Sir Peter MacCallum Department of Oncology - Research Publications

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    ATRT-17. A phase II study of continuous low dose panobinostat in paediatric patients with malignant rhabdoid tumours and atypical teratoid rhabdoid tumours.
    Wood, P ; Desai, J ; Waldeck, K ; Cain, J ; Gottardo, N ; Strong, R ; Kinross, K ; Carr, M ; Jones, J ; Wong, L ; Ziegler, D ; Hansford, J ; Michael, M ; Ashley, D (Oxford University Press (OUP), 2022-06-03)
    Abstract BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumours (MRT) and atypical teratoid rhabdoid tumours (ATRT) in pre-clinical models. We report results of the open label, phase II study of oral panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumour activity of low dose, continuous oral panobinostat as well as its associated toxicities. To assess the biological activity of low dose panobinostat by measuring histone H4 acetylation status in peripheral mononuclear cells (PMNC), and differentiation markers. METHODS: Following primary institutional standard of care induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2/day, with a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat at different dosing levels. Patients were monitored for toxicity; dose reductions were in decrements of 2mg/m2/day. RESULTS: A total of 13 patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled. The average age at enrollment was 3.6 years (range 0.8-6.8 years). The mean treatment duration was 206 days (13-344 days). Currently, six patients (42.9%) remain on study with a mean study duration of 531 days (range 13-895 days). 6/14 patients (42.9%) were removed due to disease progression at a mean study duration of 245 days (44-560 days). 2/14 patients (14.3%) withdrew due to toxicity. 12/14 patients (85.7%) required dose reductions. The main toxicities were thrombocytopaenia and leukopaenia (Grade III-IV). Real-time pharmacodynamic assessment of panobinostat, at a dose as low as 6mg/m2/day resulted in significant acetylation of histone H4 in PMNC. CONCLUSIONS: Treatment with low dose panobinostat is well tolerated in infants and children with MRT/ATRT, with significant acetylation of histone H4 in PMNC.
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    22. International Multicenter Study Comparing Cancer to Non-Cancer Patients with COVID-19: Impact of Risk Factors and Treatment Modalities on Outcome
    Hachem, RY ; Chaftari, A-M ; Masayuki, N ; Hamerschlak, N ; Dagher, H ; Jiang, Y ; Siddiqui, B ; Bayle, A ; Somer, R ; Cruz, AF ; Gorak, E ; Bhinder, A ; Mori, N ; Datoguia, T ; Shelanski, S ; Dragvich, T ; Kiat, YEV ; Fakhreddine, S ; Hanna, PA ; Chemaly, RF ; Mulanovich, VE ; Adachi, J ; Borjan, J ; Khawaja, F ; Granwehr, B ; John, T ; Guevara, EY ; Torres, HA ; Slavin, M ; Teh, B ; Subbiah, V ; Kontoyiannis, DP ; Malek, A ; Raad, II (Oxford University Press (OUP), 2021-12-04)
    Abstract Background Given the limited collaborative international studies that evaluated COVID-19 in patients with cancer in comparison to patients without cancer, we aimed to determine the independent risk factors associated with increased 30-day mortality and the impact of novel treatment modalities in a large group of cancer and non-cancer patients with COVID-19 from multiple countries. Methods We retrospectively collected de-identified data on cancer and non-cancer patients diagnosed with COVID-19 between January and November 2020, at 16 centers in Asia, Australia, Europe, North America, and South America. A logistic regression model was used to identify independent predictors of all-cause mortality within 30 days after COVID-19 diagnosis. Results Of the total 4015 COVID-19 confirmed patients entered, we analyzed 3966 patients, 1115 cancer and 2851 non-cancer patients. Cancer patients were older than non-cancer patients (median age, 61 vs 50 years; p< 0.0001); more likely to be pancytopenic , had pulmonary disorders, hypertension, diabetes mellitus. In addition, they were more likely to present with higher inflammatory biomarkers (D-dimer, ferritin and procalcitonin), but were less likely to present with clinical symptoms. By multivariable logistic regression analysis, cancer was an independent risk factor for 30-day mortality (OR 1.46; 95% CI 1.03 to 2.07; p=0.035). Older age (≥65 years) was the strongest predictor of 30-day mortality in all patients (OR 4.55; 95% CI 3.34 to 6.20; p< 0.0001). Remdesivir