Medicine (St Vincent's) - Research Publications

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    Epidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study
    Tan, N ; Ngu, N ; Worland, T ; Lee, T ; Abrahams, T ; Pandya, K ; Freeman, E ; Hannah, N ; Gazelakis, K ; Madden, RG ; Lynch, KD ; Valaydon, Z ; Sood, S ; Dev, A ; Bell, S ; Thompson, A ; Ding, J ; Nicoll, AJ ; Liu, K ; Gow, P ; Lubel, J ; Kemp, W ; Roberts, SK ; Majeed, A (SPRINGER, 2022-06-03)
    BACKGROUND AND AIMS: Little is known regarding the epidemiology and outcomes of patients with primary sclerosing cholangitis (PSC) in Australia. We, therefore, evaluated the epidemiology and clinical outcomes of PSC in a large cohort of Australian patients and compared these to the general population. METHODS: We conducted a multicentre, retrospective cohort study of PSC patients at nine tertiary liver centers across three Australian states, including two liver transplant centers. RESULTS: A total of 413 PSC patients with 3,285 person-years of follow-up were included. Three hundred and seventy-one (90%) patients had large duct PSC and 294 (71%) had associated inflammatory bowel disease. A total of 168 (41%) patients developed cirrhosis (including 34 at the time of PSC diagnosis) after a median of 15.8 (95% CI 12.4, NA) years. The composite endpoint of death or liver transplantation occurred in 49 (12%) and 78 (19%) patients, respectively, with a median transplant-free survival of 13.4 (95% CI 12.2-15) years. Compared to the general population, PSC accounted for a 240-fold increased risk of development of cholangiocarcinoma (CCA) and CCA-related death. CCA risk was increased with older age of PSC diagnosis, presence of dominant stricture and colectomy. Compared to same-aged counterparts in the general population, PSC patients who were diagnosed at an older age or with longer disease duration had reduced relative survival. CONCLUSION: In this large retrospective cohort study of PSC patients in Australia, increased age and time from diagnosis was associated with increased mortality and morbidity particularly from CCA and development of cirrhosis, necessitating need for liver transplant.
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    The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee.
    Campo, E ; Jaffe, ES ; Cook, JR ; Quintanilla-Martinez, L ; Swerdlow, SH ; Anderson, KC ; Brousset, P ; Cerroni, L ; de Leval, L ; Dirnhofer, S ; Dogan, A ; Feldman, AL ; Fend, F ; Friedberg, JW ; Gaulard, P ; Ghia, P ; Horwitz, SM ; King, RL ; Salles, G ; San-Miguel, J ; Seymour, JF ; Treon, SP ; Vose, JM ; Zucca, E ; Advani, R ; Ansell, S ; Au, W-Y ; Barrionuevo, C ; Bergsagel, L ; Chan, WC ; Cohen, JI ; d'Amore, F ; Davies, A ; Falini, B ; Ghobrial, IM ; Goodlad, JR ; Gribben, JG ; Hsi, ED ; Kahl, BS ; Kim, W-S ; Kumar, S ; LaCasce, AS ; Laurent, C ; Lenz, G ; Leonard, JP ; Link, MP ; Lopez-Guillermo, A ; Mateos, MV ; Macintyre, E ; Melnick, AM ; Morschhauser, F ; Nakamura, S ; Narbaitz, M ; Pavlovsky, A ; Pileri, SA ; Piris, M ; Pro, B ; Rajkumar, V ; Rosen, ST ; Sander, B ; Sehn, L ; Shipp, MA ; Smith, SM ; Staudt, LM ; Thieblemont, C ; Tousseyn, T ; Wilson, WH ; Yoshino, T ; Zinzani, P-L ; Dreyling, M ; Scott, DW ; Winter, JN ; Zelenetz, AD (American Society of Hematology, 2022-09-15)
    Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.
