Medicine (St Vincent's) - Research Publications
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ItemCD30-positive lymphoproliferative disorders-An Australian Clinical Practice Statement from the Peter MacCallum Cancer Centre.(Wiley, 2023-05)The CD30-postive lymphoproliferative disorders, including lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, account for up to 30% of all cutaneous T-cell lymphomas (CTCLs) and are the second most common form of CTCLs after mycosis fungoides. Both conditions differ in their clinical presentations; however, they share the expression of the CD30 antigen as a common immunophenotypic hallmark. There is a wide spectrum of management options depending on factors such as extent of disease, staging and treatment tolerability. This Clinical Practice Statement is reflective of the current clinical practice in Australia.
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ItemProspective comprehensive profiling of immune responses to COVID-19 vaccination in patients on zanubrutinib therapy.(Wiley, 2023-02)Zanubrutinib-treated and treatment-naïve patients with chronic lymphocytic leukaemia (CLL) or Waldenstrom's macroglobulinaemia were recruited in this prospective study to comprehensively profile humoral and cellular immune responses to COVID-19 vaccination. Overall, 45 patients (median 72 years old) were recruited; the majority were male (71%), had CLL (76%) and were on zanubrutinib (78%). Seroconversion rates were 65% and 77% following two and three doses, respectively. CD4+ and CD8+ T-cell response rates increased with third dose. In zanubrutinib-treated patients, 86% developed either a humoral or cellular response. Patients on zanubrutinib developed substantial immune responses following two COVID-19 vaccine doses, which further improved following a third dose.
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ItemRetinal ganglion cell-specific genetic regulation in primary open-angle glaucoma.(Elsevier BV, 2022-06-08)To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared with those from healthy individuals. We performed single-cell RNA sequencing of a total of 247,520 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 4,443 significant loci across all cell types, 312 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 97 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.
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ItemCommunication about early palliative care: A qualitative study of oncology providers' perspectives of navigating the artful introduction to the palliative care team(FRONTIERS MEDIA SA, 2022-12-09)BACKGROUND: Despite robust evidence for the integration of early palliative care for patients with advanced cancer, many patients still access this approach to care late. Communication about the introduction of Early Palliative Care is an important skill of healthcare providers working in this setting. In the context of limited community understanding about palliative care, patients and their families may express fear or negative reactions to its early introduction. Health professionals may lack the confidence or skill to describe the role and benefits of early palliative care. AIM: This study sought to explore clinicians' perspectives on communication about referral to early palliative care, specifically identifying facilitators in undertaking this communication task. METHODS: An exploratory qualitative study set within a tertiary oncology service in Victoria, Australia. Semi-structured interviews were conducted with purposively sampled oncology clinicians exploring their perspectives on communication about referral to early palliative care. A reflexive thematic analysis was undertaken by two researchers, including both latent and semantic coding relevant to the research question. Reporting of the research was guided by the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist. RESULTS: Twelve oncology clinicians (58% female, with 67% > 15 years clinical experience) from medical oncology, surgical oncology, and haematology participated. The artful navigation of communication about early palliative care was characterised by the need for a 'spiel' involving the adoption of a series of strategies or 'tactics' when introducing this service. These themes included: 1) Using carefully selected and rehearsed language; 2) Framing in terms of symptom control; 3) Framing as additive to patient care; 4) Selling the service benefits of early palliative care; 5) Framing acceptance of referral as an altruistic act; and 6) Adopting a phased approach to delivering information about palliative care. IMPLICATIONS: This study highlights the wide ranging and innovative communication strategies and skills required by health professionals to facilitate referral to early palliative care for cancer patients and their families. Future focus on upskilling clinicians around communication of this topic will be important to ensure successful implementation of models of early palliative care in routine cancer care.
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ItemCompulsive-like eating of high-fat high-sugar food is associated with 'addiction-like' glutamatergic dysfunction in obesity prone rats(WILEY, 2022-09-01)Chronic overeating is a core feature of diet-induced obesity. There is increasing evidence that in vulnerable individuals, such overeating could become compulsive, resembling an addictive disorder. The transition to compulsive substance use has been linked with changes at glutamatergic synapses in the nucleus accumbens. In this study, we investigated a potential link between such glutamatergic dysregulation and compulsive-like eating using a rat model of diet-induced obesity. A conditioned suppression task demonstrated that diet-induced obese rats display eating despite negative consequences, as their consumption was insensitive to an aversive cue. Moreover, nucleus accumbens expression of GluA1 and xCT proteins was upregulated in diet-induced obese animals. Lastly, both a computed 'addiction score' (based on performance across three criteria) and weight gain were positively correlated with changes in GluA1 and xCT expression in the nucleus accumbens. These data demonstrate that the propensity for diet-induced obesity is associated with compulsive-like eating of highly palatable food and is accompanied by 'addiction-like' glutamatergic dysregulation in the nucleus accumbens, thus providing neurobiological evidence of addiction-like pathology in this model of obesity.
