Medicine (St Vincent's) - Research Publications

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    OR32-06 Opportunistic Assessment of Pituitary Gland with Routine MRI and PET/CT Can Guide in Earlier and Increased Identification of Hypophysitis in Patients Treated with Combination Checkpoint Inhibitors
    Galligan, A ; Iravani, A ; Lasocki, A ; Wallace, R ; Weppler, A ; Au-Yeung, G ; Sachithanandan, N ; Chiang, CY ; Wentworth, J ; Colman, PG ; Kay, TW ; Krishnamurthy, B ; Sandhu, S ( 2020-05)
    Abstract Background: Hypophysitis is one of the commonly reported adverse events related to immune checkpoint inhibitors (ICI), and the incidence is expected to rise with increased use of combined programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associated protein 4 (CTLA4) blockade. The clinical diagnosis can be delayed due to non-specific symptoms. At our centre, subjects undergo periodic imaging to assess tumour response to ICI. We reviewed whether neuroimaging studies can guide us in the diagnosis of hypophysitis and whether early changes can be detected before the onset of the clinical syndrome. Methods: We retrospectively reviewed the medical charts, biochemistry, structural brain imaging and whole-body positron emission tomography (PET) with specific reference to hypophysitis in 162 patients treated with combination ICI at a tertiary melanoma referral centre. Suspected cases were identified based on meeting one or more of the following criteria: 1) A documented diagnosis of hypophysitis or pituitary dysfunction found on chart review, 2) A relative change in pituitary size or appearance from baseline on neuroimaging studies, or 3) An increase in pituitary maximum standardized uptake value (SUVmax) greater than 25% from baseline on 18F-FDG PET. Results: 58/162 patients (36%) met criteria for suspected hypophysitis. Only 4 patients were identified on routine screening of early morning cortisol. 14 patients presented with symptoms leading to biochemical work up. A further 40 patients were found to have suspicious imaging changes, 13 of which went on to receive a formal diagnosis of hypophysitis. Of the remaining 27 patients, 23 were receiving high dose glucocorticoids for concomitant immune related adverse events at the time of the abnormal imaging study.Conclusion: We report the highest incidence to date of suspected hypophysitis in cohort of patients treated with combination ICI. This study highlights the important role of structural and functional neuroimaging in the early recognition of hypophysitis. Imaging may also play a role when the clinical syndrome is masked by concurrent glucocorticoid use.
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    SUN-127 Diagnostic Challenges Associated with the Rising Incidence of Endocrine Toxicity in the Era of Combination Immunotherapy
    Galligan, A ; Iravani, A ; Lasocki, A ; Wallace, R ; Weppler, A ; Au-Yeung, G ; Sachithanandan, N ; Chiang, CY ; Wentworth, J ; Colman, PG ; Kay, TW ; Krishnamurthy, B ; Sandhu, S ( 2020-05)
    Abstract Background: Immune checkpoint blockade is now established as standard of care in several malignancies. Trials involving combined cytotoxic T lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD1) blockade demonstrate improved tumour responses in melanoma but at the cost of severe grade 3-4 immune related adverse events (irAEs) in 55%, and endocrine irAEs in up to 10% [1]. Immune-mediated damage to endocrine glands can be a diagnostic and management challenge. We aimed to review the incidence, biochemical evolution and imaging findings of endocrine toxicity related to combined anti CTLA-4 and anti-PD-1 therapy. Methods: We undertook a retrospective chart review of patients who received combined ipilimumab and nivolumab for metastatic melanoma at a tertiary referral centre between 2016-2019. We recorded onset and duration of abnormal biochemistry in endocrine irAEs, reviewed all available MRI images for pituitary size (mm) and appearance and 18-F FDG PET images for features of hypophysitis, thyroiditis and pancreatitis. Results: 162 patients received combination therapy. At least one irAE was recorded in 135 patients (83%), 100 (62%) required glucocorticoids, and 84 (52%) had an unplanned hospital presentation due to irAEs. Thyroiditis occurred in 50 (30.9%), with median time to onset of 30.9 days (range 1-234 days). 35 cases were identified with routine biochemistry performed every 4-6 weeks. TSH receptor antibody was measured in 13 patients and all were negative. 