Medicine (St Vincent's) - Research Publications

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    Childhood antibiotics are a risk factor for developing Crohn's disease. The ENIGMA international cohort study
    Mak, JWY ; Sun, Y ; Wilson-O'Brien, AL ; Lin, X ; Morrison, M ; Ching, JYL ; Niu, J ; Hamilton, AL ; Feng, R ; Tang, W ; Or, L ; Trakman, GL ; Lin, W ; Chen, MH ; Mao, Y ; Kamm, MA ; Ng, SC (WILEY, 2021-08-01)
    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, 2021-09-01)
    IntroductionNearly one quarter of a million Australian workers experience a work injury annually and make a benefit claim through one of the nation’s eleven workers’ compensation (WC) systems. The total cost to Australian society has most recently been estimated at $61.8 billion or 4.1% of GDP. The disaggregation of legislative responsibility between jurisdictions has contributed to a lack of common data standards, and thus minimal understanding of the efficiency or effectiveness of service provision in the Australian WC sector. Objectives and ApproachThis project developed a new multi-jurisdictional work disability database including detailed information on work disability duration, health and social care service provision. Service level payment data contained in structured WC insurance claims datasets held by five large WC jurisdictions with >60% coverage of the Australian labour force was collected for all cases of work-related low back pain, fractures and limb soft tissue disease over between 2010 and 2015. Database development involved creation and coding of harmonised service-level indicators for individual episodes of healthcare provision and weekly periods of wage replacement. ResultsA total of 253,000 cases and 10.7 million service episodes are included in the database. Initial exploratory analyses focused on the frequency, prevalence, timing, intensity and continuity of General Practitioner (GP) services to each of the injury groups. Regression modelling examined occupational, injury, demographic and jurisdictional factors affecting GP service use outcomes. As anticipated, service patterns varied by injury type, age, gender and occupational group. Significant differences in service use between WC jurisdictions were observed. Conclusion / ImplicationsThis exploratory study demonstrates the feasibility of developing a population-based service level database for monitoring health service delivery to injured Australian workers. Future studies will examine the impact of jurisdictional policy differences on service delivery, and the relationship between service delivery and outcomes such as disability duration.
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    Efficacy and safety of carfilzomib, dexamethasone, daratumumab (KdD) twice-weekly at 56 mg/m(2) and once-weekly at 70 mg/m(2) 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, 2020-12-01)
    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.
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    ABROCITINIB TREATMENT IN ADOLESCENTS AND ADULTS WITH MODERATE-TO-SEVERE ATOPIC DERMATITIS: EARLY PRURITUS RESPONSES FROM PHASE 3 TRIALS JADE MONO-1 AND JADE MONO-2
    Stander, S ; Yosipovitch, G ; Silverberg, JI ; Simpson, EL ; Sinclair, R ; Su, JC ; Kerkmann, U ; Gallardo, WR ; Valdez, H ; Rojo, R ; Biswas, P ; Farooqui, SA (ACTA DERMATO-VENEREOLOGICA, 2021-01-01)
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    Autologous stem cell transplantation for untreated transformed indolent B-cell lymphoma in first remission: an international, multi-centre propensity-score-matched study
    Chin, CK ; Lim, KJ ; Lewis, K ; Jain, P ; Qing, Y ; Feng, L ; Cheah, CY ; Seymour, JF ; Ritchie, D ; Burbury, K ; Tam, CS ; Fowler, NH ; Fayad, LE ; Westin, JR ; Neelapu, SS ; Hagemeister, FB ; Samaniego, F ; Flowers, CR ; Nastoupil, LJ ; Dickinson, MJ (WILEY, 2020-10-16)
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    Lupus Low Disease Activity State and Reduced Direct Health Care Costs in Patients With Systemic Lupus Erythematosus
    Yeo, AL ; Koelmeyer, R ; Kandane-Rathnayake, R ; Golder, V ; Hoi, A ; Huq, M ; Hammond, E ; Nab, H ; Nikpour, M ; Morand, EF (WILEY, 2020-09-01)
    OBJECTIVE: Treat-to-target end points for systemic lupus erythematosus (SLE) have been assessed for their impact on damage accrual and flare, but whether they have an impact on the high health care utilization and costs in SLE has not been studied. The purpose of this study was to examine our hypothesis that the recently described lupus low disease activity state (LLDAS) would be associated with reduced health care cost. METHODS: Data from a single tertiary hospital longitudinal SLE cohort were assessed. Baseline demographics, disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K], physician global assessment [PhGA], and flare index), and medication use were evaluated, and direct health care utilization and cost data were obtained from hospital information systems. LLDAS was defined as previously published: briefly, SLEDAI-2K ≤4 with no new activity, PhGA ≤1, prednisolone ≤7.5 mg/day, and optimal standard immunosuppressive agents. Analysis was performed using multivariable linear regression. RESULTS: Two hundred SLE patients, contributing 357.8 person-years of observation, were included. A history of lupus nephritis was present in 42% of patients, and damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index >0) was present at study commencement in 57.3% of patients. The mean ± SD annual direct medical cost per patient was US$7,413 ± 13,133/year. In multivariable analysis, increased cost was associated with the presence of baseline organ damage (41.7% increase; P = 0.009) and corticosteroid use (>7.5-15 mg/day: 55.7% increase; P = 0.02; and >15 mg/day: 202% increase; P < 0.001). In contrast, spending ≥50% of the observation period in LLDAS was associated with a 25.9% reduction in annual direct medical cost (P = 0.04). CONCLUSION: Greater time spent in LLDAS was associated with significantly reduced direct hospital health care costs among patients with SLE.
