Sir Peter MacCallum Department of Oncology - Research Publications

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    Imaging for assessment of cancer treatment response to immune checkpoint inhibitors can be complementary in identifying hypophysitis
    Galligan, A ; Iravani, A ; Lasocki, A ; Wallace, R ; Weppler, AM ; Sachithanandan, N ; Chiang, C ; Colman, PG ; Wentworth, J ; Spain, L ; Au-Yeung, G ; Lee, B ; Kay, TWH ; Hicks, RJ ; Sandhu, S ; Krishnamurthy, B (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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    Increased Thyroidal Activity on Routine FDG-PET/CT after Combination Immune Checkpoint Inhibition: Temporal Associations with Clinical and Biochemical Thyroiditis
    Galligan, A ; Wallace, R ; Krishnamurthy, B ; Kay, TWH ; Sachithanandan, N ; Chiang, C ; Sandhu, S ; Hicks, RJ ; Iravani, A (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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    Timely cancer diagnosis and treatment: towards a generalisable research framework studying timeliness to appropriate care
    Zhang, J ; IJzerman, MJ ; Emery, JD (AME Publishing Company, 2023)
    Cancer is the second leading cause of death after cardiovascular diseases worldwide. To improve survival and quality of life from this life-threatening disease, early diagnosis and treatment are essential. Also, at the health system level, it is important to ensure sufficient capacity to deliver equitable and early accessible care through adequate workforce and facilities along the patient journey
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    SLAM-ITseq identifies that Nrf2 induces liver regeneration through the pentose phosphate pathway
    Tan, VWT ; Salmi, TM ; Karamalakis, AP ; Gillespie, A ; Ong, AJS ; Balic, JJ ; Chan, Y-C ; Bladen, CE ; Brown, KK ; Dawson, MA ; Cox, AG (CELL PRESS, 2024-04-08)
    The liver exhibits a remarkable capacity to regenerate following injury. Despite this unique attribute, toxic injury is a leading cause of liver failure. The temporal processes by which the liver senses injury and initiates regeneration remain unclear. Here, we developed a transgenic zebrafish model wherein hepatocyte-specific expression of uracil phosphoribosyltransferase (UPRT) enabled the implementation of SLAM-ITseq to investigate the nascent transcriptome during initiation of liver injury and regeneration. Using this approach, we identified a rapid metabolic transition from the fed to the fasted state that was followed by induction of the nuclear erythroid 2-related factor (Nrf2) antioxidant program. We find that activation of Nrf2 in hepatocytes is required to induce the pentose phosphate pathway (PPP) and improve survival following liver injury. Mechanistically, we demonstrate that inhibition of the PPP disrupts nucleotide biosynthesis to prevent liver regeneration. Together, these studies provide fundamental insights into the mechanism by which early metabolic adaptation to injury facilitates tissue regeneration.
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    Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.
    Morra, A ; Schreurs, MAC ; Andrulis, IL ; Anton-Culver, H ; Augustinsson, A ; Beckmann, MW ; Behrens, S ; Bojesen, SE ; Bolla, MK ; Brauch, H ; Broeks, A ; Buys, SS ; Camp, NJ ; Castelao, JE ; Cessna, MH ; Chang-Claude, J ; Chung, WK ; Collaborators, N ; Colonna, SV ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Dennis, J ; Devilee, P ; Dörk, T ; Dunning, AM ; Dwek, M ; Easton, DF ; Eccles, DM ; Eriksson, M ; Evans, DG ; Fasching, PA ; Fehm, TN ; Figueroa, JD ; Flyger, H ; Gabrielson, M ; Gago-Dominguez, M ; García-Closas, M ; García-Sáenz, JA ; Genkinger, J ; Grassmann, F ; Gündert, M ; Hahnen, E ; Haiman, CA ; Hamann, U ; Harrington, PA ; Hartikainen, JM ; Hoppe, R ; Hopper, JL ; Houlston, RS ; Howell, A ; Investigators, A ; Investigators, K ; Jakubowska, A ; Janni, W ; Jernström, H ; John, EM ; Johnson, N ; Jones, ME ; Kristensen, VN ; Kurian, AW ; Lambrechts, D ; Marchand, LL ; Lindblom, A ; Lubiński, J ; Lux, MP ; Mannermaa, A ; Mavroudis, D ; Mulligan, AM ; Muranen, TA ; Nevanlinna, H ; Nevelsteen, I ; Neven, P ; Newman, WG ; Obi, N ; Offit, K ; Olshan, AF ; Park-Simon, T-W ; Patel, AV ; Peterlongo, P ; Phillips, K-A ; Plaseska-Karanfilska, D ; Polley, EC ; Presneau, N ; Pylkäs, K ; Rack, B ; Radice, P ; Rashid, MU ; Rhenius, V ; Robson, M ; Romero, A ; Saloustros, E ; Sawyer, EJ ; Schmutzler, RK ; Schuetze, S ; Scott, C ; Shah, M ; Smichkoska, S ; Southey, MC ; Tapper, WJ ; Teras, LR ; Tollenaar, RAEM ; Tomczyk, K ; Tomlinson, I ; Troester, MA ; Vachon, CM ; van Veen, EM ; Wang, Q ; Wendt, C ; Wildiers, H ; Winqvist, R ; Ziogas, A ; Hall, P ; Pharoah, PDP ; Adank, MA ; Hollestelle, A ; Schmidt, MK ; Hooning, MJ ( 2023-02-13)
    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. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of 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. 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)]. In 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. (Main MS: 3201 words).
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    A novel MYB::PAIP1 oncogenic fusion in pediatric blastic plasmacytoid dendritic cell neoplasm (BPDCN) is dependent on BCL2 expression and is sensitive to venetoclax
    Kosasih, HJ ; Healey, G ; Brennan, MS ; Bjelosevic, S ; Sadras, T ; Jalud, FB ; Ibnat, T ; Ng, AP ; Mayoh, C ; Mao, J ; Tax, G ; Ludlow, LEA ; Johnstone, RW ; Herold, MJ ; Khaw, SL ; de Bock, CE ; Ekert, PG (WILEY, 2024-02)
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    Colorectal cancer survivors' experiences and views of shared and telehealth models of survivorship care: A qualitative study
    Gore, C ; Lisy, K ; O'Callaghan, C ; Wood, C ; Emery, J ; Martin, A ; De Abreu Lourenco, R ; Schofield, P ; Jefford, M (Wiley, 2024-01)
    OBJECTIVES: The number of colorectal cancer (CRC) survivors is increasing and current models of survivorship care are unsustainable. There is a drive to implement alternative models of care including shared care between general practitioners (GPs) and hospital-based providers. The primary objective of this study was to explore perspectives on facilitators and barriers to shared care. The secondary objective was to explore experiences of telehealth-delivered care. METHOD: Qualitative data were collected via semi-structured interviews with participants in the Shared Care for Colorectal Cancer Survivors (SCORE) randomised controlled trial. Interviews explored patient experiences of usual and shared survivorship care during the SCORE trial. In response to the COVID pandemic, participant experiences of telehealth appointments were also explored. Interviews were recorded and transcribed for thematic analysis. RESULTS: Twenty survivors of CRC were interviewed with an even number in the shared and usual care arms; 14 (70%) were male. Facilitators to shared care included: good relationships with GPs; convenience of GPs; good communication between providers; desire to reduce public health system pressures. Barriers included: poor communication between clinicians; inaccessibility of GPs; beliefs about GP capacity; and a preference for follow-up care with the hospital after positive treatment experiences. Participants also commonly expressed a preference for telehealth-based follow-up when there was no need for a clinical examination. CONCLUSIONS: This is one of few studies that have explored patient experiences with shared and telehealth-based survivorship care. Findings can guide the implementation of these models, particularly around care coordination, communication, preparation, and personalised pathways of care.
