Surgery (RMH) - Research Publications
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ItemDefining Prostatic Vascular Pedicle Recurrence and the Anatomy of Local Recurrence of Prostate Cancer on Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography.(Elsevier BV, 2022-07)BACKGROUND: The term local recurrence in prostate cancer is considered to mean persistent local disease in the prostatic bed, most commonly at the site of the vesicourethral anastomosis (VUA). Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging for assessment of early biochemical recurrence (BCR), we have found histologically confirmed prostate cancer in the prostatic vascular pedicle (PVP). If a significant proportion of local recurrences are distant to the VUA, it may be possible to alter adjuvant and salvage radiation fields in order to reduce the potential morbidity of radiation in selected patients. OBJECTIVE: To describe PVP local recurrence and to map the anatomic pattern of prostate bed recurrence on PSMA PET/CT. DESIGN SETTING AND PARTICIPANTS: This was a retrospective multicentre study of 185 patients imaged with PSMA PET/CT following radical prostatectomy (RP) between January 2016 and November 2018. All patient data and clinical outcomes were prospectively collected. Recurrences were documented according to anatomic location. For patients presenting with local recurrence, the precise location of the recurrence within the prostate bed was documented. INTERVENTION: PSMA PET/CT for BCR following RP. RESULTS AND LIMITATIONS: A total of 43 local recurrences in 41/185 patients (22%) were identified. Tumour recurrence at the PVP was found in 26 (63%), VUA in 15 (37%), and within a retained seminal vesicle and along the anterior rectal wall in the region of the neurovascular bundle in one (2.4%) each. Histological and surgical evidence of PVP recurrence was acquired in two patients. The study is limited by its retrospective nature with inherent selection bias. This is an observational study reporting on the anatomy of local recurrence and does not include follow-up for patient outcomes. CONCLUSIONS: Our study showed that prostate cancer can recur in the PVP and is distant to the VUA more commonly than previously thought. This may have implications for RP technique and for the treatment of selected patients in the local recurrence setting. PATIENT SUMMARY: We investigated more precise identification of the location of tumour recurrence after removal of the prostate for prostate cancer. We describe a new definition of local recurrence in an area called the prostatic vascular pedicle. This new concept may alter the treatment recommended for recurrent disease.
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ItemMolecular classification of hormone-sensitive and castration-resistant prostate cancer, using nonnegative matrix factorization molecular subtyping of primary and metastatic specimens(WILEY, 2022-04-18)BACKGROUND: Despite the rapidly evolving therapeutic landscape, immunotherapy has demonstrated limited activity in prostate cancer. A greater understanding of the molecular landscape, particularly the expression of immune-related pathways, will inform future immunotherapeutic strategies. Consensus nonnegative matrix factorization (cNMF) is a novel model of molecular classification analyzing gene expression data, focusing on biological interpretation of metagenes and selecting meaningful clusters. OBJECTIVE: We aimed to identify molecular subtypes of prostate cancer using cNMF and correlate these with existing biomarkers to inform future immunotherapeutic strategies. METHODS: A cohort of archival tumor specimens from hormone-sensitive and castration-resistant disease was studied. Whole transcriptomic profiles were generated using TruSeq RNA Access technology and subjected to cNMF. Comprehensive genomic profiling was performed with the FoundationOne assay. NMF subtypes were characterized by gene expression pathways, genomic alterations and correlated with clinical data, then applied to The Cancer Genome Atlas data set. RESULTS: We studied 164 specimens, including 52 castration-resistant and 13 paired primary/metastatic specimens. cNMF identified four distinct subtypes. NMF1 (19%) is enriched for immune-related and stromal-related pathways with transforming growth factor β (TGFβ) signature. NMF2 (36%) is associated with FOXO-mediated transcription signature and AKT signaling, NMF3 (26%) is enriched for ribosomal RNA processing, while NMF4 (19%) is enriched for cell cycle and DNA-repair pathways. The most common gene alterations included TMPRSS22 (42%), TP53 (23%), and DNA-repair genes (19%), occurring across all subtypes. NMF4 is significantly enriched for MYC and Wnt-signaling gene alterations. TMB, CD8 density, and PD-L1 expression were low overall. NMF1 and NMF4 were NMF2 was associated with superior overall survival. CONCLUSIONS: Using cNMF, we identified four molecularly distinct subtypes which may inform treatment selection. NMF1 demonstrates the most inflammatory signature with asuppressive TGFβ signature, suggesting potential benefit with immunotherapy combination strategies targeting TGFβ and PD-(L)1. Prospective studies are required to evaluate the use of this novel model to molecularly stratify patients for optimal treatment selection.