29 (58%) developed permanent hypothyroidism. Central cortisol deficiency was documented in 31 (19%) with a median time to diagnosis of 67.5 days (range 5-286). 4 cases were diagnosed on routine biochemistry and 14 presented with symptoms prompting investigation. 13 were diagnosed after routine neuroimaging demonstrated a pituitary abnormality, and a further 27 patients without the clinical syndrome had features of hypophysitis on neuroimaging. New onset diabetes occurred in 3 people, in which pancreatic inflammation on imaging was found in 2. A further 3/5 patients with an asymptomatic elevated lipase were found to have abnormal pancreatic imaging. In one patient with no features of endocrine or exocrine failure, there was a significant increase in FDG uptake and a subsequent loss of pancreatic volume. Conclusion: We report real world incidence of endocrine irAEs with combination immunotherapy. Routine biochemistry leads to the detection of some but not all cases. Early recognition and avoidance of unplanned presentations remains a challenge. Opportunistic assessment of endocrine gland appearance on routine imaging studies may provide useful early diagnostic information. Reference: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. (2015) 1:23-34. 10.1056/NEJMoa1504030
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    INFERRING PATIENT-SPECIFIC PHYSIOLOGICAL PARAMETERS FROM INTRACRANIAL EEG: APPLICATION TO CLINICAL DATA
    Shmuely, S ; Freestone, DR ; Grayden, DB ; Nesic, D ; Cook, M (WILEY-BLACKWELL, 2012-09-01)
    Purpose: Intracranial EEG (iEEG) provides information regarding where and when seizures occur, whilst the underlying mechanisms are hidden. However physiologically plausible mechanisms for seizure generation and termination are explained by neural mass models, which describe the macroscopic neural dynamics. Fusion of models with patient-specific data allows estimation and tracking of the normally hidden physiological parameters. By monitoring changes in physiology, a new understanding of seizures can be achieved. This work addresses model-data fusion for iEEG for application in a clinical setting. Method: Data was recorded from three patients undergoing evaluation for epilepsy-related surgery at St. Vincent's Hospital, Melbourne. Using this data, we created patient-specific neural mass mathematical models based on the formulation of Jansen and Rit (1995). The parameters that were estimated include the synaptic gains, time constants, and the firing threshold. The estimation algorithm utilized the Unscented Kalman Filter (Julier and Uhlmann, 1997). Result: We demonstrate how parameters changed in relation to seizure initiation, evolution and termination. We also show within-patient (across different seizures) and between-patient specificity of the parameter estimates. Conclusion: The fusion of clinical data and mathematical models can be used to infer valuable information about the underlying mechanisms of epileptic seizure generation. This information could be used to develop novel therapeutic strategies
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    INFERRING PATIENT-SPECIFIC PHYSIOLOGICAL PARAMETERS FROM INTRACRANIAL EEG: THEORETICAL STUDIES
    Freestone, DR ; Grayden, DB ; Cook, M ; Nesic, D (WILEY-BLACKWELL, 2012-09)
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    Identification of a Neural Mass Model of Burst Suppression
    Jafarian, A ; Freestone, DR ; Nesic, D ; Grayden, D (IEEE, 2019)
    Burst suppression includes alternating patterns of silent and fast spike activities in neuronal activities observable in micro to macro scale recordings. Biological models of burst suppression are given as dynamical systems with slow and fast states. The aim of this paper is to give a method to identify parameters of a mesoscopic model of burst suppression that can provide insights into study underlying generators of intracranial electroencephalogram (iEEG) data. An optimisation technique based upon a genetic algorithm (GA) is employed to find feasible model parameters to replicate burst patterns in the iEEG data with paroxysmal transitions. Then, a continuous discrete unscented Kalman filter (CD-UKF) is used to infer hidden states of the model and to enhance the identification results from the GA. The results show promise in finding the model parameters of a partially observed mesoscopic model of burst suppression.