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    PEMBROLIZUMAB PLUS LENVATINIB VS CHEMOTHERAPY AND LENVATINIB MONOTHERAPY FOR RECURRENT/METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA THAT PROGRESSED ON PLATINUM THERAPY AND IMMUNOTHERAPY: LEAP-009
    Harrington, K ; Cohen, E ; Siu, L ; Rischin, D ; Licitra, L ; Vermorken, J ; Quynh-Thu, L ; Tahara, M ; Machiels, J-P ; Hawk, N ; Ge, J ; Bidadi, B ; Swaby, R ; Burtness, B (BMJ PUBLISHING GROUP, 2020-11-01)
    Background Pembrolizumab alone and in combination with platinum-based chemotherapy have become standard first-line treatment options for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), and there is a growing unmet need for safe and efficacious treatment options for R/M HNSCC that has progressed on or after platinum-based chemotherapy and immunotherapy. Data from Study 111/KEYNOTE-146 showed promising antitumor activity and acceptable safety for the PD-1 inhibitor pembrolizumab given in combination with the multikinase inhibitor lenvatinib in patients with metastatic HNSCC.1 LEAP-009 (NCT04428151), a global, randomized, open-label, phase 2 trial, will assess the efficacy and safety of pembrolizumab in combination with lenvatinib versus SOC chemotherapy, as well as the efficacy and safety of lenvatinib monotherapy, in patients with R/M HNSCC that has progressed after platinum-based chemotherapy and a PD-(L)1 inhibitor. Methods Eligible patients are adults with histologically confirmed, locally incurable R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx, disease progression at any time during or after platinum-containing chemotherapy (with or without cetuximab), disease progression within 12 weeks from the last dose of treatment with ≥2 doses of a PD-(L)1 inhibitor, measurable disease based on RECIST v1.1 as confirmed by BICR, ECOG performance status of 0 or 1, and no major blood vessel invasion/infiltration. Patients will be randomized 3:3:2 to pembrolizumab (200 mg IV Q3W for up to 35 cycles) plus lenvatinib (20 mg orally once daily), investigator’s choice of SOC chemotherapy (docetaxel, paclitaxel, cetuximab, or capecitabine), or lenvatinib monotherapy (24 mg orally once daily). Randomization will be stratified by PD-L1 tumor proportion score (<50% versus ≥50%) and ECOG performance status (0 versus 1). Treatment will continue until centrally verified disease progression, unacceptable toxicity, or decision to withdraw. Patients in the chemotherapy and lenvatinib monotherapy arms may be eligible to receive pembrolizumab plus lenvatinib upon disease progression. The primary endpoint is ORR according to modified RECIST v1.1 as assessed by BICR. Secondary endpoints include PFS, OS, DOR, and safety. Interim futility analysis will be conducted for the lenvatinib monotherapy arm. Tumor imaging by CT or MRI will be performed 6 weeks after randomization, every 6 weeks through year 1, and every 9 weeks thereafter. Safety will be monitored throughout the study and for 30 days after treatment end (90 days for serious AEs if no new anticancer treatment is initiated, and at any time if the AE is considered treatment-related). Recruitment is ongoing; Planned enrollment is ~400 patients. Results N/A Conclusions N/A Trial Registration ClinicalTrials. gov Identifier, NCT04428151 Ethics Approval The study and protocol were approved by the Institutional Review Board or ethics committee at each site. Consent All patients provided written informed consent to participate in the clinical trial. Reference Matthew H Taylor, Chung-Han Lee, Vicky Makker, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol 2020;38(11):1154–1163.