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ItemGenetic factors associated with prostate cancer conversion from active surveillance to treatment(ELSEVIER, 2022-01-13)Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.
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ItemFournier's gangrene in a man on empagliflozin for treatment of Type2 diabetes(WILEY, 2017-11-01)BACKGROUND: Sodium-glucose cotransporter 2 (SLGT2) inhibitors has been associated with an increased risk of genital infections secondary to increased glycosuria. CASE REPORT: We report a case of a 41-year-old man with type 2 diabetes treated with empagliflozin and metformin who presented with scrotal swelling. He described multiple preceding episodes of genital thrush for which he self-administered over-the-counter anti-fungal treatment. On examination, he was afebrile and hemodynamically stable. Perineal examination revealed grossly swollen and indurated scrotum with bilateral inguinal lymphadenopathy. Investigations showed elevated inflammatory markers and HbA1c of 99 mmol/mol (11.2%). Computed tomography revealed features consistent with Fournier's gangrene. He underwent emergency exploration and debridement under anaesthetic with a later return to theatre for further exploration, washout and application of a vacuum dressing. He then received a split skin graft to his perineum. He required a 2-week course of intravenous antibiotics and was discharged home on oral antibiotics. Empagliflozin was ceased on admission and he was commenced on a basal bolus insulin regimen for glycaemic optimisation. CONCLUSION: There is a wide clinical spectrum of genital infections associated with SGLT2 inhibitors with most being generally mild and easily treated. However, risk factors such as diabetes, obesity, immunosuppressed states, smoking, alcohol abuse and end-stage renal or liver failure may increase the risk of potentially more severe infections such as Fournier's gangrene. Timely cessation of SGLT2 inhibitors in individuals with multiple risk factors may help prevent progression to more severe genital infections.
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ItemChanging face of robot-assisted radical prostatectomy in Melbourne over 12 years(WILEY, 2018-03-01)BACKGROUND: This study aims to characterize the trends in disease presentation for robot-assisted radical prostatectomy (RARP) over a 12-year period in Melbourne, Australia. METHODS: All patients undergoing an RARP between 2004 and October 2016 while under the care of six high-volume surgeons were included in this study. Data were collected prospectively regarding patient demographics and clinical details of their cancer. RESULTS: Over the 12-year time span of the study, 3075 men underwent an RARP with a median age of 63.01 years. Temporal analysis demonstrated that the median age of patients undergoing prostatectomy advanced with time with the median age in 2016 being 65.51 years compared with 61.0 years in 2004 (P < 0.001). There was also a significant trend to increased D'Amico risk groups over time with the percentage procedures for high-risk patients increasing from 12.6% to 28.10% from 2004 to 2016 (P < 0.001). Upgrade rates between biopsy and pathological Gleason grade scoring significantly trended down over the period of the study (P < 0.001). There was also a shift to increased pathological stage over the 12 years with 22.1% of men having T3 disease in 2004 compared with 49.8% in 2016. CONCLUSION: Our analysis demonstrates increasing treatment of older men with higher risk tumours, consistent with international trends. While this largely reflects a shift in case selection, further work is needed to assess whether the stage shift may relate partially to a decline in screening and increased presentation of higher risk disease.
