Sir Peter MacCallum Department of Oncology - Research Publications

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    Stepped-care cognitive behaviour therapy program for treating cancer-related fatigue: protocol for a feasibility study.
    Williams, LK ; Ftanou, M ; Pearson, EJ (Springer Science and Business Media LLC, 2022-05-27)
    BACKGROUND: Cancer-related fatigue (CRF) is a commonly experienced and often debilitating side effect of cancer treatment that can persist for years after treatment completion. The benefits of cognitive behaviour therapy (CBT) for CRF are well established; however, these interventions are typically not included in standard clinical care. Traditional CBT is resource-intensive, limiting implementation in hospital settings. Stepped-care approaches can offer benefits to more people, using the same personnel as traditional models. METHOD/DESIGN: This is a single-arm feasibility study. Fifty people with a cancer diagnosis, at least 12 weeks post-treatment or on long-term maintenance treatment, with persistent CRF that is affecting daily activities, will enrol in a stepped-care CBT program. INTERVENTION: The stepped-care program involves two steps. Step 1: All participants begin with a 5-week supported self-management CBT progam targeting fatigue. Step 2: If fatigue remains severe or has changed less than the minimal clinically important difference on the fatigue measure after step 1, participants will be offered four sessions of therapist-directed group CBT. MEASURES: Participants will complete questionnaires at baseline and 6 and 10 weeks. The primary outcome is feasibility of the REFRESH program. The implementation evaluation comprises acceptability, satisfaction, appropriateness, and feasibility of the study intervention, along with administrative data including cost, processes, procedures and implementation. Secondary outcomes are changes in fatigue, quality of life and self-efficacy. CONCLUSION: The REFRESH program will be the first stepped-care CBT intervention for persistent CRF in Australia. Assessing feasibility of REFRESH is an important first step to establishing future implementation and efficacy.
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    Targeting wild-type TP53 using AMG 232 in combination with MAPK inhibition in Metastatic Melanoma; a phase 1 study
    Moschos, SJ ; Sandhu, S ; Lewis, KD ; Sullivan, RJ ; Puzanov, I ; Johnson, DB ; Henary, HA ; Wong, H ; Upreti, VV ; Long, GV ; Flaherty, KT (SPRINGER, 2022-05-30)
    BACKGROUND: Targeting the MDM2-p53 interaction using AMG 232 is synergistic with MAPK inhibitors (MAPKi) in preclinical melanoma models. We postulated that AMG 232 plus MAPKi is safe and more effective than MAPKi alone in TP53-wild type, MAPKi-naïve metastatic melanoma. METHODS: Patients were treated with increasing (120 mg, 180 mg, 240 mg) oral doses of AMG 232 (seven-days-on, 15-days-off, 21-day cycle) plus dabrafenib (D) and trametinib (T) (Arm 1, BRAFV600-mutant) or T alone (Arm 2, BRAFV600-wild type). Patients were treated for seven days with AMG 232 alone before adding T±D. Safety and efficacy were assessed using CTCAE v4.0 and RECIST v1.1 criteria, respectively. Pharmacokinetic (PK) analysis was performed at baseline and steady-state levels for AMG 232. RESULTS: 31 patients were enrolled. Ten and 21 patients were enrolled in Arm 1 and Arm 2, respectively. The most common AMG 232-related adverse events (AEs) were nausea (87%), diarrhea (77%), and fatigue (74%). Seven patients (23%) were withdrawn from the study due to AMG 232-related AEs. Three dose-limiting AEs occurred (Arm 1, 180 mg, nausea; Arm 2, 240 mg, grade 3 pulmonary embolism; Arm 2, 180 mg, grade 4 thrombocytopenia). AMG 232 PK exposures were not altered when AMG 232 was combined with T±D. Objective responses were seen in 8/10 (Arm 1) and 3/20 (Arm 2) evaluable patients. The median progression-free survival for Arm 1 and Arm 2 was 19.0 months-not reached and 2.8 months, respectively. CONCLUSION: The maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T±D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T±D did not confer additional clinical benefit.
