Medicine (St Vincent's) - Research Publications

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    FDG PET in the evaluation of immune-related hypophysitis and thyroiditis following combination ipilimumab and nivolumab in advanced melanoma
    Iravani, A ; Galligan, A ; Lasocki, A ; Wallace, R ; Weppler, A ; Yeung, GA ; Akhurst, T ; Sachithanandan, N ; Chiang, C ; Sandhu, S ; Hicks, R (Society of Nuclear Medicine and Molecular Imaging, 2020-05-01)
    Objectives: Hypophysitis and thyroiditis are among the most commonly reported immune-related adverse events (irAEs) following combined ipilimumab/nivolumab therapy for melanoma. The role of 18F-FDG PET/CT (FDG-PET) in the evaluation of these endocrinopathies has not been systematically assessed. Methods: Between 2016 to 2019, all patients (pts) with advanced melanoma who received combined ipilimumab/nivolumab therapy were reviewed. Pts with a pre-treatment and post-treatment FDG-PET were included. On FDG-PET, PET-hypophysitis was defined as a discernable new uptake in the pituitary fossa and PET-thyroiditis as new diffuse uptake in the thyroid. Pre- and post-treatment SUVmax of pituitary and thyroid gland was measured. ROC analysis was used to derive the optimal threshold for metabolic changes on FDG-PET for distinguishing endocrinopathy. FDG-PET, clinical data and brain MRI were reviewed independently by a Nuclear Medicine physician, endocrinologist, and radiologist, respectively, and then findings were correlated. Results: Of 162 pts, 133 and 134 had assessable FDG-PET for hypophysitis and thyroiditis, respectively, with post-treatment FDG-PET performed at a median 76 days (IQR 52-83, range 18-225) from the start of immunotherapy. Overall 41/133 (29%) pts had PET-hypophysitis, of which 18 were clinically-confirmed, 3 were false-positive and 20 were not clinically-assessable due to receiving high-dose glucocorticoids for a concurrent irAE at the time of imaging, although 6 of these also had supportive contemporaneous MRI findings. For PET-hypophysitis pts, median pre- and post-treatment pituitary SUVmax were 2.7 (IQR 2.5-2.9, range 1.9-3.9) and 4.7 (IQR 3.6-5.5, range 2.6-16.2), with a percentage increase of 63% (IQR 39-94%, range 13-431%). The abnormal PET findings preceded the clinical diagnosis in 7/18 pts by a median of 16 days (range 5-50). FDG-PET was negative for hypophysitis in 12/29 pts with a prior or subsequent clinical diagnosis of hypophysitis. Where the clinical presentation was not masked by high-dose glucocorticoids, the positive and negative predictive value of FDG-PET for hypophysitis was 86% and 87%, respectively. Based on ROC analysis the optimal percentage change in SUVmax was 30% for distinguishing hypophysitis. PET-thyroiditis was detected in 30/134(22%) pts. The pre- and post-treatment SUVmax were 2.1 (IQR 1.7-2.3, range 1.3-3.3) and 4.8 (IQR 3.8-5.9, range 2.8-9.1), respectively, with an increase of 116% (IQR 84-177%, range 52-300%). Overall 41/134 (31%) pts had documented biochemical evidence of thyroiditis. The positive and negative predictive value of PET was 97% and 89%, respectively. Based on ROC analysis, the optimal percentage change in SUVmax for distinguishing thyroiditis was 42%. Further follow-up FDG-PET (30/39 pts with PET-hypophysitis and 25/30 pts with PET-thyroiditis) revealed resolution of SUVmax to baseline in all cases by a median of 104 days (IQR 77-133, range 40-484) and 32 days (IQR 79-194, range 49-1045), respectively. Conclusions: FDG-PET detects transient increases in FDG uptake in the pituitary and thyroid gland following combined ipilimumab/nivolumab which appears to be highly predictive of the development of these endocrinopathies, therefore prompting more stringent monitoring. A high incidence of uninterpretable biochemical assessment of the pituitary-adrenal axis likely contributed to the underestimation of hypophysitis incidence. A multimodality approach is important in the timely diagnosis of immune-related endocrinopathies.
