Surgery (St Vincent's) - Research Publications
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ItemPatterns of care and outcomes for men diagnosed with prostate cancer in Victoria: an update(WILEY, 2018-10)BACKGROUND: To update patterns of care for men diagnosed with prostate cancer in Victoria, Australia between 2008 and 2015. METHODS: From August 2008 to December 2015, 14 025 men diagnosed with prostate cancer were included. These data were obtained from the Prostate Cancer Outcome Registry - Victoria (PCOR-Vic). Frequencies were used to describe hospital and patient characteristics and treatment types. Comparisons were made between previous period of analysis (2008-2011) to the most recent period (2011-2015). Survival analysis using a stepwise Cox proportional hazards regression model was performed. RESULTS: Mean age of diagnosis was 66.5 years and 44% of patients were diagnosed with Gleason 7 prostate cancer. Majority of notifications (63.6%) were received from a private institution and 70.2% of patients were diagnosed at a metropolitan institution. Most patients (95.3%) were diagnosed with clinically localized disease. Within 12 months of diagnosis, 55.9% of patients with low-risk disease received no active treatment. Radical prostatectomy was the most common primary treatment with curative intent (47%). When comparing of patterns of care between 2008-2011 and 2011-2015, the proportion of patients diagnosed with Gleason 9-10 disease increased, as has the proportion of patients diagnosed with metastatic disease. CONCLUSION: With the PCOR-Vic, we were able to identify that increasing number of patients were diagnosed with high-risk and metastatic disease. There has been an overall decrease in radical treatment rates, likely due to active surveillance playing a significant role especially in patients with low-risk prostate cancer.
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ItemNo Preview AvailablePatient derived organoid model of penile squamous cell carcinoma(Elsevier BV, 2020-07)
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ItemNo Preview AvailableThe Inferior Gluteal Artery Myocutaneous Flap Is Preferable for Reconstructing the Complex Perineal Defect Following Pelvic Exenteration(Ovid Technologies (Wolters Kluwer Health), 2020)
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ItemARE VICTORIAN WOMEN INTERESTED IN RISK STRATIFIED BREAST SCREENING?(CHURCHILL LIVINGSTONE, 2020-04)
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ItemCD8+TISSUE-RESIDENT MEMORY T CELLS ARE TUMOUR REACTIVE AND INCREASE AFTER IMMUNOTHERAPY IN A CASE OF METASTATIC MUCOSAL MELANOMA(BMJ PUBLISHING GROUP, 2020-11)Background Mucosal melanoma is a rare subtype of melanoma originating from mucosal tissues (1), metastases are very aggressive and respond poorly to therapy, including immune checkpoint inhibitors (ICI) such as anti-CTLA4 and anti-PD1 antibodies (2–5). CD8+ T cells constitute the most abundant immune infiltrate in metastatic melanoma, of which the Tissue Resident Memory subset (TRM) is of particular interest (6). CD8+ TRM cells express the highest levels of immune checkpoint receptors, proliferate in response to ICI and correlate with longer disease-free and overall survival (6–8). The immune landscape in mucosal melanoma remains poorly characterized. We aimed to: 1) phenotype CD8+ T cells and TRM infiltrating metastatic mucosal melanoma, 2) characterize the clonality of TRM in relation to other CD8+ T cell subsets and 3) define the capacity of CD8+ T cells and TRM to respond to melanoma cells and to in vivo and in vitro anti-PD1 treatment. Methods We investigated the CD8+ T and TRM cells infiltrating two temporally- and spatially-distant subcutaneous metastases, these originated from a primary vaginal mucosal melanoma. One metastasis was excised prior to anti-PD1 treatment and one was anti-PD1 refractory, having progressed on treatment. We used mass cytometry and single-cell RNA and TCR sequencing to characterise the phenotype and clonality of the T cells, multiplex immunohistochemistry to define their spatial relationship with tumour cells and other T cells, and functional assays to determine TRM response to tumour cells (figure 1). Results CD8+ TRM frequency increased with time and anti-PD1 treatment, forming clusters at the tumour margin. T cells in the anti-PD1 refractory lesion were more activated than T cells in the first tumour and were bound by anti-PD1 antibody in vivo. T cells could not be stimulated by anti-PD1 directly ex vivo. Both metastatic lesions shared common T cell clusters including TRM. Furthermore, TRM in each tumour shared T cell clones, suggesting the presence of common antigens between metastatic sites. Indeed, the two metastases had a similar mutational profile. In vitro expanded tumour infiltrating lymphocytes from both lesions recognized tumour cells from both lesions and the same neoantigen generated from a single point mutation in the gene CDKN1C. Finally, tumour cells stimulated TRM cells more robustly than other T cells subsets. Abstract 548 Figure 1Graphical depiction of the methods used to characterise T cells in mucosal metastatic melanoma Conclusions In this patient with vaginal mucosal melanoma, subsequent melanoma metastases of clonal origin attracted CD8+ T cells of similar specificity, among which TRM cells responded more vigorously to tumour cells than other T cells subsets. Acknowledgements