Medicine (St Vincent's) - Research Publications
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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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ItemInsulinoma: Metastatic Recurrence 38 Years Following Initial Diagnosis in Pregnancy.(The Endocrine Society, 2024-02)A case of recurrent insulinoma spanning 4 decades is described. Following a delayed diagnosis, hyperinsulinemic hypoglycemia was confirmed in a 24-year-old woman during early pregnancy. Initial surgery, culminating in subtotal pancreatectomy, was noncurative. A 1-cm insulinoma was subsequently resected from the head of the pancreas postpartum, with postoperative resolution of hypoglycemia. However, 32 years later, the patient experienced a recurrence of hypoglycemic symptoms. Eventually, a subcentimeter extrapancreatic lesion was identified anterior to the pancreatic head on gallium-68 DOTA-Exendin-4 positron emission tomography/computed tomography. In 2022, a third operation was performed, with excision of a 4 × 3 mm tumor adjacent to the pancreatic head, and histology confirming insulinoma. She was again cured of symptoms.
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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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ItemSevere Osteoporosis With Pathogenic LRP5 Variant.(The Endocrine Society, 2024-03)A 24-year-old female patient was diagnosed with osteoporosis after presenting with numerous fractures throughout her childhood and adolescence. Risk factors included chronic constipation, severe vitamin D deficiency, and long-term high-dose steroid use for severe eczema. Metabolic bone disorder clinical exome screening (limited panel of metabolic bone disorders and gastrointestinal disorders) was undertaken and revealed a class 4 likely pathogenic variant in the LRP5 gene known to cause osteoporosis. Optimal treatment for patients with this variant is not well defined. A literature review of the condition and potential treatment options is discussed.
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ItemInteractive calculator to estimate insulin sensitivity in type 1 diabetes(WILEY, 2024-05)The gold standard for measuring insulin sensitivity (IS) is the hyperinsulinemic-euglycemic clamp, a time, costly, and labor-intensive research tool. A low insulin sensitivity is associated with a complication-risk in type 1 diabetes. Various formulae using clinical data have been developed and correlated with measured IS in type 1 diabetes. We consolidated multiple formulae into an online calculator (bit.ly/estimated-GDR), enabling comparison of IS and its probability of IS <4.45 mg/kg/min (low) or >6.50 mg/kg/min (high), as measured in a validation set of clamps in 104 adults with type 1 diabetes. Insulin sensitivity calculations using different formulae varied significantly, with correlations (R2) ranging 0.005-0.87 with agreement in detecting low and high glucose disposal rates in the range 49-93% and 89-100%, respectively. We demonstrate that although the calculated IS varies between formulae, their interpretation remains consistent. Our free online calculator offers a user-friendly tool for individual IS calculations and also offers efficient batch processing of data for research.
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ItemUtility of Repeat Sampling in Bilateral Aldosterone Suppression During Adrenal Vein Sampling for Primary Aldosteronism.(The Endocrine Society, 2024-04)Primary aldosteronism (PA) is the most common form of secondary hypertension. Accurate subtyping of PA is essential to identify unilateral disease, as adrenalectomy improves outcomes. Subtyping PA requires adrenal vein sampling (AVS), which is technically challenging and results from AVS may not always be conclusive. We present a case of a 37-year-old man with PA whose AVS studies were inconclusive due to apparent bilateral aldosterone suppression (ABAS). As a result, our patient was misdiagnosed as having bilateral PA and medically managed until a repeat AVS showed lateralization to the right adrenal gland. ABAS is an underrecognized phenomenon that may confound the subtyping of PA. We recommend repeating AVS in such cases and discuss strategies to minimize ABAS.
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ItemERG and c-MYC regulate a critical gene network in BCR::ABL1-driven B cell acute lymphoblastic leukemia(AMER ASSOC ADVANCEMENT SCIENCE, 2024-03-08)Philadelphia chromosome-positive B cell acute lymphoblastic leukemia (B-ALL), characterized by the BCR::ABL1 fusion gene, remains a poor prognosis cancer needing new therapeutic approaches. Transcriptomic profiling identified up-regulation of oncogenic transcription factors ERG and c-MYC in BCR::ABL1 B-ALL with ERG and c-MYC required for BCR::ABL1 B-ALL in murine and human models. Profiling of ERG- and c-MYC-dependent gene expression and analysis of ChIP-seq data established ERG and c-MYC coordinate a regulatory network in BCR::ABL1 B-ALL that controls expression of genes involved in several biological processes. Prominent was control of ribosome biogenesis, including expression of RNA polymerase I (POL I) subunits, the importance of which was validated by inhibition of BCR::ABL1 cells by POL I inhibitors, including CX-5461, that prevents promoter recruitment and transcription initiation by POL I. Our results reveal an essential ERG- and c-MYC-dependent transcriptional network involved in regulation of metabolic and ribosome biogenesis pathways in BCR::ABL1 B-ALL, from which previously unidentified vulnerabilities and therapeutic targets may emerge.
