Surgery (Austin & Northern Health) - Research Publications

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    Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer
    Mondschein, R ; Bolton, D ; Clouston, D ; Dowty, J ; Kavanagh, L ; Murphy, D ; Scott, P ; Taylor, RA ; Thorne, H (MDPI, 2022-08-01)
    Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4-5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D'Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions:ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.
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    Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes
    Trigos, AS ; Pasam, A ; Banks, P ; Wallace, R ; Guo, C ; Keam, S ; Thorne, H ; Mitchell, C ; Lade, S ; Clouston, D ; Hakansson, A ; Liu, Y ; Blyth, B ; Murphy, D ; Lawrentschuk, N ; Bolton, D ; Moon, D ; Darcy, P ; Haupt, Y ; Williams, SG ; Castro, E ; Olmos, D ; Goode, D ; Neeson, P ; Sandhu, S (BMJ PUBLISHING GROUP, 2022-06-01)
    BACKGROUND: Aberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. Spatial distribution of immune cells in a range of cancers identifies novel disease subtypes and is related to prognosis. In this study we aimed to determine the differences in the TIME of PCa with and without germline (g) HRR mutations. METHODS: We performed gene expression analysis, multiplex immunohistochemistry of T and B cells and quantitative spatial analysis of PCa samples from 36 patients with gHRD and 26 patients with sporadic PCa. Samples were archival tumor tissue from radical prostatectomies with the exception of one biopsy. Results were validated in several independent cohorts. RESULTS: Although the composition of the T cell and B cells was similar in the tumor areas of gHRD-mutated and sporadic tumors, the spatial profiles differed between these cohorts. We describe two T-cell spatial profiles across primary PCa, a clustered immune spatial (CIS) profile characterized by dense clusters of CD4+ T cells closely interacting with PD-L1+ cells, and a free immune spatial (FIS) profile of CD8+ cells in close proximity to tumor cells. gHRD tumors had a more T-cell inflamed microenvironment than sporadic tumors. The CIS profile was mainly observed in sporadic tumors, whereas a FIS profile was enriched in gHRD tumors. A FIS profile was associated with lower Gleason scores, smaller tumors and longer time to biochemical recurrence and metastasis. CONCLUSIONS: gHRD-mutated tumors have a distinct immune microenvironment compared with sporadic tumors. Spatial profiling of T-cells provides additional information beyond T-cell density and is associated with time to biochemical recurrence, time to metastasis, tumor size and Gleason scores.
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    PSMA PET-CT Imaging Predicts Treatment Progression in Men with Biochemically Recurrent Prostate Cancer-A Prospective Study of Men with 3 Year Follow Up
    Ong, S ; Pascoe, C ; Kelly, BD ; Ballok, Z ; Webb, D ; Bolton, D ; Murphy, D ; Sengupta, S ; Bowden, P ; Lawrentschuk, N (MDPI, 2022-06-01)
    Prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET-CT) is a novel imaging modality used to stage recurrent prostate cancer. It has the potential to improve prognostication and ultimately guide the timing of treatment for men with recurrent prostate cancer. This study aims to assess the clinical impact of PSMA PET-CT by analyzing its predictive value of treatment progression after 3 years of follow-up. In this prospective cohort study of 100 men, patients received a PSMA PET-CT for restaging of their disease which was used by a multi-disciplinary team to make a treatment decision. The primary endpoint was treatment progression. This was defined as the addition or change of any treatment modalities such as androgen deprivation therapy (ADT), radiation therapy or chemotherapy. The median follow-up time was 36 months (IQR 24-40 months). No treatment progression was found in 72 (75%) men and therefore 24 (25%) patients were found to have treatment progression. In men with a negative PSMA PET-CT result, 5/33 (15.1%) had treatment progression and 28/33 (84.8%) had no treatment progression. In conclusion, clinical decisions made with PSMA PET-CT results led to 75% of men having no treatment progression at 3 years of follow-up. In men with negative PSMA PET-CT results, this increased to 85% of men.
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    Review of the use of prophylactic drain tubes post-robotic radical prostatectomy: Dogma or decent practice?
    Nzenza, TC ; Ngweso, S ; Eapen, R ; Rajarubendra, N ; Bolton, D ; Murphy, D ; Lawrentschuk, N (Wiley, 2020-09)
    Objective: To assess the necessity of routine prophylactic drain tube use following robot-assisted radical prostatectomy (RARP). Method: We performed a literature review using the Medline, Scopus, and Web of Science databases with no restriction of language from January 1900 to January 2020. The following terms we used in the literature search: prostatectomy, radical prostatectomy, robot assisted, drainage, and drain tube. Results: We identified six studies that examined the use of routine prophylactic drain tubes following RARP. One of these studies was a randomized study that included 189 patients, with 97 in the pelvic drain (PD) arm and 92 in the no pelvic drain (ND) arm. This non-inferiority showed an early (90-day) complication rate of 17.4% in the ND arm versus 26.8% in the PD arm (P < .001). Another non-inferiority randomized control trial (RCT) showed a complication rate of 28.9% in the PD group versus 20.4% in the ND group (P = .254). Similarly, the other studies found no benefit of routine use of prophylactic drain tube after RARP. Conclusion: Drain tubes play a role during robotic-assisted radical prostatectomy, however, following a review of the current available literature, they can be safely omitted and we suggest that clinicians may be selective in their use.