The authors would like to acknowledge imCORE La Hoffmann- Roche Ltd. for funding. Ethics Approval Patients diagnosed with stage 3 or 4 metastatic melanoma and undergoing clinically indicated surgery were enrolled in prospective studies approved by the Peter MacCallum Cancer Centre human ethics research committee (13/141). All experimental protocols have been approved and clinical data has been collected prospectively. References Carvajal RD, Hamid O, Ariyan C. Mucosal Melanoma. [cited 2020 Apr 1]; Available from: https://www.uptodate.com/contents/mucosal-melanoma Del Vecchio M, Di Guardo L, Ascierto PA, Grimaldi AM, Sileni VC, Pigozzo J, et al. Efficacy and safety of ipilimumab 3 mg/kg in patients with pretreated, metastatic, mucosal melanoma. Eur J Cancer Oxf Engl 1990; 2014 Jan;50(1):121–7. Postow MA, Luke JJ, Bluth MJ, Ramaiya N, Panageas KS, Lawrence DP, et al. Ipilimumab for patients with advanced mucosal melanoma. The Oncologist 2013 Jun;18(6):726–32. D’Angelo SP, Larkin J, Sosman JA, Lebbé C, Brady B, Neyns B, et al. Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2017 Jan 10;35(2):226–35. Hamid O, Robert C, Ribas A, Hodi FS, Walpole E, Daud A, et al. Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006. Br J Cancer 2018;119(6):670–4. Boddupalli CS, Bar N, Kadaveru K, Krauthammer M, Pornputtapong N, Mai Z, et al. Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells. JCI Insight [Internet]. 2016 Dec 22 [cited 2019 Apr 24];1(21). Available from: https://insight.jci.org/articles/view/88955 Edwards J, Wilmott JS, Madore J, Gide TN, Quek C, Tasker A, et al. CD103+ Tumor-resident CD8+ T cells are associated with improved survival in immunotherapy-naïve melanoma patients and expand significantly during anti-PD-1 treatment. Clin Cancer Res Off J Am Assoc Cancer Res 2018 Jul 1;24(13):3036–45. Savas P, Virassamy B, Ye C, Salim A, Mintoff CP, Caramia F, et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med 2018 Jul;24(7):986–93.
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Item3-YEAR RESULTS OF THE PHASE 2 RANDOMIZED TRIAL FOR TALIMOGENE LAHERPAREPVEC (T-VEC) NEOADJUVANT TREATMENT PLUS SURGERY VS SURGERY IN PATIENTS WITH RESECTABLE STAGE IIIB-IVM1A MELANOMA(BMJ PUBLISHING GROUP, 2020-11)Background Neoadjuvant immunotherapies and targeted therapies for advanced melanoma are an active area of investigation. This is the first clinical trial of an approved oncolytic viral immunotherapy as a neoadjuvant treatment in advanced melanoma and the largest randomized controlled neoadjuvant trial including all types of resectable regional metastases to date. Previously published 2-year primary analysis results reported improved recurrence-free survival (RFS, HR 0.66, P=0.038) and overall survival (OS, HR 0.49, P=0.050) for neoadjuvant T-VEC plus surgery vs immediate surgery in resectable stage IIIB-IVM1a melanoma patients.1 Here, we report the 3-year interim analysis results. Methods Patients with resectable stage IIIB-IVM1a melanoma and ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions were randomized 1:1 to receive 6 doses/12 weeks of neoadjuvant T-VEC then surgery (Arm 1) vs immediate surgical resection (Arm 2). T-VEC was administered until surgery, no remaining injectable tumors, or intolerance. RFS was defined as time from randomization to the first of local, regional, or distant recurrence, or death, where patients who did not receive surgery were imputed as events at baseline. Key secondary and exploratory endpoints include safety, an RFS sensitivity analysis that censored events at the start of subsequent anticancer therapy, OS, and event-free survival (EFS), defined as time from randomization to disease progression that precludes surgery, or local, regional or distant recurrence post-surgery, or death from any cause, whichever occurs first. All P values are descriptive. NCT02211131. Results As of April 30, 2020, median follow-up for all patients was 41.3 months. For Arm 1 vs. Arm 2, the 3-year KM estimates of RFS were 46.5% vs. 31.0% (HR 0.67, P=0.043). In the RFS sensitivity analysis that removed the potential effect of subsequent anticancer therapy on RFS, the 3-year Kaplan-Meier (KM) estimates of RFS were 49.1% for Arm 1 and 22.9% for Arm 2 (HR 0.60, P=0.022). The 3-year KM estimates of EFS were 50.3% for Arm 1 and 32.7% for Arm 2 (HR 0.58, P=0.015). For OS, the 3-year KM estimates were 83.2% for Arm 1 and 71.6% for Arm 2 (HR 0.54, P=0.061). No new safety signals were detected. Conclusions At 3-year follow up, we continued to observe improved RFS and OS and observed improved EFS with neoadjuvant T-VEC plus surgery compared with surgery alone. These results build upon the prior 2-year results to support the treatment effect of neoadjuvant T-VEC on advanced resectable melanoma. The final analysis will occur at 5 years. Acknowledgements • The authors thank the investigators, patients, and study staff who are contributing to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.). Trial Registration NCT02211131 Ethics Approval The study was approved by all institutional ethics boards. Reference Dummer R, Gyorki DE, Hyngstrom J, et al. Primary 2-year (yr) results of a phase II, multicenter, randomized, open-label trial of efficacy and safety for talimogene laherparepvec (T-VEC) neoadjuvant (neo) treatment (tx) plus surgery (surg) vs surg in patients (pts) with resectable stage IIIB-IVM1a melanoma. Ann Oncol 2019;30;V903.