Research

 

The Tissue Pathology & Diagnostic Oncology department at the Royal Prince Alfred Hospital is a leading academic teaching hospital pathology department in Australia. Research is a key part of our work and our staff were authors or co-authors of 84 peer reviewed journal articles published in 2017, including prestigious journal such as New England Journal of Medicine, Nature, Lancet, Cell, Nature Genetics, Nature Communications,  CA: A Cancer Journal for Clinicians, Lancet Oncology, and Journal of Clinical Oncology.

Leading areas of research include melanoma, prostate cancer, head and neck cancer, pancreaticobiliary cancer, transplant pathology lung cancer, and interstitial lung disease.

There are numerous research opportunities both within the department and through our local, national and international collaborations. Our research, which is aimed at improving patient management and outcome, spans many areas of pathology including genomics, translational medicine, clinical trials, diagnostic surgical pathology, laboratory methods and quality assurance. Through staff involvement in research and international subspecialty groups, our team have authored chapters to prestigious textbooks such as the AJCC staging system manual and the WHO tumour books, in addition to consensus documents such as the Cancer Council Australia Guidelines and the International Collaboration on Cancer Reporting.

Our staff also supervise honours, masters and PhD students engaged in research within the department. Registrars have many opportunities to participate in research and are supported and encouraged to publish their research work. Research opportunities range from case reports though to case series, original research projects and advanced degrees.

A selection of key publications in various research categories is presented below:  

Genomics

Hayward NK, Wilmott JS, Waddell N, ... Scolyer RA, Mann GJ. Whole genome landscapes of melanoma subtypes. Nature 2017;545:175-80 First whole genome sequencing profile of cutaneous, acral and mucosal melanoma melanoma

Raphael BJ, Hruban RH, Aguirre AJ,..Kench JG, et al. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 2017;32:185-203. Analyzes the complex molecular landscape of pancreatic ductal adenocarcinoma paving the path for precision medicine for this lethal cancer.

Scarpa A, Chang DK, Nones K,...Kench JG, et al. Whole genomes redefine the genomic landscape of pancreatic neuroendocrine tumours. Nature 2017;543:65-71

Kahles A, Lehmann K-V, Toussaint NC... Scolyer RA, et al. Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients. Cancer Cell 2018;34(2):211-224.e216. Demonstrates that tumours have thousands of alternative splicing events not detectable in normal samples.

Joo JE, Dowty JG, Milne RL,…..,Salisbury E, et al. Heritable DNA methylation marks associated with susceptibility to breast cancer. Nat Commun. 2018 Feb 28;9(1):867. doi: 10.1038/s41467-018-03058-6. Analyzes the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families.

Kalsbeek A, Chan EFK, Grogan J,...Gupta R,...Kench JG, et al. Mutational load of the mitochondrial genome predicts pathological features and biochemical recurrence in prostate cancer. Aging 2016;8:2702-12. First study to demonstrate the prognostic potential of mitochondrial DNA (mtDNA) mutational burden in prostate cancer.

Basic sciences and translational medicine

Eroglu Z, Zaretsky JM, Hu-Lieskovan S,...Scolyer RA, et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature 2018;553(7688):347-350. Patients with advanced desmoplastic melanoma derive substantial clinical benefit from immune checkpoint blockade therapy.

Valdes Mora F, Gould C, Colino Sanguino Y, Qu W, Song J, Taylor K, Buske F, Statham AL, Nair S, Armstrong N, Kench J, Lee K, Horvath L, Qiu M, Ilinykh A, Yeo-The N, Gallego-Ortega D, Stirzaker C, Clark S. Acetylated histone variant H2A.Z is involved in the activation of neo-enhancers in prostate cancer. Nature Comm 2017;8:1346. Incorporation of acetylated histone variant H2A.Z containing nucleosomes is a pre-requisite for activation of Androgen receptor (AR) associated enhancers and correlate with poorer prognosis.

Duivenvoorden HM, Rautela J, Edgington-Mitchell LE, Spurling A, Greening DW, Nowell CJ, Molloy TJ, Robbins E, Brockwell NK, Lee CS, Chen M, Holliday A, Selinger CI, Hu M, Britt KL, Stroud DA, Bogyo M, Möller A, Polyak K, Sloane BF, O'Toole SA, Parker BS. Myoepithelial cell-specific expression of stefin A as a suppressor of early breast cancer invasion. J Pathol. 2017 Dec;243(4):496-509. Evaluates the mechanism of invasion in early breast cancer.

Gallagher SJ, Gunatilake D, Beaumont KA, Ferguson PM et al. HDAC inhibitors restore BRAF-inhibitor sensitivity by altering PI3K and survival signalling in a subset of melanoma. Int J Cancer 2018;142(9):1926-1937. 2D and 3D cell culture models were used to demonstrate that combination of HDAC and MAPK inhibitors may play a role in the treatment of some BRAF inhibitor resistant melanomas.