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ItemAn online psychological intervention can improve the sexual satisfaction of men following treatment for localized prostate cancer: outcomes of a Randomised Controlled Trial evaluating My Road Ahead(WILEY, 2017-07-01)BACKGROUND: Prostate cancer treatment often results in significant psycho-sexual challenges for men following treatment; however, many men report difficulty in accessing appropriate care. METHODS: A randomized controlled trial was undertaken to assess the efficacy of a 10-week self-guided online psychological intervention called My Road Ahead (MRA) for men with localized prostate cancer in improving sexual satisfaction. Participants were randomized to 1 of 3 conditions MRA alone or MRA plus online forum, or forum access alone. Pre, post, and follow-up assessments of overall sexual satisfaction were conducted. Mixed models and structural equation modeling were used to analyze the data. RESULTS: One hundred forty-two men (mean age 61 y; SD = 7) participated. The majority of participants had undergone radical prostatectomy (88%) and all men had received treatment for localized prostate cancer. Significant differences were obtained for the 3 groups (P = .026) and a significant improvement in total sexual satisfaction was observed only for participants who were allocated to MRA + forum with a large effect size (P = .004, partial η2 = 0.256). Structural equation modeling indicated that increases in sexual function, masculine self-esteem, and sexual confidence contributed significantly to overall sexual satisfaction for the MRA + forum plus forum condition. CONCLUSIONS: This study is the first, to our knowledge, that has evaluated a self-guided online psychological intervention tailored to the specific needs of men with prostate cancer. The findings indicate the potential for MRA to deliver support that men may not otherwise receive and also highlight the importance of psychological intervention to facilitate improved sexual outcomes.
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ItemFeasibility for active surveillance in biopsy Gleason 3+4 prostate cancer: an Australian radical prostatectomy cohort(WILEY, 2016-04-01)OBJECTIVE: To examine the feasibility of active surveillance for low volume Gleason sum (GS) 3 + 4 disease compared to GS 3 + 3 disease. PATIENTS AND METHODS: Retrospective review of 929 patients, with biopsy proven GS 3 + 3 and 3 + 4 PCa, undergoing upfront radical prostatectomy (RP) was performed. Suitability for AS was adapted from protocols by Royal Marsden Hospital, University of Toronto, and PRIAS by allowing Gleason 3 + 4 disease. The outcomes assessed were adverse pathology at RP (upgrading ≥GS 4 + 3 and/or upstaging ≥pT3) and biochemical recurrence (BCR) after RP. RESULTS: Adverse pathology at RP was compared between GS 3 + 3 vs 3 + 4 groups. When selecting patients using Royal Marsden (n = 714) or University of Toronto (n = 699) protocols, there was statistically significantly more adverse pathology at RP in GS 3 + 4 group (21% vs 31%, P = 0.0028 and 19% vs 33%, P=<0.001 respectively). Using the more stringent PRIAS protocol (n = 198), there was no statistical significant difference in groups. There was no difference in BCR survival between biopsy GS 3 + 3 and 3 + 4 groups, regardless of which AS protocol assessed. Pre-operative PSA and clinical staging were the predictors for BCR. CONCLUSION: Presence of Gleason 3 + 4 at biopsy, when compared to 3 + 3, increases the risk of adverse pathology being present at radical prostatectomy for less stringent selection criteria. When considering AS, a stricter protocol such as PRIAS, limiting PSA density and number of positive cores to ≤2, appears to decrease the risk of adverse pathology. No differences in BCR were seen between biopsy 3 + 3 and 3 + 4 disease, regardless of AS selection criteria.
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ItemTranscriptome sequencing and multi-plex imaging of prostate cancer microenvironment reveals a dominant role for monocytic cells in progression(BMC, 2021-07-22)BACKGROUND: Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. RESULTS: In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. CONCLUSIONS: This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.
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ItemLoss of SNAI2 in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy(LIPPINCOTT WILLIAMS & WILKINS, 2021-06-01)PURPOSE: Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS: We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS: We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION: We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.
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