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    Beyond standard data collection - the promise and potential of BRAIN (Brain tumour Registry Australia INnovation and translation registry)
    Gately, L ; Drummond, K ; Rosenthal, M ; Harrup, R ; Dowling, A ; Gogos, A ; Lwin, Z ; Collins, I ; Campbell, D ; Ahern, E ; Phillips, C ; Gan, HK ; Bennett, I ; Sieber, OM ; Gibbs, P (BMC, 2022-06-02)
    BACKGROUND: Real-world data (RWD) is increasingly being embraced as an invaluable source of information to address clinical and policy-relevant questions that are unlikely to ever be answered by clinical trials. However, the largely unrealised potential of RWD is the value to be gained by supporting prospective studies and translational research. Here we describe the design and implementation of an Australian brain cancer registry, BRAIN, which is pursuing these opportunities. METHODS: BRAIN was designed by a panel of clinicians in conjunction with BIOGRID to capture comprehensive clinical data on patients diagnosed with brain tumours from diagnosis through treatment to recurrence or death. Extensive internal and external testing was undertaken, followed by implementation at multiple sites across Victoria and Tasmania. RESULTS: Between February 2021 and December 2021, a total of 350 new patients from 10 sites, including one private and two regional, were entered into BRAIN. Additionally, BRAIN supports the world's first registry trial in neuro-oncology, EX-TEM, addressing the optimal duration of post-radiation temozolomide; and BioBRAIN, a dedicated brain tumour translational program providing a pipeline for biospecimen collection matched with linked clinical data. CONCLUSIONS: Here we report on the first data collection effort in brain tumours for Australia, which we believe to be unique worldwide given the number of sites and patients involved and the extent to which the registry resource is being leveraged to support clinical and translational research. Further directions such as passive data flow and data linkages, use of artificial intelligence and inclusion of patient-entered data are being explored.
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    Including migrant oncology patients in research: A multisite pilot randomised controlled trial testing consultation audio-recordings and question prompt lists.
    Hyatt, A ; Lipson-Smith, R ; Gough, K ; Butow, P ; Jefford, M ; Hack, TF ; Hale, S ; Zucchi, E ; White, S ; Ozolins, U ; Schofield, P (Elsevier BV, 2022-08)
    Background: Oncology patients who are migrants or refugees face worse outcomes due to language and communication barriers impacting care. Interventions such as consultation audio-recordings and question prompt lists may prove beneficial in mediating communication challenges. However, designing robust research inclusive of patients who do not speak English is challenging. This study therefore aimed to: a) pilot test and assess the appropriateness of the proposed research design and methods for engaging migrant populations, and b) determine whether a multi-site RCT efficacy assessment of the communication intervention utilising these methods is feasible. Methods: This study is a mixed-methods parallel-group, randomised controlled feasibility pilot trial. Feasibility outcomes comprised assessment of: i) screening and recruitment processes, ii) design and procedures, and iii) research time and costing. The communication intervention comprised audio-recordings of a key medical consultation with an interpreter, and question prompt lists and cancer information translated into Arabic, Greek, Traditional, and Simplified Chinese. Results: Assessment of feasibility parameters revealed that despite barriers, methods utilised in this study supported the inclusion of migrant oncology patients in research. A future multi-site RCT efficacy assessment of the INFORM communication intervention using these methods is feasible if recommendations to strengthen screening and recruitment are adopted. Importantly, hiring of bilingual research assistants, and engagement with community and consumer advocates is essential. Early involvement of clinical and interpreting staff as key stakeholders is likewise recommended. Conclusion: Results from this feasibility RCT help us better understand and overcome the challenges and misconceptions about including migrant patients in clinical research.