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    Persistent gravitational radiation from glitching pulsars - II. Updated scaling with vortex number
    Cheunchitra, T ; Melatos, A ; Carlin, JB ; Howitt, G (OXFORD UNIV PRESS, 2024-01-23)
    ABSTRACT Superfluid vortices pinned to nuclear lattice sites or magnetic flux tubes in a neutron star evolve abruptly through a sequence of metastable spatial configurations, punctuated by unpinning avalanches associated with rotational glitches, as the stellar crust spins down electromagnetically. The metastable configurations are approximately but not exactly axisymmetric, causing the emission of persistent, quasimonochromatic, current quadrupole gravitational radiation. The characteristic gravitational wave strain h0 as a function of the spin frequency f and distance D from the Earth is bounded above by $h_0 = 1.2\substack{+1.3 \\ -0.9} \times 10^{-32} (f/30\,\,{\rm Hz})^{2.5} (D/1\,\,{\rm kpc})^{-1}$, corresponding to a Poissonian spatial configuration (equal probability per unit area, i.e. zero inter-vortex repulsion), and bounded below by $h_0 = 1.8\substack{+2.0 \\ -1.5} \times 10^{-50} (f/30\,\,{\rm Hz})^{1.5} (D/1\,\,{\rm kpc})^{-1}$, corresponding to a regular array (periodic separation, i.e. maximum inter-vortex repulsion). N-body point vortex simulations predict an intermediate scaling, $h_0 = 7.3\substack{+7.9 \\ -5.4} \times 10^{-42} (f/30\,\,{\rm Hz})^{1.9} (D/1\,\,{\rm kpc})^{-1}$, which reflects a balance between the randomizing but spatially correlated action of superfluid vortex avalanches and the regularizing action of inter-vortex repulsion. The scaling is calibrated by conducting simulations with Nv ≤ 5 × 103 vortices and extrapolated to the astrophysical regime Nv ∼ 1017(f/30 Hz). The scaling is provisional, pending future computational advances to raise Nv and include three-dimensional effects such as vortex tension and turbulence.
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    Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer
    Burdett, NL ; Willis, MO ; Pandey, A ; Fereday, S ; DeFazio, A ; Bowtell, DDL ; Christie, EL (NATURE PORTFOLIO, 2023-12-10)
    While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2. This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment.
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    Evaluating the cost-effectiveness of [18F]FDG-PET/CT for investigation of persistent or recurrent neutropenic fever in high-risk haematology patients
    Tew, M ; Douglas, AP ; Szer, J ; Bajel, A ; Harrison, SJ ; Tio, SY ; Worth, LJ ; Hicks, RJ ; Ritchie, D ; Slavin, MA ; Thursky, KA ; Dalziel, K (BMC, 2023-12-15)
    BACKGROUND: A recent randomised trial demonstrated [18F]fluorodeoxyglucose positron-emission tomography in combination with low-dose CT (FDG-PET/CT), compared to standard of care computed tomography (CT) imaging, positively impacted antimicrobial management and outcomes of acute leukaemia and haematopoietic stem cell transplant recipients with persistent and recurrent neutropenic fever. We conducted an economic evaluation from a healthcare perspective alongside the clinical trial. METHODS: Unit costs in Australian dollars were applied to all resources used (antimicrobials, diagnostic tests, ICU and hospital bed days). Effectiveness was measured as number of patients with antimicrobial rationalisation, 6-month mortality and quality-adjusted life years (QALYs) derived from patient-reported trial-based health-related quality-of-life. Generalised linear models were used to analyse costs and outcomes. Incremental cost-effectiveness ratios (ICERs) for all outcomes and net monetary benefit (NMB) for QALYs were calculated. We performed bootstrapping with 1000 replications using the recycled predictions method. RESULTS: The adjusted healthcare costs were lower for FDG-PET/CT (mean $49,563; 95%CI 36,867, 65,133) compared to CT (mean $57,574; 95% CI 44,837, 73,347). The difference in QALYs between the two groups was small (0.001; 95% CI -0.001, 0.004). When simulated 1000 times, FDG-PET/CT was the dominant strategy as it was cheaper with better outcomes than the standard CT group in 74% of simulations. The estimated NMBs at willingness-to-pay thresholds of $50,000 and $100,000 per QALY were positive, thus FDG-PET/CT remained cost-effective at these thresholds. CONCLUSIONS: FDG-PET/CT is cost effective when compared to CT for investigation of persistent/recurrent neutropenic fever in high-risk patients, providing further support for incorporation of FDG-PET/CT into clinical guidelines and funding. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT03429387.