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    Long-term safety for patients with tisagenlecleucel-treated relapsed/refractory diffuse large B-cell lymphoma
    Jaeger, U ; Tam, CS ; Borchmann, P ; McGuirk, JP ; Johansen, M ; Waller, EK ; Jaglowski, S ; Andreadis, C ; Foley, SR ; Westin, JR ; Fleury, I ; Ho, PJ ; Mielke, S ; Teshima, T ; Salles, G ; Schuster, SJ ; He, F ; Maziarz, RT ; Mayer, S ; Makita, S ; Kersten, MJ ; Ghosh, M ; Wagner-Johnston, N ; Kato, K ; Corradini, P ; Goto, H ; Colicino, S ; Agarwal, A ; Lobetti-Bodoni, C ; Bishop, MR (ELSEVIER, 2022-08-23)
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    Depth of response and response kinetics of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma
    Martin, T ; Mikhael, J ; Hajek, R ; Kim, K ; Suzuki, K ; Hulin, C ; Garg, M ; Quach, H ; Sia, H ; George, A ; Konstantinova, T ; Risse, M-L ; Asset, G ; Mace, S ; van de Velde, H ; Moreau, P (ELSEVIER, 2022-08-09)
    The IKEMA study (Randomized, Open Label, Multicenter Study Assessing the Clinical Benefit of Isatuximab Combined With Carfilzomib [Kyprolis®] and Dexamethasone Versus Carfilzomib With Dexamethasone in Patients With Relapse and/or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines; #NCT03275285) was a randomized, open-label, multicenter phase 3 study investigating isatuximab plus carfilzomib and dexamethasone (Isa-Kd) vs Kd in patients with relapsed multiple myeloma. This subanalysis analyzed the depth of response of Isa-Kd vs Kd. The primary end point was progression-free survival (PFS); secondary end points included overall response rate, very good partial response or better (≥VGPR) rate, complete response (CR) rate, and minimal residual disease (MRD) negativity rate (assessed in patients with ≥VGPR by next-generation sequencing at a 10-5 sensitivity level). At a median follow-up of 20.7 months, deeper responses were observed in the Isa-Kd arm vs the Kd arm, with ≥VGPR 72.6% vs 56.1% and CR of 39.7% vs 27.6%, respectively. MRD negativity occurred in 53 (29.6%) of 179 patients in the Isa-Kd arm vs 16 (13.0%) of 123 patients in the Kd arm, with 20.1% (Isa-Kd, 36 of 179 patients) vs 10.6% (Kd, 13 of 123 patients) reaching MRD-negative CR status. Achieving MRD negativity resulted in better PFS in both arms. A positive PFS treatment effect was seen with Isa-Kd in both MRD-negative patients (hazard ratio, 0.578; 95% CI, 0.052-6.405) and MRD-positive patients (hazard ratio, 0.670; 95% CI, 0.452-0.993). Exploratory analysis indicates that both current CR and MRD-negative CR rates are underestimated due to M-protein interference (potential adjusted CR rate, 45.8%; potential adjusted MRD-negative CR rate, 24.0%). In conclusion, there was a clinically meaningful improvement in depth of response with Isa-Kd. The CR rate in Isa-Kd was 39.7%. Mass spectrometry suggests that the potential adjusted CR rate could reach an unprecedented 45.8% of patients treated with Isa-Kd.
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    Myocardial fibrosis and arrhythmic burden in systemic sclerosis
    Ross, L ; Costello, B ; Brown, Z ; Hansen, D ; Lindqvist, A ; Stevens, W ; Burns, A ; Prior, D ; Nikpour, M ; La Gerche, A (OXFORD UNIV PRESS, 2022-02-08)
    OBJECTIVES: Cardiac complications of SSc are a leading cause of SSc-associated death. Cardiac imaging for identifying substrate abnormality may be useful in predicting risk of cardiac arrhythmias or future cardiac failure. The aim of this study was to quantify the burden of asymptomatic fibro-inflammatory myocardial disease using cardiac magnetic resonance imaging (CMR) and assess the relationship between asymptomatic myocardial fibrosis and cardiac arrhythmias in SSc. METHODS: Thirty-two patients with SSc with no documented history of pulmonary vascular or heart disease underwent CMR with gadolinium and 24-h ambulatory ECG. Focal myocardial fibrosis was assessed using post-gadolinium imaging and diffuse fibro-inflammatory myocardial disease quantified using T1- and T2-mapping. CMR results were compared with an age- and sex-matched control group. RESULTS: Post-gadolinium focal fibrosis was prevalent in SSc but not controls (30% vs 0%, p < 0.01).. T1-mapping values (as a marker of diffuse fibrosis) were greater in SSc than controls [saturated recovery single-shot acquisition (SASHA): 1584 ms vs 1515 ms, P < 0.001; shortened Modified look locker sequence (ShMOLLI): 1218 ms vs 1138 ms, p < 0.001]. More than one-fifth (22.6%) of the participants had ventricular arrhythmias on ambulatory ECG, but no associations between focal or diffuse myocardial fibrosis and arrhythmias were evident. CONCLUSION: In SSc patients without evidence of overt cardiac disease, a high burden of myocardial fibrosis and arrhythmias was identified. However, there was no clear association between focal or diffuse myocardial fibrosis and arrhythmias, suggesting CMR may have limited use as a screening tool to identify SSc patients at risk of future significant arrhythmias.