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    SUBA-Itraconazole for Primary Antifungal Prophylaxis After Allogeneic Hematopoietic Cell Transplantation
    Lindsay, J ; Othman, J ; Kong, Y ; Yip, A ; Van Hal, S ; Larsen, S ; Bryant, C ; Gibson, J ; Kerridge, I ; Fay, K ; Stevenson, W ; Arthur, C ; Chen, SCA ; Kong, DCM ; Greenwood, M ; Pergam, SA ; Liu, C ; Slavin, MA (OXFORD UNIV PRESS INC, 2021-11-01)
    Background: Itraconazole (ITZ) is an effective agent when used as primary invasive fungal disease (IFD) prophylaxis, but is limited by drug tolerability and variability in serum concentrations. A new formulation, SUBA-itraconazole (for "super bioavailability"; S-ITZ), addresses the limitations of conventional ITZ formulations. Methods: We conducted a retrospective cohort study at 2 Australian centers to evaluate the safety, tolerability, and effectiveness of S-ITZ as primary antifungal prophylaxis in hematopoietic cell transplant (HCT) recipients without grade II-IV acute graft-vs-host disease, from day 1 until approximately day 100 (cohort A) or day 1 until neutrophil engraftment (cohort B). A total of 204 patients and 1410 trough plasma ITZ concentrations were assessed. Results: The incidence of breakthrough proven/probable IFD at day 180 was 1.0% (95% confidence interval [CI], .2%-3.2%), with 1.6% in cohort A and 0% in cohort B, and overall fungal-free survival of proven/probable IFD was 82.9% (95% CI, 76.8%-87.4%). Preengraftment early permanent S-ITZ discontinuation was 3.4% overall, with no significant difference between cohorts. No patients required cessation due to gastrointestinal intolerance attributed to S-ITZ. The geometric mean trough plasma ITZ concentration was 1130ng/mL (interquartile range, 566-1801ng/mL; coefficient of variation, 56.57%) and the median time to achieve therapeutic levels was 10 days. Conclusions: S-ITZ is a safe and well-tolerated oral formulation and is a novel alternative for primary IFD prophylaxis after HCT.
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    The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression
    Xiao, L ; Karsa, M ; Ronca, E ; Bongers, A ; Kosciolek, A ; El-Ayoubi, A ; Revalde, JL ; Seneviratne, JA ; Cheung, BB ; Cheung, LC ; Kotecha, RS ; Newbold, A ; Bjelosevic, S ; Arndt, GM ; Lock, RB ; Johnstone, RW ; Gudkov, AV ; Gurova, KV ; Haber, M ; Norris, MD ; Henderson, MJ ; Somers, K (FRONTIERS MEDIA SA, 2022-05-23)
    Rearrangements of the Mixed Lineage Leukemia (MLL/KMT2A) gene are present in approximately 10% of acute leukemias and characteristically define disease with poor outcome. Driven by the unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that the novel anti-cancer agent, curaxin CBL0137, induces decondensation of chromatin in cancer cells, delays leukemia progression and potentiates standard of care chemotherapies in preclinical KMT2A-rearranged leukemia models. Based on the promising potential of histone deacetylase (HDAC) inhibitors as targeted anti-cancer agents for KMT2A-rearranged leukemia and the fact that HDAC inhibitors also decondense chromatin via an alternate mechanism, we investigated whether CBL0137 could potentiate the efficacy of the HDAC inhibitor panobinostat in KMT2A-rearranged leukemia models. The combination of CBL0137 and panobinostat rapidly killed KMT2A-rearranged leukemia cells by apoptosis and significantly delayed leukemia progression and extended survival in an aggressive model of MLL-AF9 (KMT2A:MLLT3) driven murine acute myeloid leukemia. The drug combination also exerted a strong anti-leukemia response in a rapidly progressing xenograft model derived from an infant with KMT2A-rearranged acute lymphoblastic leukemia, significantly extending survival compared to either monotherapy. The therapeutic enhancement between CBL0137 and panobinostat in KMT2A-r leukemia cells does not appear to be mediated through cooperative effects of the drugs on KMT2A rearrangement-associated histone modifications. Our data has identified the CBL0137/panobinostat combination as a potential novel targeted therapeutic approach to improve outcome for KMT2A-rearranged leukemia.