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    OR32-06 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
    Galligan, A ; Iravani, A ; Lasocki, A ; Wallace, R ; Weppler, A ; Au-Yeung, G ; Sachithanandan, N ; Chiang, CY ; Wentworth, J ; Colman, PG ; Kay, TW ; Krishnamurthy, B ; Sandhu, S ( 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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    SUN-127 Diagnostic Challenges Associated with the Rising Incidence of Endocrine Toxicity in the Era of Combination Immunotherapy
    Galligan, A ; Iravani, A ; Lasocki, A ; Wallace, R ; Weppler, A ; Au-Yeung, G ; Sachithanandan, N ; Chiang, CY ; Wentworth, J ; Colman, PG ; Kay, TW ; Krishnamurthy, B ; Sandhu, S ( 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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    Validation of Formulae to Estimate Insulin Sensitivity in Type 1 Diabetes
    Januszewski, AS ; Niedzwiecki, P ; Sachithanandan, N ; Ward, GM ; Karschimkus, C ; O'Neal, DN ; Zozulinska-Ziolkiewicz, D ; Uruska, A ; Jenkins, A (American Diabetes Association, 2021-06)
    Introduction: The “gold standard” measure of insulin sensitivity (IS), a euglycemic hyperinsulinemic clamp, is costly, time- and labour-intensive. Several formulae, developed using clamp data estimate insulin sensitivity, expressed as estimated glucose disposal rate (eGDR) or insulin sensitivity index (eM/I or elog10M/I). Due to clamp complexity and cost these formulae often lacks independent validation. Aim: To validate several formulae estimating IS using independent euglycaemic hyperinsulinemic clamp data. Methods: Euglycemic, hyperinsulinemic clamps were performed in 108 T1D adults (age (mean±SD) 34±7 yrs, T1D duration 10±4 yrs, HbA1c 7.7±1.5%; 33 with microvascular complications). Measured GDR (last 30min of the clamp) ranged 0.5 - 9.6 mg/kg/min (median (LQ, UQ) 4.45 (3.04, 6.5 mg/kg/min) were compared with eGDR and eLog10M/I calculated using simple formulae by (1) Williams, (2) Zheng, (3) Dabelea and (4) and (5) (Australia (AU)) authors, all derived from routine clinical chemistry and demographics. eGDR formula (Duca) was not assessed as it includes adiponectin levels. Results: Results are in Table 1. Conclusion: Authors (AU) formulae to estimate IS, including age, sex, HDL-C, BMI, HbA1c, pulse pressure and WHR had highest correlation with measured GDR and better performance (AUROC) in detecting low IS than other formulae.
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    Insulin Autoimmune Syndrome: A Case of Clopidogrel-induced Autoimmune Hypoglycemia
    Calder, GL ; Ward, GM ; Sachithanandan, N ; MacIsaac, RJ (ENDOCRINE SOC, 2020-04)
    CONTEXT: Insulin autoimmune syndrome (IAS) is characterized by hyperinsulinemic hypoglycemia with elevated anti-insulin antibodies. Most commonly observed in the Japanese population, elsewhere it is rare and associated with autoimmune diseases, plasma cell dyscrasias, or sulfhydryl group medications. The active metabolite of clopidogrel has a sulfhydryl group and here we report a case of clopidogrel-induced IAS. CASE DESCRIPTION: A 67-year-old man was admitted with severe hyperinsulinemic hypoglycemia requiring continuous intravenous infusion of 10% dextrose to sustain euglycemia. His symptoms of hypoglycemia had started after commencing dual antiplatelet therapy (including clopidogrel) for ischemic heart disease 9 months earlier. The hypoglycemia was associated with elevated insulin, proinsulin, c-peptide, and anti-insulin antibody titers as well as the HLA-DRB1*04 haplotype. Multiple localizing studies were negative for an insulinoma. A diagnosis of IAS was thus made. Clopidogrel cessation, oral dexamethasone, and diazoxide therapy were not sufficient to safely wean the dextrose infusion. Plasma exchange was ultimately effective. CONCLUSIONS: This case highlights a case of severe IAS. Given the ubiquity of clopidogrel, IAS should be remembered as a rare adverse effect.
