Medicine (St Vincent's) - Research Publications

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    Chronic intracranial EEG recordings and interictal spike rate reveal multiscale temporal modulations in seizure states
    Schroeder, GM ; Karoly, PJ ; Maturana, M ; Panagiotopoulou, M ; Taylor, PN ; Cook, MJ ; Wang, Y (OXFORD UNIV PRESS, 2023-08-31)
    Many biological processes are modulated by rhythms on circadian and multidien timescales. In focal epilepsy, various seizure features, such as spread and duration, can change from one seizure to the next within the same patient. However, the specific timescales of this variability, as well as the specific seizure characteristics that change over time, are unclear. Here, in a cross-sectional observational study, we analysed within-patient seizure variability in 10 patients with chronic intracranial EEG recordings (185-767 days of recording time, 57-452 analysed seizures/patient). We characterized the seizure evolutions as sequences of a finite number of patient-specific functional seizure network states. We then compared seizure network state occurrence and duration to (1) time since implantation and (2) patient-specific circadian and multidien cycles in interictal spike rate. In most patients, the occurrence or duration of at least one seizure network state was associated with the time since implantation. Some patients had one or more seizure network states that were associated with phases of circadian and/or multidien spike rate cycles. A given seizure network state's occurrence and duration were usually not associated with the same timescale. Our results suggest that different time-varying factors modulate within-patient seizure evolutions over multiple timescales, with separate processes modulating a seizure network state's occurrence and duration. These findings imply that the development of time-adaptive treatments in epilepsy must account for several separate properties of epileptic seizures and similar principles likely apply to other neurological conditions.
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    Discontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis
    Hall, SAL ; Vogrin, S ; Wawryk, O ; Burns, GS ; Visvanathan, K ; Sundararajan, V ; Thompson, A (BMJ PUBLISHING GROUP, 2022-08)
    BACKGROUND AND AIMS: Sustained virological suppression and hepatitis B surface antigen (HBsAg) loss have been described after nucleot(s)ide analogue (NA) discontinuation for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We performed a meta-analysis of the clinical outcomes after NA discontinuation for HBeAg-negative CHB. METHODS: Studies involving NA cessation in HBeAg-negative CHB individuals with a median follow-up of ≥12 months were included. Participants were HBeAg-negative at the time of NA initiation. Random effects meta-analyses were performed for the following clinical outcomes: (1) virological relapse (VR) at 6 and 12 months; (2) clinical relapse (CR) at 6 and 12 months and (3) HBsAg loss. Effect of other variables was estimated using subgroup analysis and meta-regression. Studies including patients stopping entecavir (ETV) and/or tenofovir disoproxil fumarate (TDF) were considered separately to studies including patients stopping older generation NA. RESULTS: N=37 studies met inclusion criteria. Cumulative incidence of VR and CR after stopping ETV/TDF was 44% and 17% at 6 months and 63% and 35% at 12 months. Similar relapse rates were observed after stopping older NAs. Among patients stopping ETV/TDF, TDF cessation was associated with increased CR rates at 6 months versus ETV. There was an association between follow-up ≥4 years and HBsAg loss rates when stopping older NAs. Hepatic decompensation and hepatocellular carcinoma were rare but occurred more frequently in studies including cirrhotic individuals. CONCLUSION: VR is common after NA discontinuation, however, CR was only seen in one-third of patients at 12 months. Stopping NA therapy can be followed by HBsAg clearance, and rates are higher with longer follow-up.
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    IS QUALITY OF LIFE RECOVERY ASSOCIATED WITH LOWER MORTALITY 5 YEARS POST-FRACTURE IN COMMUNITY-DWELLING OLDER ADULTS?
    Talevski, J ; Sanders, K ; Vogrin, S ; Beauchamp, A ; Seeman, E ; Iuliano, S ; Svedbom, A ; Borgstrom, F ; Kanis, J ; Brennan-Olsen, S (SPRINGER LONDON LTD, 2022-04)
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    A PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMOURS AND ATYPICAL TERATOID RHABDOID TUMOURS
    Wood, P ; Desai, J ; Waldeck, K ; Cain, J ; Gottardo, N ; Strong, R ; Kinross, K ; Carr, M ; Jones, J ; Wong, L ; Ziegler, D ; Hansford, J ; Michael, M ; Ashley, D (OXFORD UNIV PRESS INC, 2022-06)
    Abstract BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumours (MRT) and atypical teratoid rhabdoid tumours (ATRT) in pre-clinical models. We report results of the open label, phase II study of oral panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumour activity of low dose, continuous oral panobinostat as well as its associated toxicities. To assess the biological activity of low dose panobinostat by measuring histone H4 acetylation status in peripheral mononuclear cells (PMNC), and differentiation markers. METHODS: Following primary institutional standard of care induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2/day, with a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat at different dosing levels. Patients were monitored for toxicity; dose reductions were in decrements of 2mg/m2/day. RESULTS: A total of 13 patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled. The average age at enrollment was 3.6 years (range 0.8-6.8 years). The mean treatment duration was 206 days (13-344 days). Currently, six patients (42.9%) remain on study with a mean study duration of 531 days (range 13-895 days). 6/14 patients (42.9%) were removed due to disease progression at a mean study duration of 245 days (44-560 days). 2/14 patients (14.3%) withdrew due to toxicity. 12/14 patients (85.7%) required dose reductions. The main toxicities were thrombocytopaenia and leukopaenia (Grade III-IV). Real-time pharmacodynamic assessment of panobinostat, at a dose as low as 6mg/m2/day resulted in significant acetylation of histone H4 in PMNC. CONCLUSIONS: Treatment with low dose panobinostat is well tolerated in infants and children with MRT/ATRT, with significant acetylation of histone H4 in PMNC.