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    Clinical covariates that improve surgical risk prediction and guide targeted prehabilitation: an exploratory, retrospective cohort study of major colorectal cancer surgery patients evaluated with preoperative cardiopulmonary exercise testing
    Bolshinsky, V ; Ismail, H ; Li, M ; Basto, J ; Schier, R ; Hagemeier, A ; Ho, K-M ; Heriot, A ; Riedel, B (BMC, 2022-05-26)
    BACKGROUND: Preoperative risk stratification is used to derive an optimal treatment plan for patients requiring cancer surgery. Patients with reversible risk factors are candidates for prehabilitation programmes. This pilot study explores the impact of preoperative covariates of comorbid disease (Charlson Co-morbidity Index), preoperative serum biomarkers, and traditional cardiopulmonary exercise testing (CPET)-derived parameters of functional capacity on postoperative outcomes after major colorectal cancer surgery. METHODS: Consecutive patients who underwent CPET prior to colorectal cancer surgery over a 2-year period were identified and a minimum of 2-year postoperative follow-up was performed. Postoperative assessment included: Clavien-Dindo complication score, Comprehensive Complication Index, Days at Home within 90 days (DAH-90) after surgery, and overall survival. RESULTS: The Charlson Co-morbidity Index did not discriminate postoperative complications, or overall survival. In contrast, low preoperative haemoglobin, low albumin, or high neutrophil count were associated with postoperative complications and reduced overall survival. CPET-derived parameters predictive of postoperative complications, DAH-90, and reduced overall survival included measures of VCO2 kinetics at anaerobic threshold (AT), peakVO2 (corrected to body surface area), and VO2 kinetics during the post-exercise recovery phase. Inflammatory parameters and CO2 kinetics added significant predictive value to peakVO2 within bi-variable models for postoperative complications and overall survival (P < 0.0001). CONCLUSION: Consideration of modifiable 'triple low' preoperative risk (anaemia, malnutrition, deconditioning) factors and inflammation will improve surgical risk prediction and guide prehabilitation. Gas exchange parameters that focus on VCO2 kinetics at AT and correcting peakVO2 to body surface area (rather than absolute weight) may improve CPET-derived preoperative risk assessment.
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    Interrogating the Impassable: A Case Series and Literature Review of Unilateral SPECT-CT Groin Visualization in Men With Penile Cancer
    O'Brien, JS ; Teh, J ; Kelly, BD ; Chen, K ; Manning, T ; Furrer, M ; Chee, J ; Lawrentschuk, N (FRONTIERS MEDIA SA, 2022-05-18)
    Penile squamous cell carcinoma (SCC) is a rare malignancy, which is known to invade local inguinal lymph nodes prior to progressing to the pelvis. Dynamic sentinel lymph node biopsy (DSLNB) is a standard for the minimally invasive assessment of lymphadenopathy in patients with subclinical groin metastasis. Hybrid 99mTc Single-Photon Emission Computed Tomography (SPECT-CT) has been shown to increase the accuracy of identifying first draining "sentinel" nodes (SN). Unilateral inguinal visualization on SPECT-CT is a rare presentation, which may increase the likelihood of a false negative SN biopsy. Retrospective analysis from three-penile cancer uro-oncologists in Melbourne, Australia identified 78 groins undergoing DSLNB for intermediate/high risk primary disease. Unilateral SPECT-CT results were observed in four patients suggesting a functional pattern of lymph diversion. Analysis confirmed malignancy (n = 2), sarcoidosis (n = 1), and evidence of local inflammation in SPECT-CT negative groins. Findings re-iterate the role of SPECT-CT a pre-operative adjunct. Experienced multimodal groin assessment using palpation, SPECT-CT, lymphoscintigraphy, and blue dye tracking remains paramount. Unilateral SN on pre-operative SPECT-CT in men with intermediate/high-risk penile SCC should elicit a higher degree of clinical suspicion. We recommend a low threshold for recommending radical inguinal lymph node dissection (ILND) for groins refractory to minimally invasive assessment.