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ItemPalliative Approach Remains Lacking in Terminal Hospital Admissions for Chronic Disease Across Rural Settings: Multisite Retrospective Medical Record Audit.(Elsevier BV, 2024-05)INTRODUCTION/AIM: Despite clear benefit from palliative care in end-stage chronic diseases, access is often limited, and rural access largely undescribed. This study sought to determine if a palliative approach is provided to people with chronic disease in their terminal hospital admission. METHODS: Multisite, retrospective medical record audit, of decedents with a primary diagnosis of chronic lung, heart, or renal failure, or multimorbidity of these conditions over 2019. RESULTS: Of 241 decedents, across five clinical sites, 143 (59.3%) were men, with mean age 80.47 years (SD 11.509), and diagnoses of chronic lung (n = 56, 23.2%), heart (n = 56, 23.2%), renal (n = 24, 10.0%) or multimorbidity disease (n = 105, 43.6%), and had 2.88 (3.04SD) admissions within 12 months. Outpatient chronic disease care was evident (n = 171, 73.7%), however, contact with a private physician (n = 91, 37.8%), chronic disease program (n = 61, 25.3%), or specialist nurse (n = 17, 7.1%) were less apparent. "Not-for-resuscitation" orders were common (n = 139, 57.7%), however, advance care planning (n = 71, 29.5%), preferred place of death (n = 18, 7.9%), and spiritual support (n = 18, 7.5%) were rarely documented. Referral to and input from palliative services were low (n = 74, 30.7% and n = 49, 20.3%), as was review of nonessential medications or blood tests (n = 86, 35.7%, and n = 78, 32.4%). Opioids were prescribed in 45.2% (n = 109). Hospital site and diagnosis were significantly associated with outpatient care and palliative approach (P<0.001). CONCLUSIONS: End-of-life planning and specialist palliative care involvement occurred infrequently for people with chronic disease who died in rural hospitals. Targeted strategies are necessary to improve care for these prevalent and high needs rural populations.
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ItemA qualitative study of patients with Cancer of Unknown Primary: Perceptions of communication, understanding of diagnosis and genomic testing, and information needs(WILEY, 2023-04)OBJECTIVE: Patients with Cancer of Unknown Primary (CUP) commonly report poor understanding of their illness and high levels of psychological distress. Despite the potential benefits to CUP patients, there is a paucity of research exploring the reasons behind poor understanding of a CUP diagnosis. The aim of this study was to understand patients' experiences of communication with doctors, their understanding of diagnosis and the role of genomic testing, as well as their information needs. METHODS: Semi-structured interviews explored CUP patients' perceptions of communication with their doctors, understanding of their illness, and their needs regarding medical information. Qualitative inductive thematic analysis of transcribed audio-recordings was employed. SETTING/PARTICIPANTS: Nineteen patients were recruited from within a prospective cohort study involving routine genomic testing of CUP patients. RESULTS: CUP patients had varied perceptions of communication with doctors as well as different levels of need, readiness, and capacity for information. Some patients felt well understood and supported by their doctors while others did not. Many patients reported feeling overwhelmed and shocked when receiving their cancer diagnosis and emphasized the importance of family support in receiving and understanding medical information. While patients understood the implications of genomic testing for treatment and diagnosis, few had a detailed understanding of genomic testing. CONCLUSIONS: Patients' experience of communication and understanding of CUP could be potentially improved by clinicians' assessment of the communication style preferred by each patient and their family and the development of online resources to meet their evolving information needs.
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ItemAssociation of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival(WILEY, 2023-08)BACKGROUND: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. AIM: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. METHODS: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. RESULTS: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)]. CONCLUSION: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.