Medicine (RMH) - Research Publications
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ItemOR32-06 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( 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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ItemSUN-127 Diagnostic Challenges Associated with the Rising Incidence of Endocrine Toxicity in the Era of Combination Immunotherapy( 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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ItemNo Preview AvailableINCREASED PLASMA NEUROFILAMENT LIGHT AND CEREBRAL ATROPHY IN PATIENTS WITH TYPE 2 DIABETES AND LEFT VENTRICULAR HYPERTROPHY(LIPPINCOTT WILLIAMS & WILKINS, 2023-01)
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ItemNo Preview AvailableChampioning Better Care for Young People with Stroke: Australia's New Young Stroke Service(Sage, 2023-08)Background: The Australian Stroke Clinical Registry collects information on national acute stroke care standards. Variation in care between hospitals impacts patient outcomes. Aims: To illustrate hospital performance in four priority areas of acute stroke care (stroke unit treatment, time to neuroimaging, thrombolysis door-to-needle time (DTNT), and swallowing assessments). Methods: Across 7 states/territories, 60 adult public hospitals provided 2021 data. Adherence was determined as the percentage of eligible patients treated. Funnel plots were used identify exceptional (>3 standard deviations above national average) and poor (>3 standard deviations below national average) performance. For continuous outcomes (neuroimaging timing or DTNT), we described hospitals with performance outside of the national interquartile range. Results: Overall, 16,458 episodes of stroke were analysed (median age 75 years, 43% female, 81% ischaemic). There were 27 hospitals with exceptional adherence to stroke unit care, 13 with poor adherence and 3 with no episodes treated in a stroke unit. Stroke unit treatment was less common in regional hospitals (68% vs metropolitan 80%, p<0.001). Median time from arrival to neuroimaging was 41 minutes, 2 hospitals were above the 75th percentile (>87 minutes) and 5 hospitals were below the 25th percentile (<20 minutes). Among 1320 patients with ischaemic stroke who received intravenous thrombolysis, the median DTNT was 77 minutes. Only 5 (8%) hospitals had a median DTNT ⩽60 minutes, 4 (7%) below the 25th percentile (56.5 minutes), while 18 (30%) had DTNT above the 75th percentile (107 minutes). Only 58% of all patients had their swallowing screened/assessed prior to oral intake; and 29% within 4 hours of arrival (9 hospitals with exceptional adherence; 12 with poor adherence). Conclusion: Despite strong evidence for recommended acute stroke care practices, there remains significant variation between Australian hospitals. The standardised registry data are essential to identifying areas for improvement against national benchmarks and to support stroke unit certification.
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ItemHow actionable are infection prevention and control guidelines in residential aged care? A document analysis based on a behaviour specification framework(BMC, 2023-09-07)Background: Older people living in residential aged care are susceptible to transmissible infections such as influenza, COVID-19, and gastroenteritis. Effective infection prevention and control (IPC) practice in residential aged care is therefore imperative. To enable this, national and aged care provider-level IPC guidelines need to be specific enough to be actionable by residential aged care staff and organisations. The aim of this study was to assess the actionability of IPC national guidelines and residential aged care policies and procedures. We chose to examine the guidelines around healthcare associated infection (HAI) surveillance in residential aged care. Methods: A content analysis of the Australian IPC guidelines, and IPC policies and procedures from Victorian residential aged care facilities was conducted. Data extraction, coding and interpretation of findings were directed by the action-actor-context-target-time (AACTT) framework. Results: National guidelines did not specify recommendations related to HAI surveillance but include general statements of support for data collection on HAI and outbreaks, suggest best epidemiologic principles that should be applied in data collection, and suggest that data should be fed back to appropriate staff groups and administrators. Provider-level policies and procedures varied in specificity. Conclusions: While it is recommended that aged care providers undertake HAI surveillance, national guideline recommendations are open to interpretation and are not specific or actionable. Provider-level guidelines also need improving to facilitate actionability. To increase uptake of effective HAI surveillance in residential aged care, local policies and procedures need to be written with greater behavioural specificity.