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ItemJAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2018-06-01)Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
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ItemDietary intake of animal-based products and likelihood of follicular lymphoma and survival: A population-based family case-control study(FRONTIERS MEDIA SA, 2023-01-04)BACKGROUND: The association between dietary intake of foods of animal origin and follicular lymphoma (FL) risk and survival is uncertain. In this study, we examined the relationship between dietary intake of dairy foods and fats, meat, fish and seafoods, and the likelihood of FL and survival. METHODS: We conducted a population-based family case-control study in Australia between 2011 and 2016 and included 710 cases, 303 siblings and 186 spouse/partner controls. We assessed dietary intake of animal products prior to diagnosis (the year before last) using a structured food frequency questionnaire and followed-up cases over a median of 6.9 years using record linkage to national death data. We examined associations with the likelihood of FL using logistic regression and used Cox regression to assess association with all-cause and FL-specific mortality among cases. RESULTS: We observed an increased likelihood of FL with increasing daily quantity of oily fish consumption in the year before last (highest category OR = 1.96, CI = 1.02-3.77; p-trend 0.06) among cases and sibling controls, but no associations with spouse/partner controls. We found no association between the likelihood of FL and the consumption of other types of fish or seafood, meats or dairy foods and fats. In FL cases, we found no association between meat or oily fish intake and all-cause or FL-specific mortality. CONCLUSION: Our study showed suggestive evidence of a positive association between oily fish intake and the likelihood of FL, but findings varied by control type. Further investigation of the potential role of environmental contaminants in oily fish on FL etiology is warranted.
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ItemNo Preview AvailableShortages of oral antiseizure medications and estimation of the number of patients impacted by shortages in Australia(Epilepsy Society of Australia, 2021)
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ItemNo Preview AvailableAntiseizure medication shortages are associated with increased product switching: an analysis of levetiracetam(AESNet, 2021)Rationale: Product switching (brand/manufacturer or dose/formulation of the same drug) is associated with non-adherence and breakthrough seizures in patients with epilepsy. Rates of product switching and discontinuation were characterized in patients on levetiracetam (LEV) brands experiencing shortages in Australia, and compared with non-shortage periods to understand how antiseizure medication (ASM) shortages affect product switching and discontinuation in patients with epilepsy. LEV was chosen as the focus due to multiple shortages in the Medicine Shortage Information Initiative (MSII), widespread usage in multiple seizure types and ages, and limited use outside epilepsy. Methods: Data were obtained from the Australian Therapeutic Goods Administration MSII on all LEV shortages between Jan 2019 and Nov 2020. Shortage dates were cross-referenced with IQVIA-NostraData Longitudinal Dispensation data, which collects pharmacy dispensing data from 25 million patients in Australia with 75% coverage of retail pharmacies nationwide. Patients dispensed a LEV product (brand-formulation-strength combination) appearing in MSII in the 90 days before a shortage were designated as “on therapy.” Patients on therapy and with two consecutive dispensations of a relevant product before start of a shortage were classified as “continuing” (only dispensation of index product throughout shortage), “switching” (dispensation of ≥ 1 different LEV ASM during the shortage), or “discontinuing” (no further LEV dispensations throughout shortage). Switching patterns were compared with the corresponding (non-shortage) period in the prior year to estimate how shortages were associated with rates of product switching and discontinuation. Results: 118 LEV product shortages were identified and 100% were generic brands. Overlapping shortages of same product were consolidated, leaving 23 distinct shortages (Table 1). Median shortage was 133 days (interquartile range 80, 229.5). Of 11 government funded generic brands of LEV, seven (64%) were affected by shortages over 23 months, representing 93% of total volume of generic LEV dispensed over study period. 46,037 patients had ≥ 1 dispensation for generic LEV over study period. 43,531 (95%) of these patients (non-unique) were affected by shortages. Across all shortages, 24% of patients on therapy at point of shortage continued on therapy across the shortage period vs 46% (non-shortage periods); 68% switched to a different product vs 47% (non-shortage periods); 8% discontinued LEV in shortage periods vs 7% (non-shortage periods) (Table 1). Conclusions: Shortages affected most brands of generic LEV in Australia, but not the originator brand Keppra. Shortages were associated with increased product switching compared with non-shortage periods. The results suggest that consideration may be necessary when initiating or switching patients to generic ASM brands due to high rates of generic ASMs being in shortage, and associated product switching in shortage periods, which in independent research has been associated with non-adherence and breakthrough seizures. Funding: Please list any funding that was received in support of this abstract.: UCB Pharma-funded.
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ItemPeripheral neuropathy in the hands of people with diabetes mellitus(ELSEVIER IRELAND LTD, 2016-09-01)AIMS: Peripheral sensorimotor neuropathy is a recognised complication of diabetes mellitus however little attention has been given to its development in the hands. The aim of this study was to determine the prevalence of sensory impairment in the hands of participants with diabetes, the agreement between two measurement tools for assessing sensation and the association between hand sensibility, age, glycaemic control and end-organ damage. METHODS: A total of 162 participants were recruited and divided into two cohorts based on a diagnosis of diabetes. Participants were tested for the presence of hand neuropathy using Semmes-Weinstein monofilaments and the AsTex™. Medical records of participants with diabetes were accessed retrospectively to determine glycaemic control and diabetes complications. RESULTS: A highly statistically significant association was found between neuropathy and diabetes status (P<0.001) on monofilament testing. The prevalence of neuropathy was 64% compared to ∼10% amongst participants without diabetes. Age, male gender and diabetic retinopathy were associated with neuropathy. The AsTex™ identified participants with diminished protective sensation on monofilament testing. CONCLUSIONS: This study demonstrates a relationship between diabetes and upper limb neuropathy. Age, male gender and retinopathy were associated with diminished hand sensation. The AsTex™ may have a role as a screening tool for identifying clinically significant hand neuropathy.