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    Impact of a Mediterranean diet on hepatic and metabolic outcomes in non-alcoholic fatty liver disease: The MEDINA randomised controlled trial
    George, ES ; Reddy, A ; Nicoll, AJ ; Ryan, MC ; Itsiopoulos, C ; Abbott, G ; Johnson, NA ; Sood, S ; Roberts, SK ; Tierney, AC (WILEY, 2022-04-26)
    BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is predominantly managed by lifestyle intervention, in the absence of effective pharmacotherapies. Mediterranean diet (MedDiet) is the recommended diet, albeit with limited evidence. AIMS: To compare an ad libitum MedDiet to low-fat diet (LFD) in patients with NAFLD for reducing intrahepatic lipids (IHL) by proton magnetic resonance spectroscopy (1 H-MRS). Secondary outcomes include insulin resistance by homeostatic model of assessment (HOMA-IR), visceral fat by bioelectrical impedance analysis (BIA), liver stiffness measurement (LSM) and other metabolic outcomes. METHODS: In this parallel multicentre RCT, subjects were randomised (1:1) to MedDiet or LFD for 12 weeks. RESULTS: Forty-two participants (25 females [60%], mean age 52.3 ± 12.6 years) were included, 23 randomised to LFD and 19 to MedDiet.; 39 completed the study. Following 12 weeks, there were no between-group differences. IHL improved significantly within the LFD group (-17% [log scale]; p = .02) but not within the MedDiet group (-8%, p = .069). HOMA-IR reduced in the LFD group (6.5 ± 5.6 to 5.5 ± 5.5, p < .01) but not in the MedDiet group (4.4 ± 3.2 to 3.9 ± 2.3, p = .07). No differences were found for LSM (MedDiet 7.8 ± 4.0 to 7.6 ± 5.2, p = .429; LFD 11.8 ± 14.3 to 10.8 ± 10.2 p = .99). Visceral fat reduced significantly in both groups; LFD (-76% [log scale], p = <.0005), MedDiet (-61%, p = <.0005). CONCLUSIONS: There were no between-group differences for hepatic and metabolic outcomes when comparing MedDiet to LFD. LFD improved IHL and insulin resistance. Significant improvements in visceral fat were seen within both groups. This study highlights provision of dietary interventions in free-living adults with NAFLD is challenging.
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    The current understanding of precision medicine and personalised medicine in selected research disciplines: study protocol of a systematic concept analysis
    Brew-Sam, N ; Parkinson, A ; Lueck, C ; Brown, E ; Brown, K ; Bruestle, A ; Chisholm, K ; Collins, S ; Cook, M ; Daskalaki, E ; Drew, J ; Ebbeck, H ; Elisha, M ; Fanning, V ; Henschke, A ; Herron, J ; Matthews, E ; Murugappan, K ; Neshev, D ; Nolan, CJ ; Pedley, L ; Phillips, C ; Suominen, H ; Tricoli, A ; Wright, K ; Desborough, J (BMJ, 2022-09-07)
    Introduction The terms ‘precision medicine’ and ‘personalised medicine’ have become key terms in health-related research and in science-related public communication. However, the application of these two concepts and their interpretation in various disciplines are heterogeneous, which also affects research translation and public awareness. This leads to confusion regarding the use and distinction of the two concepts. Our aim is to provide a snapshot of the current understanding of these concepts. Methods and analysis Our study will use Rodgers’ evolutionary concept analysis to systematically examine the current understanding of the concepts ‘precision medicine’ and ‘personalised medicine’ in clinical medicine, biomedicine (incorporating genomics and bioinformatics), health services research, physics, chemistry, engineering, machine learning and artificial intelligence, and to identify their respective attributes (clusters of characteristics) and surrogate and related terms. A systematic search of the literature will be conducted for 2016–2022 using databases relevant to each of these disciplines: ACM Digital Library, CINAHL, Cochrane Library, F1000Research, IEEE Xplore, PubMed/Medline, Science Direct, Scopus and Web of Science. These are among the most representative databases for the included disciplines. We will examine similarities and differences in definitions of ‘precision medicine’ and ‘personalised medicine’ in the respective disciplines and across (sub)disciplines, including attributes of each term. This will enable us to determine how these two concepts are distinguished. Ethics and dissemination Following ethical and research standards, we will comprehensively report the methodology for a systematic analysis following Rodgers’ concept analysis method. Our systematic concept analysis will contribute to the clarification of the two concepts and distinction in their application in given settings and circumstances. Such a broad concept analysis will contribute to non-systematic syntheses of the concepts, or occasional systematic reviews on one of the concepts that have been published in specific disciplines, in order to facilitate interdisciplinary communication, translational medical research and implementation science.
