA recorded in the two year post-treatment were included. We calculated PSAV by linear regression. RESULTS: The mean number of PSA measurements in the 2year period was 4.4 (SD1.9). The median PSAVs across quartiles (Q1-Q4) were -4.17, -1.29, -0.38 and 0.20ng/ml/yr. In multivariable analysis, a U-shaped relationship was seen between PSAV and PCSM with Q1-Q4 hazard ratios (HR) being 3.82 (1.46-10.00), 3.07 (1.10-8.58), 1, 5.15 (1.99-13.30) respectively. HR for all cause mortality in a similar model were 1.79 (1.07-2.98), 1.55 (0.93-2.59), 1.00 and 1.74 (1.04-2.90) for Q1 to Q4 respectively. A rapid PSA decline in the first year was a strong predictor of PCSM. However, in the second year PSA increase was positively associated with PCSM. CONCLUSION: A rapid decline in PSA in the first year following EBRT is positively associated with PCSM. This may be a useful early indicator of the need for additional therapies.

Electrolysis - a new method of renal ablation?

OBJECTIVE: • To present a novel method of renal ablation using direct current electrolysis, using a porcine model to assess the safety and efficacy of the technique. MATERIALS AND METHODS: • In all, 20 anaesthetised pigs were used, after receiving ethical approval. The pigs were housed and managed in accordance with Institute of Medical and Veterinary Science guidelines. • A single 6 F catheter incorporating cathode and anode was inserted directly into the renal parenchyma via a loin incision. A direct current of 100 mA was applied for varying times. • Several treatments were performed in each pig and a total of 72 treatments were analysed. • The pigs were recovered and observed for 3 days with an analysis of electrolytes and creatinine after ablation. The pigs were humanely killed at 3 days and the kidneys submitted for histological analysis. RESULTS: • Complete tissue destruction was seen in the area of kidney treated with no viable cells. • A sharp line of demarcation was noted between normal renal parenchyma and the area of coagulative necrosis. The area of tissue ablation was reliably predicted from the duration of application of the electrolytic current. • One pig developed a secondary haemorrhage. CONCLUSIONS: • Renal electrolysis is a new method of focal renal ablation. The procedure may be carried out using a fine ablation catheter (6 F) allowing for the development of minimal intervention treatment of small renal masses. • This study shows the technique to be effective and safe. As with other renal ablative techniques there is a small risk of postoperative haemorrhage.

Recurrent torsion after previous testicular fixation.

BACKGROUND: Occasionally patients present with acute testicular pain having undergone a previous testicular fixation for torsion. The aim of this article is to review the literature and determine whether recurrent torsion of the testis is possible and whether the technique used at initial fixation is relevant. METHODS: A literature search was performed using MEDLINE, Pre-MEDLINE, EMBASE and CIANHL databases using the terms 'spermatic cord torsion' and 'testicular torsion' in combination with 'treatment failure', 're-operation' or 'recurrence'. RESULTS: Twenty cases of recurrent testicular torsion after fixation are described. Fifteen of the 17 that specified the type of suture used at initial fixation had used absorbable suture. Animal models suggest that to produce dense adhesions at testicular fixation, the tunica vaginalis must be everted behind the testis with or without fixation, before the testis is returned to the scrotum. Without this eversion, the adhesions around the testis are fine and only located at the site of fixation suture. The use of non-absorbable suture led to abscess formation in 30% of testes in animal models. CONCLUSIONS: The higher incidence of recurrent torsion after fixation using absorbable rather than non-absorbable sutures in the literature may be caused by a greater number of fixations being carried out using absorbable suture. Use of non-absorbable suture is limited by the high rate of abscess formation. The most important factor for adhesion formation would appear to be the eversion of the tunica vaginalis and it is recommended that this is carried out at all testicular fixations.