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    Detection and localisation of primary prostate cancer using (68)gallium prostate-specific membrane antigen positron emission tomography/computed tomography compared with multiparametric magnetic resonance imaging and radical prostatectomy specimen pathology
    Kalapara, AA ; Nzenza, T ; Pan, HYC ; Ballok, Z ; Ramdave, S ; O'Sullivan, R ; Ryan, A ; Cherk, M ; Hofman, MS ; Konety, BR ; Lawrentschuk, N ; Bolton, D ; Murphy, DG ; Grummet, JP ; Frydenberg, M (WILEY, 2020-07-01)
    OBJECTIVE: To compare the accuracy of 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography (68 Ga-PSMA PET/CT) with multiparametric MRI (mpMRI) in detecting and localising primary prostate cancer when compared with radical prostatectomy (RP) specimen pathology. PATIENTS AND METHODS: Retrospective review of men who underwent 68 Ga-PSMA PET/CT and mpMRI for primary prostate cancer before RP across four centres between 2015 and 2018. Patients undergoing imaging for recurrent disease or before non-surgical treatment were excluded. We defined pathological index tumour as the lesion with highest International Society of Urological Pathology Grade Group (GG) on RP specimen pathology. Our primary outcomes were rates of accurate detection and localisation of RP specimen pathology index tumour using 68 Ga-PSMA PET/CT or mpMRI. We defined tumour detection as imaging lesion corresponding with RP specimen tumour on any imaging plane, and localisation as imaging lesion matching RP specimen index tumour in all sagittal, axial, and coronal planes. Secondary outcomes included localisation of clinically significant and transition zone (TZ) index tumours. We defined clinically significant disease as GG 3-5. We used descriptive statistics and the Mann-Whitney U-test to define and compare demographic and pathological characteristics between detected, missed and localised tumours using either imaging modality. We used the McNemar test to compare detection and localisation rates using 68 Ga-PSMA PET/CT and mpMRI. RESULTS: In all, 205 men were included in our analysis, including 133 with clinically significant disease. There was no significant difference between 68 Ga-PSMA PET/CT and mpMRI in the detection of any tumour (94% vs 95%, P > 0.9). There was also no significant difference between localisation of all index tumours (91% vs 89%, P = 0.47), clinically significant index tumours (96% vs 91%, P = 0.15) or TZ tumours (85% vs 80%, P > 0.9) using 68 Ga-PSMA PET/CT and mpMRI. Limitations include retrospective study design and non-central review of imaging and pathology. CONCLUSION: We found no significant difference in the detection or localisation of primary prostate cancer between 68 Ga-PSMA PET/CT and mpMRI. Further prospective studies are required to evaluate a combined PET/MRI model in minimising tumours missed by either modality.
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    Case series - Peritoneal and port-site metastasis following robotic-assisted radical prostatectomy
    O'Connor, E ; Timm, B ; Chislett, B ; Teh, J ; Lawrentschuk, N ; Murphy, DG ; Bolton, D (CANADIAN UROLOGICAL ASSOCIATION, 2021-01-01)
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    Patterns of primary staging for newly diagnosed prostate cancer in the era of prostate specific membrane antigen positron emission tomography: A population-based analysis
    Papa, N ; Perera, M ; Murphy, DG ; Lawrentschuk, N ; Evans, M ; Millar, JL ; Bolton, D (WILEY, 2021-03-05)
    INTRODUCTION: There has been a growing body of evidence highlighting the improved sensitivity and specificity for prostate specific membrane antigen (PSMA) positron emission tomography (PET) in advanced prostate cancer imaging. We aimed to assess prostate cancer staging practice patterns in Australia using population-based data. SUBJECT AND METHODS: We extracted data on men diagnosed with prostate cancer between October 2016 and December 2018 from the Prostate Cancer Outcomes Registry-Victoria (PCOR-Vic). We evaluated trends and comparisons between patients receiving PET/CT (with or without conventional imaging (CImg)), and CImg alone, and analysed imaging modality as predictor of clinical regional node positive disease (cN1 vs cN0/X), metastatic disease (cM1 vs cM0/X), and treatment received. RESULTS: In total, 6139 patients in the registry had either a staging PET scan (n = 889, 14%), CImg without PET scan (n = 2464, 40%), or no recorded PET or CImg (n = 2786, 45%). The proportion of allimaged patients who received staging PET increased from 19% to 36% from the first to last three-month period, and in the high-risk category the increase was 23-43%. After adjustment for grade group, PET vs CImg-only patients were observed to have a higher proportion of cN1 disease (OR = 2.46, 95% CI: 1.90-3.20) but not cM1 disease (OR = 1.10, 95% CI: 0.84-1.44). CONCLUSIONS: Our registry data highlights the rapid uptake of PET imaging, particularly in high-risk disease. Based on this data, we highlight the increased diagnosis of nodal disease, thus potentially optimizing patient selection prior to definitive treatment for prostate cancer.