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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    The Role of 68Ga-DOTA-Octreotate PET/CT in Follow-Up of SDH-Associated Pheochromocytoma and Paraganglioma
    Kong, G ; Schenberg, T ; Yates, CJ ; Trainer, A ; Sachithanandan, N ; Iravani, A ; Ravi Kumar, A ; Hofman, MS ; Akhurst, T ; Michael, M ; Hicks, RJ (ENDOCRINE SOCIETY, 2019-11-01)
    Purpose: Germline succinate dehydrogenase (SDHx) mutation carriers, especially SDHB, are at increased risk for malignancy and require life-long surveillance. Current guidelines recommend periodic whole-body MRI imaging. We assessed the incremental value of 68Ga-DOTA-octreotate (GaTate) positron emission tomography (PET)/CT compared with conventional imaging in such patients. Methods: SDHx mutation carriers who had GaTate PET/CT were retrospectively reviewed. Detection of lesions were compared with MRI or CT on a per-patient and per-lesion basis. Proof of lesions were based on histopathology or clinical/imaging follow-up. Results: Twenty consecutive patients (median age, 46 years; 10 males) were reviewed. Fourteen patients had SDHB, four, SDHD, one SDHC, and one SDHA mutation. Fifteen had prior surgery and/or radiotherapy. Indications for PET/CT were as follows: 7 patients for surveillance for previously treated disease, 9 residual disease, 2 asymptomatic mutation carriers, and 2 for elevated catecholamines. Median time between modalities was 1.5 months. GaTate PET/CT had higher sensitivity and specificity than conventional imaging. On a per-patient basis: PET/CT sensitivity 100%, specificity 100%; MRI/CT 85% and 50%. Per-lesion basis: PET/CT sensitivity 100%, specificity 75%; MRI/CT 80% and 25%. PET/CT correctly identified additional small nodal and osseous lesions. MRI/CT had more false-positive findings. Change of management resulted in 40% (8/20 patients): 3 received localized treatment instead of observation, 1 changed to observation given extra disease detected, 4 with metastases had radionuclide therapy. Conclusions: GaTate PET/CT provided incremental diagnostic information with consequent management impact in SDHx-pheochromocytoma and paraganglioma. Incorporating this modality as part of a surveillance program seems prudent. Further research is needed to define the optimal surveillance strategy including use of MRI.
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    Two cases of adrenocortical carcinoma
    Hong, AY ; Graf, A ; Lee, M ; Jayawardene, D ; Pattison, DA ; MacIsaac, RJ ; Sachithanandan, N (Wiley, 2018-06)
    Adrenocortical carcinomas are rare but patients often present with advanced disease and display symptoms of hormone hypersecretion or tumour burden/mass effect. Here we present two cases of adrenocortical carcinoma to highlight the challenges of managing this condition. Case 1: A 48 year old female initially presented with an incidental adrenal mass measuring 42 mm. On triple-phase CT the mass was reported as an adrenal myelolipoma and no further followup was arranged. She represented 3 years later with abdominal bloating, facial plethora, hirsutism and weight gain. Investigations revealed hypercortisolism and hyperandrogenism in the setting of a 16 cm adrenal mass with retroperitoneal lymphadenopathy but no distant metastases. She underwent an open right adrenalectomy and histology was consistent with a 17 cm adrenocortical carcinoma with a high Ki-67 index of 40% and positive lymph nodes. Post-operative workup revealed residual local disease as well as pulmonary metastases. She then received adjuvant therapy with etoposide/doxorubicin/cisplatin and mitotane. Progressive disease was further treated with radionucleotide therapy (I131-metomidate), immunotherapy (PD-1 antibody BGB-A317) and sunitinib. Despite multiple lines of treatment, disease control was never achieved and the patient died 2 years following her initial surgery. Case 2: A 35 year old female presented with weight gain, amenorrhoea, hirsutism and abdominal striae. Workup revealed hyperandrogenism and hypercortisolism with a large right adrenal mass. A 94 mm adrenocortical carcinoma with a Ki-67 index of 30% was resected. She underwent adjuvant therapy with mitotane however follow-up imaging revealed new pulmonary and hepatic metastases. She received first-line chemotherapy with etoposide/doxorubicin/cisplatin as well as mitotane and metyrapone to control florid Cushing's syndrome. She progressed to second-line chemotherapy with capecitabine/gemcitabine however died soon after. An actionable mutation suitable for targeted therapy was not identified on next-generation sequencing in either case. These cases emphasise the need for improved treatments for metastatic disease.
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    Decrease in serum potassium levels post saline suppression test in primary aldosteronism: an under-recognised phenomenon?
    Lee, MH ; Moxey, JE ; Derbyshire, MM ; Ward, GM ; Maclsaac, RJ ; Sachithanandan, N (NATURE PUBLISHING GROUP, 2016-11)
    Seventeen subjects with confirmed primary aldosteronism and stable serum potassium (K) levels ≥ 3.5 mmol l-1 underwent saline suppression testing. They were retrospectively evaluated for changes in serum K levels post test. We found that there was a significant decrease in serum K levels post saline suppression test (3.7 ± 0.05 vs 3.5 ± 0.08, P = 0.01). This effect of saline suppression testing on serum K levels is not well described. We conclude that a decrease in serum K is common post-saline suppression test, even in subjects who are normokalemic pretest. The factors which predispose to the decrease in serum K level post saline load remain unclear.