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ItemNo Preview AvailableLongitudinal Asthma Phenotypes from Childhood to Middle-Age A Population-based Cohort Study(AMER THORACIC SOC, 2023-07-15)Rationale: Asthma is a heterogeneous condition, and longitudinal phenotyping may provide new insights into the origins and outcomes of the disease. Objectives: We aimed to characterize the longitudinal phenotypes of asthma between the first and sixth decades of life in a population-based cohort study. Methods: Respiratory questionnaires were collected at seven time points in the TAHS (Tasmanian Longitudinal Health Study) when participants were aged 7, 13, 18, 32, 43, 50, and 53 years. Current-asthma and ever-asthma status was determined at each time point, and group-based trajectory modeling was used to characterize distinct longitudinal phenotypes. Linear and logistic regression models were fitted to investigate associations of the longitudinal phenotypes with childhood factors and adult outcomes. Measurements and Main Results: Of 8,583 original participants, 1,506 had reported ever asthma. Five longitudinal asthma phenotypes were identified: early-onset adolescent-remitting (40%), early-onset adult-remitting (11%), early-onset persistent (9%), late-onset remitting (13%), and late-onset persistent (27%). All phenotypes were associated with chronic obstructive pulmonary disease at age 53 years, except for late-onset remitting asthma (odds ratios: early-onset adolescent-remitting, 2.00 [95% confidence interval (CI), 1.13-3.56]; early-onset adult-remitting, 3.61 [95% CI, 1.30-10.02]; early-onset persistent, 8.73 [95% CI, 4.10-18.55]; and late-onset persistent, 6.69 [95% CI, 3.81-11.73]). Late-onset persistent asthma was associated with the greatest comorbidity at age 53 years, with increased risk of mental health disorders and cardiovascular risk factors. Conclusions: Five longitudinal asthma phenotypes were identified between the first and sixth decades of life, including two novel remitting phenotypes. We found differential effects of these phenotypes on risk of chronic obstructive pulmonary disease and nonrespiratory comorbidities in middle age.
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ItemNo Preview AvailableThe risk of secondary progressive multiple sclerosis is geographically determined but modifiable(OXFORD UNIV PRESS, 2023-11-02)Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.
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ItemVariability of the response to immunotherapy among subgroups of patients with multiple sclerosis(WILEY, 2023-04)BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.
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ItemNo Preview AvailableSustained benefits for thrombectomy triage using the act-fast algorithm after real-world implementation(SAGE, 2022-10-01)Background and Aims: The severity-based ACT-FAST algorithm for pre-hospital triage of large vessel occlusion (LVO) has previously been validated in a large paramedic-led study. We examined the subsequent real-world diagnostic utility of this tool for ambulance triage in the western metropolitan region of Melbourne, Australia. Methods: A manual audit was conducted of all patients presenting to a central comprehensive center for patients in the catchment of two spoke primary centers where ACT-FAST bypass was active from April 2020 to March 2021. Diagnostic performance was determined for LVO and overall need for comprehensive center care, including and excluding concurrent mobile stroke unit (MSU) cases. Results: Of 1222 presentations screened, 182 (15%) patients were in the bypass zone. These included 15 secondary inter-hospital LVO transfers, of which 9 had high severity (NIHSS⩾10). In contrast, 23 ACTFAST- Positive LVOs were bypassed (6 MSU-facilitated) in addition to 11 ICH and 1 intracerebral tumour. There were 8 bypassed false-positives (6 infarcts, 2 mimics) of which only 1 received thrombolysis. Bypassed patients received significantly faster EVT from ambulance dispatch (median 177min vs 237 min, p=0.001) whereas there was no significant difference in thrombolysis time (113min vs 101min, p=0.486). Conclusions: Implementation of ACT-FAST triaging avoided >70% of secondary transfers for high-severity LVO with significant time savings to thrombectomy and low rates of false-positive bypass (<1/month). Thrombolysis delay was minimal in our metropolitan setting and triage benefit was complementary to that provided by an active MSU service in the area.
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