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    "I want to get myself as fit as I can and not die just yet" - Perceptions of exercise in people with advanced cancer and cachexia: a qualitative study
    Bland, KA ; Krishnasamy, M ; Parr, EB ; Mulder, S ; Martin, P ; van Loon, LJC ; Cormie, P ; Michael, N ; Zopf, EM (BMC, 2022-05-17)
    Cachexia is a prevalent muscle wasting syndrome among people with advanced cancer that profoundly impacts patient quality of life (QoL) and physical function. Exercise can improve QoL, physical function, and overall health in people with cancer and may be an important addition to treatment approaches for cancer cachexia. Greater understanding of patients' perception of exercise can help elucidate the feasibility of implementing exercise interventions for cancer cachexia and facilitate the design of patient-centered interventions. We aimed to describe the perception of exercise in patients with advanced cancer and cachexia, and capture exercise motivators, barriers, and preferences, to inform the feasibility of exercise interventions. Individual interviews (n = 20) with patients with locally advanced or metastatic cancer with cachexia were conducted and analyzed using reflexive thematic analysis. Main themes from interviews were: 1) Life is disrupted by cancer and cachexia; 2) Exercise offers hope; 3) Exercise barriers are multifaceted; and 4) Exercise access and support are important. Participants reported that their cancer and cachexia had intensely altered their lives, including ability to exercise. Exercise was perceived as important and participants described a hope for exercise to improve their health and wellbeing. Yet, several complex exercise barriers, such as burdensome cancer symptoms and the overwhelming impact of the COVID-19 pandemic, hindered exercise participation and prevented participants from fully realizing the perceived benefits of exercise. Factors believed to improve exercise engagement and overcome exercise barriers included increased exercise support (e.g., professional supervision) and accessibility (e.g., convenient locations). Patient-reported exercise barriers and preferences can inform the design of exercise interventions, particularly within future research studies aiming to establish exercise feasibility and efficacy in people with advanced cancer and cachexia.
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    Tankyrase-mediated ADP-ribosylation is a regulator of TNF-induced death
    Liu, L ; Sandow, JJ ; Pedrioli, DML ; Samson, AL ; Silke, N ; Kratina, T ; Ambrose, RL ; Doerflinger, M ; Hu, Z ; Morrish, E ; Chau, D ; Kueh, AJ ; Fitzibbon, C ; Pellegrini, M ; Pearson, JS ; Hottiger, MO ; Webb, A ; Lalaoui, N ; Silke, J (AMER ASSOC ADVANCEMENT SCIENCE, 2022-05-01)
    Tumor necrosis factor (TNF) is a key component of the innate immune response. Upon binding to its receptor, TNFR1, it promotes production of other cytokines via a membrane-bound complex 1 or induces cell death via a cytosolic complex 2. To understand how TNF-induced cell death is regulated, we performed mass spectrometry of complex 2 and identified tankyrase-1 as a native component that, upon a death stimulus, mediates complex 2 poly-ADP-ribosylation (PARylation). PARylation promotes recruitment of the E3 ligase RNF146, resulting in proteasomal degradation of complex 2, thereby limiting cell death. Expression of the ADP-ribose-binding/hydrolyzing severe acute respiratory syndrome coronavirus 2 macrodomain sensitizes cells to TNF-induced death via abolishing complex 2 PARylation. This suggests that disruption of ADP-ribosylation during an infection can prime a cell to retaliate with an inflammatory cell death.