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    Aceruloplasminaemia: a disorder of diabetes and neurodegeneration
    Calder, GL ; Lee, MH ; Sachithanandan, N ; Zeimer, H ; Bell, S ; MacIsaac, RJ (Wiley, 2017-01)
    Aceruloplasminaemia is a rare, autosomal recessive disorder of iron metabolism which results in iron deposition in the pancreas, brain, retina and liver. The clinical phenotype is distinctive: it typically leads to diabetes, anaemia and progressive neurodegeneration, but does not appear to cause functional retinal or hepatic impairment. We report an early case of aceruloplasminaemia in Australia and summarise the clinical sequelae and interesting aspects of their pathophysiology, especially that of diabetes. A Sri Lankan male was diagnosed with aceruloplasminaemia in 1994 age 44 years, after presenting with type 2 diabetes mellitus in 1989 associated with mild microcytic anaemia and abnormal iron studies. Significantly, he had low serum iron 6.4 (14.0–32 mmol/L) and serum copper 2.0 (12.5–18 μmol/L); normal transferrin 3.0 (2.0–3.6 g/L); and high ferritin 838 (40–20 μg/L). Liver biopsy showed an elevated iron content 9.91 mg/g dry weight (0.40–1.30 mg/g) with normal copper concentration 46 (15–70 μg/g), and no evidence of fibrosis. Empirical treatment with venesection resulted in profound anaemia suggesting a disorder of iron mobilisation. Ceruloplasmin was subsequently tested and found to be undetectable with a level of <0.05 (0.18–0.45 g/L) confirming a diagnosis of aceruloplasminaemia. Since diagnosis, his clinical sequelae have comprised insulin dependent diabetes, anaemia and ultimately progressive neurodegeneration involving psychosis, depression, dementia and Parkinsonism. Treatment has involved iron chelation together with insulin, oral hypoglycaemics, antipsychotics, antidepressants and donepezil. The patient now requires assistance with all activities of daily living. Aceruloplasminaemia was first described in 1987 and there are 56 case reports to date. Diabetes was developed by 85% of these patients and appears to be an early manifestation of this condition. The devastating neurodegenerative sequelae make early diagnosis and treatment essential. Screening should thus be considered when adult onset, antibody negative, insulin dependent diabetes is associated with anaemia and corroborative iron studies or unexplained neurodegenerative symptoms.
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    Hypokalaemia post-saline suppression test in primary hyperaldosteronism
    Lee, MH ; Moxey, JE ; Derbyshire, M ; Ward, G ; Sachithanandan, N ; MacIsaac, RJ (Wiley, 2016-03)
    Background: Primary hyperaldosteronism (PHA) accounts for 5–10% of patients with hypertension (1). Saline suppression test (SST) is a commonly used confirmatory test in the diagnosis of PHA. Although potassium (K) is checked at baseline with recommendations to adequately replace prior to SST, there are no recommendations to routinely check potassium post-SST. This contrasts guidelines for the fludrocortisone suppression test (FST) which is known to cause hypokalaemia. A previous study monitored K levels post-SST in a subgroup of patients, and found a non-significant decrease (-0.05 0.2 mmol/L) in potassium levels post-SST (2). We report a retrospective series of patients who became hypokalaemic in the 2 h period post-SST. Methods: A retrospective audit was conducted of patients with con-firmed PHA who underwent SST between 2005 and 2015. Pre- and 2 h post-test potassium, aldosterone and renin levels were measured. Results are expressed as mean standard error of the mean (SEM) and number (%). Results: Twenty five patients were included in the final analysis; 13(52%) were males, and mean age 53 10.5 years. Overall, there was no difference in the mean pre- and post-SST potassium levels (p = 0.08). However, there was an inverse correlation between pre-SST K and the change in post-test K levels (p = 0.01); with the highest pre-test K patients experiencing the greatest decline in post-K levels. Eight (32%) were hypokalaemic (K < 3.5 mmol/L) pre-SST and required intravenous or oral K supplements. For patients that were normokalaemic pre-SST, there was a significant decrease in serum potassium levels post-SST (3.7 0.05 vs. 3.5 0.08,p = 0.01). Seven subjects (41%) who were normokalaemic pre-test became hypokalaemic post-SST; and 5 (29%) remained hypokalaemic on day 2. Conclusion: Hypokalaemia is common post-saline suppression test in primary hyperaldosteronism. The pathophysiology remains unclear. We recommend that potassium levels be routinely measured post-test and on day 2 to detect persistent hypokalaemia.
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    False negative Ga68-DOTA-exendin-4 PET/CT in a patient with occult insulinomas
    Bongetti, EK ; Sachithanandan, N ; MacIsaac, R ; Farrell, S ; Lee, M (Wiley, 2017-01)
    Benign insulinomas are rare neuroendocrine tumours most commonly located in the pancreas. They are the most frequent cause of hyperinsulinaemia hypoglycaemia in adults without diabetes. Diagnosis can be challenging, and accurate localisation with surgical excision is the only cure. There is a growing body of evidence for the efficacy of Ga68-DOTA-exendin-4 (glucagon-like peptide-1 (GLP-1)) PET/CT scans, which centres on the premise that a near majority of insulinomas are ubiquitous for the GLP-1 receptor. We describe an 82 year-old woman with a history of fasting hyperinsulinaemic hypoglycaemia associated with neuroglycopaenic symptoms. Triple phase CT scan of the pancreas and a Ga68-DOTATATE PET/CT scan were both unremarkable. A Ga68-GLP-1 PET/CT scan showed diffuse pancreatic uptake consistent suggestive of pancreatic beta cell hyperplasia, or nesidioblastosis. The patient had further testing including an endoscopic ultrasound and calcium stimulation test which localised insulin hypersecretion to the body and tail of pancreas. Surgery revealed an insulinoma which was later con-firmed on immunohistochemistry to be GLP-1 receptor negative. Although GLP-1 scans are being increasingly used in clinical practice for work-up of hypoglycaemic disorders, they are expensive and not readily available. Clinical judgment is always crucial, and the differential of an insulinoma should not be ruled out on the basis of this scan.