was the only therapeutic agent independently associated with decreased 30-day mortality (OR 0.58; CI 0.39-0.88; p=0.009). Among patients on low-flow oxygen at admission, patients who received remdesivir had a lower 30-day mortality rate than those who were on high flow oxygen (5.9% vs 17.6%; p=0.03). Patients transfused with convalescent plasma within 1 day of diagnosis had a lower 30-day mortality rate than those transfused later (1% vs 7%, p=0.04). Conclusion Cancer is an independent risk factor for increased 30-day all-cause mortality from COVID-19. Remdesivir, particularly in patients receiving low-flow oxygen, can reduce 30-day all-cause mortality, as well as convalescent plasma given early after COVID-19 diagnosis. Disclosures Roy F. Chemaly, MD, MPH, FACP, FIDSA, AiCuris (Grant/Research Support)Ansun Biopharma (Consultant, Grant/Research Support)Chimerix (Consultant, Grant/Research Support)Clinigen (Consultant)Genentech (Consultant, Grant/Research Support)Janssen (Consultant, Grant/Research Support)Karius (Grant/Research Support)Merck (Consultant, Grant/Research Support)Molecular Partners (Consultant, Advisor or Review Panel member)Novartis (Grant/Research Support)Oxford Immunotec (Consultant, Grant/Research Support)Partner Therapeutics (Consultant)Pulmotec (Consultant, Grant/Research Support)Shire/Takeda (Consultant, Grant/Research Support)Viracor (Grant/Research Support)Xenex (Grant/Research Support) Fareed Khawaja, MBBS, Eurofins Viracor (Research Grant or Support) Monica Slavin, MBBS,MD, F2G (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Pfizer (Advisor or Review Panel member) Dimitrios P. Kontoyiannis, MD, Astellas (Consultant)Cidara Therapeutics (Advisor or Review Panel member)Gilead Sciences (Consultant, Grant/Research Support, Other Financial or Material Support, Honoraria)
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    Water or Medium: Dose Specification in Trials and Real Life
    Kron, T ; Hardcastle, N (IOP Publishing, 2020-10-16)
    Abstract Radiation dose is the therapeutic agent in radiotherapy where the objective is to maximise radiation dose to a target while minimising the dose to surrounding healthy tissues. Dose in this context is typically associated with the quantity “absorbed dose” as energy deposited per unit mass and measured in J/kg of tissue. However, even if high doses are delivered (no stochastic distribution considered) and photon or electron radiation is considered (no neutrons or heavy charged particles), there will be differences in the actual dose delivered to different tissue types as the stopping power for the electrons that deliver the vast majority of dose varies with elemental composition. Historically, radiation beam calibration and dose calculations were performed in water as a readily available, easily standardised material that closely matches the radiation properties of many human tissues. However, many superior dose calculation algorithms that have recently become available due to improved computer power (Monte Carlo Calculations, Acuros) calculate dose as deposited in the medium. The present paper examines arguments for both and proposes that based on the current scientific and political developments specification of dose as dose to medium would be the more robust and future proof choice.
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    Experiences in teaching grid computing to advanced level students
    Sinnott, R. O. ; Stell, A. J. ; Watt, J. (IEEE, 2005)
    The development of teaching materials for future software engineers is critical to the long term success of the Grid. At present however there is considerable turmoil in the Grid community both within the standards and the technology base underpinning these standards. In this context, it is especially challenging to develop teaching materials that have some sort of lifetime beyond the next wave of Grid middleware and standards. In addition, the current way in which Grid security is supported and delivered has two key problems. Firstly in the case of the UK e-Science community, scalability issues arise from a central certificate authority. Secondly, the current security mechanisms used by the Grid community are not fine grained enough. In this paper we outline how these issues are being addressed through the development of a Grid Computing module supported by an advanced authorisation infrastructure at the University of Glasgow.