Medicine (RMH) - Research Publications
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ItemThe Effect of Fabry Disease Therapy on Bone Mineral Density(MDPI, 2024-05)Fabry disease (FD) is an X-linked lysosomal storage disorder, characterised by the cellular accumulation of globotriaosylceramide due to impaired alpha-galactosidase A enzyme activity. FD may manifest with multisystem pathology, including reduced bone mineral density (BMD). Registry data suggest that the introduction of Fabry-specific therapies (enzyme replacement therapy or chaperone therapy) has led to significant improvements in overall patient outcomes; however, there are limited data on the impact on bone density. The aim of this study was to describe the effect of Fabry-specific therapies on longitudinal changes in bone mineral density (BMD) in FD. We performed a retrospective observational study analysing bone densitometry (DXA) in patients with genetically confirmed FD. Patients were grouped based on the use of Fabry-specific therapies. The between-group longitudinal change in BMD Z-score was analysed using linear mixed effects models. A total of 88 FD patients were analysed (50 untreated; 38 treated). The mean age at first DXA was 38.5 years in the untreated group (84% female) and 43.7 years in the treated group (34% female). There was no significant longitudinal between-group difference in the BMD Z-score at the lumbar spine. However, the Z-score per year at the total hip (β = -0.105, p < 0.001) and femoral neck (β = -0.081, p = 0.001) was significantly lower over time in the treated than the untreated group. This may reflect those receiving therapy having a more severe underlying disease. Nevertheless, this suggests that Fabry-specific therapies do not reverse all disease mechanisms and that the additional management of BMD may be required in this patient population.
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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 AvailableOR32-06 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(The Endocrine Society, 2020-05-08)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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ItemImaging for assessment of cancer treatment response to immune checkpoint inhibitors can be complementary in identifying hypophysitis(FRONTIERS MEDIA SA, 2023-11-29)INTRODUCTION: Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis and the relationship of imaging findings to clinical diagnostic criteria. METHODS: This retrospective cohort study identified patients treated with cICI between January 2016 and January 2019 at a quaternary melanoma service. Medical records were reviewed to identify patients with a documented diagnosis of hypophysitis based on clinical criteria. Available structural brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography (FDG-PET/CT) were assessed retrospectively. The main radiological outcome measures were a relative change in pituitary size or FDG uptake temporally attributed to cICI. RESULTS: There were 162 patients (median age 60 years, 30% female) included. A total of 100 and 134 had serial CT/MRI of the brain and FDG-PET/CT, respectively. There were 31 patients who had a documented diagnosis of hypophysitis and an additional 20 who had isolated pituitary imaging findings. The pituitary gland enlargement was mild, and the largest absolute gland size was 13 mm, with a relative increase of 7 mm from baseline. There were no cases of optic chiasm compression. Pituitary enlargement and increased FDG uptake were universally transient. High-dose glucocorticoid treatment for concurrent irAEs prevented assessment of the pituitary-adrenal axis in 90% of patients with isolated imaging findings. CONCLUSION: Careful review of changes in pituitary characteristics on imaging performed for assessment of therapeutic response to iICI may lead to increased identification and more prompt management of cICI-induced hypophysitis.
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ItemIncreased Thyroidal Activity on Routine FDG-PET/CT after Combination Immune Checkpoint Inhibition: Temporal Associations with Clinical and Biochemical Thyroiditis(MDPI, 2023-12)BACKGROUND: FDG-PET/CT used for immune checkpoint inhibitor (ICI) response assessment can incidentally identify immune-related adverse events (irAEs), including thyroiditis. This study aimed to correlate the time course of FDG-PET/CT evidence of thyroiditis with clinical and biochemical evolution of thyroid dysfunction. METHODS: A retrospective review was performed by two independent blinded nuclear medicine physicians (NMPs) of thyroidal FDG uptake in 127 patients who underwent PET/CT between January 2016 and January 2019 at baseline and during treatment monitoring of combination ICI therapy for advanced melanoma. Interobserver agreement was assessed and FDG-PET/CT performance defined by a receiver-operating characteristic (ROC) curve using thyroid function tests (TFTs) as the standard of truth. Thyroid maximum standardized uptake value (SUVmax) and its temporal changes with respect to the longitudinal biochemistry were serially recorded. RESULTS: At a median of 3 weeks after commencing ICI, 43/127 (34%) had a diagnosis of thyroiditis established by abnormal TFTs. FDG-PET/CT was performed at baseline and at a median of 11 weeks (range 3-32) following the start of therapy. ROC analysis showed an area under the curve of 0.87 (95% CI 0.80, 0.94) for FDG-PET/CT for detection of thyroiditis with a positive predictive value of 93%. Among patients with biochemical evidence of thyroiditis, those with a positive FDG-PET/CT were more likely to develop overt hypothyroidism (77% versus 35%, p < 0.01). In the evaluation of the index test, there was an almost perfect interobserver agreement between NMPs of 93.7% (95% CI 89.4-98.0), kappa 0.83. CONCLUSION: Increased metabolic activity of the thyroid on routine FDG-PET/CT performed for tumoral response of patients undergoing ICI therapy is generally detected well after routine biochemical diagnosis. Elevation of FDG uptake in the thyroid is predictive of overt clinical hypothyroidism and suggests that an ongoing robust inflammatory response beyond the initial thyrotoxic phase may be indicative of thyroid destruction.