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    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
    Galligan, A ; Iravani, A ; Lasocki, A ; Wallace, R ; Weppler, A ; Au-Yeung, G ; Sachithanandan, N ; Chiang, CY ; Wentworth, J ; Colman, PG ; Kay, TW ; Krishnamurthy, B ; Sandhu, S (The Endocrine Society, 2020-05-08)
    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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    Estimated insulin sensitivity in Type 1 diabetes adults using clinical and research biomarkers
    Januszewski, AS ; Sachithanandan, N ; Ward, G ; Karschimkus, CS ; O'Neal, DN ; Jenkins, AJ (Elsevier, 2020-09)
    Aims: Insulin resistance in people with type 1 diabetes (T1D) is associated with increased risk of chronic complications and death. The gold standard to quantify insulin sensitivity, a euglycaemic hyperinsulinaemic clamp, is not applicable to clinical practice. We have employed clamp studies to develop a panel of formulae to estimate insulin sensitivity in adults with T1D for use in clinical practice and trials. Methods: Clamps were conducted in 28 adults with T1D, who were also characterised with 38 clinical and research biomarkers. Exhaustive search analysis was used to derive equations correlating with clamp-quantified glucose disposal rate (GDR), GDR/plasma insulin (M/I) and log 10 M/I. Results: Measured insulin sensitivity correlated with BMI, WHR, HDL-C, adipokines and inflammation markers on univariate analysis. Exhaustive search analysis derived three formulae correlating with clamp-derived GDR and logM/I ( p < 0.0001), accounting for ≈62% of their variability. A formula using gender, age, HDL-C, pulse pressure and WHR performed as well as those containing inflammation and adipokine measures. Conclusions: The performance of formulae using routinely available parameters with/without research biomarkers in clinical studies and trials, particularly related to future complications, relevant lifestyle interventions, insulin delivery modes and insulin sensitisers is merited.
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    Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients' Survival
    Srougi, V ; Bancos, I ; Daher, M ; Lee, JE ; Graham, PH ; Karam, JA ; Henriquez, A ; Mckenzie, TJ ; Sada, A ; Bourdeau, I ; Poirier, J ; Vaidya, A ; Abbondanza, T ; Kiernan, CM ; Rao, SN ; Hamidi, O ; Sachithanandan, N ; Hoff, AO ; Chambo, JL ; Almeida, MQ ; Habra, MA ; Fragoso, MCB (ENDOCRINE SOC, 2022-03-24)
    CONTEXT: The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. OBJECTIVE: To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. DESIGN AND SETTING: We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance collaborative research group. PATIENTS: Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. INTERVENTION: Performance (or not) of cytoreductive surgery of the primary tumor. MAIN OUTCOME AND MEASURES: A propensity score match was done using age and the number of organs with metastasis (≤2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. RESULTS: Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65). CONCLUSION: Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.
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    Comparing Video-Based, Telehealth-Delivered Exercise and Weight Loss Programs With Online Education on Outcomes of Knee Osteoarthritis : A Randomized Trial
    Bennell, KL ; Lawford, BJ ; Keating, C ; Brown, C ; Kasza, J ; Mackenzie, D ; Metcalf, B ; Kimp, AJ ; Egerton, T ; Spiers, L ; Proietto, J ; Sumithran, P ; Harris, A ; Quicke, JG ; Hinman, RS (American College of Physicians, 2022-02)
    Background: Scalable knee osteoarthritis (OA) programs are needed to deliver recommended education, exercise and weight loss interventions. Objective: Evaluate two 6-month telehealth-delivered exercise programs, with and without dietary intervention. Design: Three-arm parallel randomized (5:5:2) trial. Setting: Australian private health insurance members. Participants: 415 people with symptomatic knee OA, body mass index 28-40 kg/m2, aged 45-80. Interventions: All groups received access to electronic OA information (Control). The Exercise program comprised six videoconferencing physiotherapist consultations for exercise, self-management advice and behavioral counselling plus exercise equipment and resources. The Diet+Exercise program included an additional six dietitian consultations for a ketogenic very low-calorie diet (two formulated meal replacements and low carbohydrate meal daily) then transition to healthy eating, and nutrition and behavioral resources. Measurements: Primary outcomes were changes in knee pain (0-10 numeric rating scale, higher worse) and physical function (0-68 WOMAC, higher worse) at 6- (primary time-point) and 12-months. Secondary outcomes were weight, physical activity, quality-of-life, mental health, global change, satisfaction, willingness for surgery, orthopaedic appointments, and knee surgery. Results: 379 (91%) and 372 (90%) participants provided 6- and 12-month primary outcomes respectively. At 6-months, both programs were superior to Control for pain (between-group mean differences: Diet+Exercise, -1.5 [95% CI, -2.1 to -0.8]; Exercise, -0.8 [CI, -1.5 to -0.2]) and function (Diet+Exercise, -9.8 [CI, -12.5 to -7.0]; Exercise, -7.0 [CI -9.7 to -4.2]) while Diet+Exercise was superior to Exercise (pain, -0.6 [CI, -1.1 to -0.2]; function, -2.8 [CI -4.7 to -0.8]). Similar findings occurred at 12-months. Limitations: Unblinded participants and clinicians. Conclusion: Telehealth-delivered exercise and diet programs improved pain and function in people with knee OA and overweight/obesity. Dietary intervention conferred modest additional pain and function benefits to exercise.
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