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    Moving the field forward: detection of epileptiform abnormalities on scalp electroencephalography using deep learning-clinical application perspectives.
    Janmohamed, M ; Nhu, D ; Kuhlmann, L ; Gilligan, A ; Tan, CW ; Perucca, P ; O'Brien, TJ ; Kwan, P (Oxford University Press (OUP), 2022)
    The application of deep learning approaches for the detection of interictal epileptiform discharges is a nascent field, with most studies published in the past 5 years. Although many recent models have been published demonstrating promising results, deficiencies in descriptions of data sets, unstandardized methods, variation in performance evaluation and lack of demonstrable generalizability have made it difficult for these algorithms to be compared and progress to clinical validity. A few recent publications have provided a detailed breakdown of data sets and relevant performance metrics to exemplify the potential of deep learning in epileptiform discharge detection. This review provides an overview of the field and equips computer and data scientists with a synopsis of EEG data sets, background and epileptiform variation, model evaluation parameters and an awareness of the performance metrics of high impact and interest to the trained clinical and neuroscientist EEG end user. The gold standard and inter-rater disagreements in defining epileptiform abnormalities remain a challenge in the field, and a hierarchical proposal for epileptiform discharge labelling options is recommended. Standardized descriptions of data sets and reporting metrics are a priority. Source code-sharing and accessibility to public EEG data sets will increase the rigour, quality and progress in the field and allow validation and real-world clinical translation.
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    Development of an Australia and New Zealand Lung Cancer Clinical Quality Registry: a protocol paper
    Smith, S ; Brand, M ; Harden, S ; Briggs, L ; Leigh, L ; Brims, F ; Brooke, M ; Brunelli, VN ; Chia, C ; Dawkins, P ; Lawrenson, R ; Duffy, M ; Evans, S ; Leong, T ; Marshall, H ; Patel, D ; Pavlakis, N ; Philip, J ; Rankin, N ; Singhal, N ; Stone, E ; Tay, R ; Vinod, S ; Windsor, M ; Wright, GM ; Leong, D ; Zalcberg, J ; Stirling, RG (BMJ PUBLISHING GROUP, 2022-08-01)
    INTRODUCTION: Lung cancer is the leading cause of cancer mortality, comprising the largest national cancer disease burden in Australia and New Zealand. Regional reports identify substantial evidence-practice gaps, unwarranted variation from best practice, and variation in processes and outcomes of care between treating centres. The Australia and New Zealand Lung Cancer Registry (ANZLCR) will be developed as a Clinical Quality Registry to monitor the safety, quality and effectiveness of lung cancer care in Australia and New Zealand. METHODS AND ANALYSIS: Patient participants will include all adults >18 years of age with a new diagnosis of non-small-cell lung cancer (NSCLC), SCLC, thymoma or mesothelioma. The ANZLCR will register confirmed diagnoses using opt-out consent. Data will address key patient, disease, management processes and outcomes reported as clinical quality indicators. Electronic data collection facilitated by local data collectors and local, state and federal data linkage will enhance completeness and accuracy. Data will be stored and maintained in a secure web-based data platform overseen by registry management. Central governance with binational representation from consumers, patients and carers, governance, administration, health department, health policy bodies, university research and healthcare workers will provide project oversight. ETHICS AND DISSEMINATION: The ANZLCR has received national ethics approval under the National Mutual Acceptance scheme. Data will be routinely reported to participating sites describing performance against measures of agreed best practice and nationally to stakeholders including federal, state and territory departments of health. Local, regional and (bi)national benchmarks, augmented with online dashboard indicator reporting will enable local targeting of quality improvement efforts.
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    How toxic is an old friend? A review of the safety of hydroxychloroquine in clinical practice.
    Fairley, JL ; Nikpour, M ; Mack, HG ; Brosnan, M ; Saracino, AM ; Pellegrini, M ; Wicks, IP (Wiley, 2022-08-15)
    Hydroxychloroquine (HCQ) and its close relative chloroquine (CQ) were initially used as antimalarial agents but are now widely prescribed in rheumatology, dermatology and immunology for the management of autoimmune diseases. HCQ is considered to have a better long-term safety profile than CQ and is therefore more commonly used. HCQ has a key role in the treatment of connective tissue diseases including systemic lupus erythematosus (SLE), where it provides beneficial immunomodulation without clinically significant immunosuppression. HCQ can also assist in managing inflammatory arthritis, including rheumatoid arthritis (RA). Debate around toxicity of HCQ in COVID-19 has challenged those who regularly prescribe HCQ to discuss its potential toxicities. Accordingly, we have reviewed the adverse effect profile of HCQ to provide guidance about this therapeutic agent in clinical practice.