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ItemPotentially modifiable dementia risk factors in all Australians and within population groups: an analysis using cross-sectional survey data(ELSEVIER SCI LTD, 2023-09)BACKGROUND: Dementia is the second leading cause of disease burden in Australia. We aimed to calculate the population attributable fractions (PAFs) of dementia attributable to 11 of 12 previously identified potentially modifiable health and social risk factors (less education, hearing loss, hypertension, obesity, smoking, depression, social isolation, physical inactivity, diabetes, alcohol excess, air pollution, and traumatic brain injury), for Australians overall and three population groups (First Nations, and those of European and Asian ancestry). METHODS: We calculated the prevalence of dementia risk factors (excluding traumatic brain injury) and PAFs, adjusted for communality, from the cross-sectional National Aboriginal and Torres Strait Islander Health Survey (2018-19), National Aboriginal and Torres Strait Islander Social Survey (2014-15), National Health Survey (2017-18), and General Social Survey (2014) conducted by the Australian Bureau of Statistics. We conducted sensitivity analyses using proxy estimates for traumatic brain injury (12th known risk factor) for which national data were not available. FINDINGS: A large proportion (38·2%, 95% CI 37·2-39·2) of dementia in Australia was theoretically attributable to the 11 risk factors; 44·9% (43·1-46·7) for First Nations Australians, 36·4% (34·8-38·1) for European ancestry, and 33·6% (30·1-37·2) for Asian ancestry. Including traumatic brain injury increased the PAF to 40·6% (39·6-41·6) for all Australians. Physical inactivity (8·3%, 7·5-9·2), hearing loss (7·0%, 6·4-7·6), and obesity (6·6%, 6·0-7·3) accounted for approximately half of the total PAF estimates across Australia, and for all three population groups. INTERPRETATION: Our PAF estimates indicate a substantial proportion of dementia in Australia is potentially preventable, which is broadly consistent with global trends and results from other countries. The highest potential for dementia prevention was among First Nations Australians, reflecting the enduring effect of upstream social, political, environmental, and economic disadvantage, leading to greater life-course exposure to dementia risk factors. Although there were common dementia risk factors across different population groups, prevention strategies should be informed by community consultation and be culturally and linguistically appropriate. FUNDING: Australian National Health and Medical Research Council and University College London Hospitals' National Institute for Health Research (NIHR) Biomedical Research Centre, and North Thames NIHR Applied Research Collaboration.
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ItemHaemodynamics of stent-mounted neural interfaces in tapered and deformed blood vessels.(Springer Science and Business Media LLC, 2024-03-27)The endovascular neural interface provides an appealing minimally invasive alternative to invasive brain electrodes for recording and stimulation. However, stents placed in blood vessels have long been known to affect blood flow (haemodynamics) and lead to neointimal growth within the blood vessel. Both the stent elements (struts and electrodes) and blood vessel wall geometries can affect the mechanical environment on the blood vessel wall, which could lead to unfavourable vascular remodelling after stent placement. With increasing applications of stents and stent-like neural interfaces in venous blood vessels in the brain, it is necessary to understand how stents affect blood flow and tissue growth in veins. We explored the haemodynamics of a stent-mounted neural interface in a blood vessel model. Results indicated that blood vessel deformation and tapering caused a substantial change to the lumen geometry and the haemodynamics. The neointimal proliferation was evaluated in sheep implanted with an endovascular neural interface. Analysis showed a negative correlation with the mean Wall Shear Stress pattern. The results presented here indicate that the optimal stent oversizing ratio must be considered to minimise the haemodynamic impact of stenting.