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    Endoscopic features of buried Barrett's mucosa: visible to the trained eye?
    Yang, L ; Holt, B ; Williams, R ; Tsoi, E ; Cameron, G ; Desmond, P ; Taylor, A (Wiley, 2019-12-01)
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    Phase 2 Study of Cemiplimab in Patients with Advanced Cutaneous Squamous Cell Carcinoma (CSCC): Longer Follow-Up
    Rischin, D ; Khushalani, N ; Schmults, C ; Guminski, A ; Chang, AL ; Lewis, K ; Lim, A ; Hernandez-Aya, L ; Hughes, B ; Schadendorf, D ; Hauschild, A ; Stankevich, E ; Booth, J ; Yoo, S-Y ; Chen, Z ; Okoye, E ; Lowy, I ; Fury, M ; Migden, M (National Society for Cutaneous Medicine, 2020-10-27)
    Abstract not available.
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    Cemiplimab Improves Health-Related Quality of Life (HRQoL) and Reduces Pain in Patients with Advanced Cutaneous Squamous Cell Carcinoma (CSCC): Results from a Post Hoc Exploratory Analysis of a Phase 2 Clinical Trial
    Migden, M ; Rischin, D ; Sasane, M ; Mastey, V ; Pavlick, A ; Schmults, C ; Chen, Z ; Guminski, A ; Hauschild, A ; Bury, D ; Hudgens, S ; Chang, AL ; Rabinowits, G ; Ibrahim, S ; Fury, M ; Lowy, I ; Li, S ; Chen, C-I (National Society for Cutaneous Medicine, 2021-01-01)
    Abstract not available.
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    The Victorian Comprehensive Cancer Centre lung cancer clinical audit: collecting the UK National Lung Cancer Audit data from hospitals in Australia
    Mileshkin, L ; Dunn, C ; Cross, H ; Duffy, M ; Shaw, M ; Antippa, P ; Mitchell, P ; Akhurst, T ; Conron, M ; Moore, M ; Philip, J ; Bartlett, J ; Emery, J ; Zambello, B (WILEY, 2019-08)
    BACKGROUND: Clinical audit may improve practice in cancer service provision. The UK National Lung Cancer Audit (NLCA) collects data for all new cases of thoracic cancers. AIM: To collect similar data for our Victorian patients from six hospitals within the Victorian Comprehensive Cancer Centre and associated Western and Central Melbourne Integrated Cancer Service. METHODS: We conducted a retrospective audit of all newly diagnosed patients with lung cancer and mesothelioma in 2013 across the six Victorian Comprehensive Cancer Centre/Western and Central Melbourne Integrated Cancer Service hospitals. The objectives were to adapt the NLCA data set for use in the Australian context, to analyse the findings using descriptive statistics and to determine feasibility of implementing a routine, ongoing audit similar to that in the UK. Individual data items were adapted from the NLCA by an expert steering committee. Data were collated from the Victorian Cancer Registry, Victorian Admitted Episodes Dataset and individual hospital databases. Individual medical records were audited for missing data. RESULTS: Eight hundred and forty-five patients were diagnosed across the sites in 2013. Most were aged 65-80 (55%) and were male (62%). Most had non-small-cell lung cancer (81%) with 9% diagnosed with small cell lung cancer and 2% with mesothelioma. Data completeness varied significantly between fields. For those with higher levels of completeness, headline indicators of clinical care were comparable with NLCA data. The Victorian population seem to lack access to specialist lung cancer nurse services. CONCLUSION: Lung cancer care at participating hospitals appeared to be comparable with the UK in 2013. In future, prospective data collection should be harmonised across sites and correlated with survival outcomes. One area of concern was a lack of documented access to specialist nursing services.
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    A case of actinic granuloma responding to oral retinoids
    Kok, Y ; Braue, A ; Martyres, R ; Varigos, G (WILEY, 2019-05)