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    Childhood antibiotics as a risk factor for Crohn's disease: The ENIGMA International Cohort Study
    Mak, JWY ; Yang, S ; Stanley, A ; Lin, X ; Morrison, M ; Ching, JYL ; Niu, J ; Wilson-O'Brien, AL ; Feng, R ; Tang, W ; Hamilton, AL ; Or, L ; Trakman, GL ; Lin, WYY ; Sung, JJY ; Chen, MH ; Mao, Y ; Kamm, MA ; Ng, SC (WILEY, 2022-06)
    BACKGROUND AND AIM: Environmental factors play a key role in development of Crohn's disease (CD), thought to be mediated by changes in the gut microbiota. We aimed to delineate the potential contribution of antibiotic exposure to subsequent development of CD, across diverse geographical populations. METHODS: This case-control study in Australia and three cities in China (Hong Kong, Guangzhou, and Kunming) included four groups: patients with CD, at-risk individuals including non-affected first-degree relatives (FDRs) and household members of CD patients (HM), and unrelated healthy controls (HCs). Environmental risk factors, including childhood antibiotic use and 13 other categories, were assessed using a self-developed questionnaire. Logistic regression and conditional logistic regression were used to determine environmental factors associated with CD development. RESULTS: From 2017 to 2019, a total of 254 patients with CD (mean age: 37.98 ± 13.76 years; 58.3% male), 73 FDR (mean age: 49.35 ± 13.28 years; 46.6% male), 122 HMs (including FDR) (mean age: 45.50 ± 13.25 years; 47.5% male), and 78 HC (mean age: 45.57 ± 11.24; 47.4% male) were included. Comparing CD patients with their FDR and HMs, antibiotic use before 18 years old was a risk factor for CD development (adjusted odds ratio [OR] 3.46, 95% confidence interval [CI] 1.38-8.69; P = 0.008). There were no significant differences in other childhood environmental risk factors between CD and their FDR or HMs. Subgroup analysis showed that antibiotic use <18 years old was a risk factor for CD development in the Chinese (adjusted OR 4.80, 95% CI 1.62-12.24; P = 0.005) but not in Australian populations (OR 1.80, 95% CI 0.33-9.95; P = 0.498). CONCLUSION: Use of antibiotics <18 years was a risk factor for CD development. Attention should be paid to identifying modifiable environmental risk factors in early childhood, especially in at-risk families.
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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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    Challenges in data linkage - experiences from an upper gastrointestinal cancer data linkage study
    Khan, N ; Ioannou, L ; Pilgrim, C ; Earnest, A ; Maharaj, A ; Croagh, D ; Liew, D ; Atwood, D ; Holland, J ; Philip, J ; Emery, J ; Ijzerman, M ; Brown, W ; Zalcberg, J ; Evans, S (OXFORD UNIV PRESS, 2021-09)
    Abstract Background Linked, population-level data is valuable for mapping patterns of care and evaluating health service utilisation, particularly in difficult-to-reach populations. Upper gastrointestinal (UGI) cancers have a dismal prognosis, creating difficulties engaging patients in research. The utility of a linked dataset in this population is of high value. Methods Key objectives included identifying the operational and feasibility issues associated with linking Australian state-based administrative and registry data for understanding health service utilisation in UGI cancers. Datasets pertained to hospital admissions, radiotherapy, community health, primary care, palliative care, Medicare and Pharmaceutical Benefits Schedule’s and UGI cancers. Results From a logistical perspective, data access request approval processes varied, with some requiring consent to be sought from individual services contributing data. The availability of unique person-level identifying information varied widely. Additionally, the time period of data capture differed between and within datasets, limiting the quality of the linked data. Significant costs were associated with linking with primary care and Medicare and Pharmaceutical Benefits Schedule’s. Federal dataset linkage required at least a one-year waiting period. Conclusions Whilst in theory data linkage is a powerful mechanism for obtaining population-level data, in reality, there are many logistical and financial barriers to linking multiple datasets. Consequently, critical data, which has the potential to inform policy and improve patient outcomes, cannot be procured. Key messages Logistical and financial challenges are associated with linking administrative and registry datasets for research, limiting the potential of data linkage.
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    Efficacy and safety of carfilzomib, dexamethasone, daratumumab (KdD) twice-weekly at 56 mg/m2 and once-weekly at 70 mg/m2 in relapsed or refractory multiple myeloma (RRMM): Cross-study comparison of candor and MMY1001.
    Leleu, X ; Beksac, M ; Chou, T ; Dimopoulos, MA ; Yoon, S-S ; Prince, HM ; Pour, L ; Shelekhova, T ; Chari, A ; Khurana, M ; Obreja, M ; Qi, M ; Oriol, A ; Siegel, DSD (LIPPINCOTT WILLIAMS & WILKINS, 2020-05-20)
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    A PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMORS/ATYPICAL TERATOID RHABDOID TUMORS
    Wood, P ; Desai, J ; Waldeck, K ; Cain, J ; Gottardo, N ; Strong, R ; Kinross, K ; Carr, M ; Jones, J ; Wong, L ; Ziegler, D ; Hansford, J ; Michael, M ; Ashley, D (OXFORD UNIV PRESS INC, 2020-12)
    Abstract

    BACKGROUND

    Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens.

    METHODS

    Following cycles of induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2 following a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2.

    RESULTS

    Six patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44–327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC.

    CONCLUSIONS

    Treatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.