Bruce HM, Stricker PD, Gupta R,...Kench JG, Horvath LG. Loss of AZGP1 as a Superior Predictor of Relapse in Margin-Positive Localized Prostate Cancer. Prostate 2016;76(16):1491-1500. Absence of AZGP1 expression was an independent predictor of biochemical recurrence in margin-positive localized prostate cancer and is associated with increased prostate cancer-specific mortality in a Phase II study.

Khoo TK, Yu B, Smith JA, Clarke AJ, Luk PP, Selinger CI, Mahon KL, Kraitsek S, Palme C, Boyer MJ, Dinger ME, Cowley MJ, O'Toole SA, Clark JR, Gupta R. Somatic mutations in salivary duct carcinoma and potential therapeutic targets. Oncotarget. 2017 May 25;8(44):75893-75903.Targeted panel somatic mutation analyses demonstrates therapeutic options for an aggressive salivary gland tumour currently lacking effective systemic therapies.

Diagnostic surgical pathology

Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472-492. Detailed analysis of 50,000 melanoma patients published in the world's highest impact factor journal.

Liu J, Ebrahimi A, Low TH, Gao K, Palme CE, Sydney C, Ashford BG, Iyer NG, Clark JR, Gupta R. Predictive value of the 8th edition American Joint Commission Cancer (AJCC) nodal staging system for patients with cutaneous squamous cell carcinoma of the head and neck.J Surg Oncol. 2018 Mar;117(4):765-772. Evaluates the prognostic utility of the current AJCC staging system in 382 patients with metastatic cutaneous squamous cell carcinoma.

McGuire HM, Shklovskaya E, Edwards J,...McKenzie CA, et al. Anti-PD-1 induced high grade hepatitis in a patient associated with corticosteroid resistant T cells. Cancer Immunology, Immunotherapy, 1-11. Highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

Tetzlaff MT, Messina JL, Stein JE...Ferguson PM, Rawson RV...Scolyer RA. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann Oncol published online June 2018. Provides a standardised approach to the pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy. 

Rawson RV, Watson GF, Mahar AM, McCarthy SW, Thompson JF, Scolyer RA. Germline BAP1 mutations also predispose to cutaneous squamous cell carcinoma. 2017 Aug;49(5):539-542. The first report of cutaneous squamous cell carcinoma with BRCA1-associated protein-1 (BAP1) loss/inactivation in a patient known to have a BAP1 germline mutation.

Clinical trials

Zhang AY, Grogan JS, Mahon KL,...Kench JG, Horvath LG. A prospective multi-center phase III validation study of AZGP1 as a biomarker in localised prostate cancer. Ann Oncol 2017;28:1903-9. Absent/low AZGP1 expression is of independent prognostic value in prostate cancer providing robust evidence for its incorporation into clinical practice.

van Zandwijk N, Pavlakis N, Kao SC,...Cooper W, et al. Safety and activity of microRNA-loaded minicells: A 'first-in-man' phase 1 study in patients with recurrent Malignant Pleural Mesothelioma (MPM). Lancet Oncology 2017; 18:1386-96. This 'first-in-man' multicentre phase 1 study showed that microRNA-loaded minicells in mesothelioma.

Rozeman EA, Van Akkooi ACJ, Menzies AM, Scolyer RA, et al. Multicenter phase 2 study to identify the optimal neo-adjuvant combination scheme of ipilimumab (IPI) and nivolumab (NIVO) (OpACIN-neo). JCO 2018; 36(S15). Will identify an optimal neoadjuvant combination scheme of anti-CTLA-4 and anti-PD-1 for resectable stage III melanoma.

Chen AC, Martin AJ, Choy B,...McKenzie CA, Scolyer RA, et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. N Eng J Med 2015;373(17):1618-1626. Showed that oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients.

Long GV, Atkinson V, Lo S,...Scolyer RA, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 2018 May;19(5):672–81.Provides evidence that combination therapy should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.

Reviews and meta-analyses

Luk PP, Selinger CI, Mahar A, Cooper WA. Biomarkers for ALK and ROS1 in Lung Cancer: Immunohistochemistry and Fluorescent In Situ Hybridization. Arch Path Lab Med 2018;142(8):922-928. Immunohistochemistry can be an effective screening method for detection of ALK and ROS1 rearrangement in non–small cell lung cancer, or a diagnostic test in the setting of ALK.

Gupta R, Cooper WA, Selinger C, Mahar A, Anderson L, Buckland ME, O'Toole SA. Fluorescent In Situ Hybridization in Surgical Pathology Practice. Adv Anat Pathol. 2018 Jul;25(4):223-237. Reviews the utility of FISH across various tumour disciplines including bone and soft tissue, head and neck, urology, breast, haematolymphoid and neuropathology.

McKenzie PR, Delahunt B, Kench JG, Sikaris KA. 5-Alpha reductase inhibitors and PSA screening for prostate cancer. Pathology. 2014 Jan;46(1):91-2. and McKenzie PR, Delahunt B, Kench JG, Ross B, Lam Q, deVoss K, Tran HA, Sikaris KA. Prostate specific antigen testing: age-related interpretation in early prostate cancer detection. Pathology. 2013 Jun;45(4):343-5. Aided the establishment of national policies and guidelines regarding PSA screening.

Buckley L, Jackett L, Clark J, Gupta R. HPV-related Oropharyngeal Carcinoma: A Review of Clinical and Pathologic Features With Emphasis on Updates in Clinical and Pathologic Staging. Adv Anat Pathol. 2018 May;25(3):180-188. A review of the recent histopathologic classifications, staging systems, and developments in the management of human papilloma virus-related oropharyngeal squamous cell carcinoma and summarizes their implications for routine diagnostic practice.

Ferguson PM, Long GV, Scolyer RA, Thompson JF. Impact of genomics on the surgical management of melanoma. Br J Surg 2018;105(2):e31-e47. Examines the evolving role of surgery for primary and advanced melanoma in the era of genomic medicine and effective systemic therapies.

Methods in surgical pathology and quality assurance

Jo HE, Glaspole IN, Levin KC,...Mahar AM, Cooper WA, et al. Clinical impact of the interstitial lung disease (ILD) multidisciplinary service. Respirology 2016; 21:1438–1444.The ILD multidisciplinary service resulted in a change in specific ILD diagnosis and management in 53% patients, demonstrating that a dedicated tertiary ILD-MDT service has an important clinical impact on the care of the ILD patient.

Morton R, Anderson L, Carter J, Pather S, Saidi SA. Intraoperative Frozen Section of Ovarian Tumors: A 6-Year Review of Performance and Potential Pitfalls in an Australian Tertiary Referral Center. Int J Gynecol Cancer. 2017 Jan;27(1):17-21. Audits of errors and deferrals to improve the diagnostic specificity and sensitivity of intraoperative frozen sections in ovarian cancers.

Cooper WA, Russell PA, Cherian M...Mahar A, et al. Intra- and Inter-Observer Reproducibility Study of PD-L1 Biomarker in Non-Small Cell Lung Cancer. Clin Cancer Res 2017;23:4569-4577. Demonstrated high concordance amongst pathologists for evaluation of PD-L1 expression.

Vargas AC, Selinger C, Satgunaseelan L, Cooper WA, Gupta R,...Scolyer RA, Karim RZ, McCarthy SW, Mahar A, O'Toole SA. FISH analysis of selected soft tissue tumors: Diagnostic experience in a tertiary center. AsiaPac J Clin Oncol 2018;1–10. Highlights the role of FISH in the diagnosis of bone soft tissue tumours.

Egevad L, Cheville J, Evans AJ, Hörnblad J, Kench JG, et al. Pathology Imagebase - A Reference Image Database for Standardization of Pathology. Histopathology 2017;71:677-685 A reference image database for prostate, urinary bladder and renal pathology, to assist pathologists in calibrating their grading, and promote consistency in the diagnosis of difficult cases.

Registrar publications

Registrar-led publications from our department cover all of the categories listed above. A short representative selection follows.

Aivazian K, Long GV, Sinclair E, Kench JG, McKenzie CA.  Histopathology of pembrolizumab-induced hepatitis: a case report. Pathology 2017;49:789-792

Allanson BM, Low TH, Clark JR, Gupta R. Squamous Cell Carcinoma of the External Auditory Canal and Temporal Bone: An Update. Head and Neck Pathol 2018;12:407.

Satgunaseelan L, Chia N, Suh H... Lum T... Gupta R. p16 expression in cutaneous squamous cell carcinoma of the head and neck is not associated with integration of high risk HPV DNA or prognosis. Pathology 2017;49(5):494-498.

Satgunaseelan L, Larsen S, Carmalt H, Cooper WA. Spindle cell variant of diffuse large B cell lymphoma occurring in the breast. Pathology 2017;7:784-786.

Wang S, Wykes J, McKenzie PR,...Gupta R. Quantifying the contribution of pathology to patient management: a review of pathology cases presented at a head and neck multidisciplinary meeting. Pathology 2015;47:S79.

 

Book chapters

Amin MB, Edge S, Greene FL... Scolyer RA, et al. (eds). AJCC Cancer Staging Manual. Springer: New York, 2016.

Scolyer R, Armstrong B, Berti E, et al. Chapters 1,2,3,5 & 6.  WHO Classification of Skin Tumours, Fourth Edition. IARC: Lyon, 2018.

Busam KJ, Gerami P, Scolyer RA (eds). Chapters 9, 14, 20, 26, 27, 32. Pathology of Melanocytic Tumors. Elsevier, 2018.

Jimenez RE, Evans A, Kench JG, et al. Pathologic Assessment and Implications Following Focal Therapy of Prostate Cancer. In: Imaging and Focal Therapy of Early Prostate Cancer.  Second Edition. Ed. Polascik TJ. Springer: New York, 2017.

Kelly JW, de Menezes D, Scolyer RA, et al. Indications and outcomes from different biopsy methods for melanoma: Evidence review and recommendations from new Australian Melanoma Clinical Practice Guidelines Cancer Council Australia Melanoma Guidelines 2017.