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1. Dynamic associations between glucose and ecological momentary cognition in Type 1 Diabetes.

Author

Jung, L, Fonseca, L, Sliwinski, M, Weinstock, R, Grinspoon, E, Xu, I, Strong, R, Singh, S, Van Dongen, H, Frumkin, M, Bulger, J, Cleveland, M, Janess, K, Kudva, Y, Pratley, R, Rickels, M, Rizvi, S, Chaytor, N, Germine, L, Hawks, Z, and Beck, Emorie

Abstract

Type 1 diabetes (T1D) is a chronic condition characterized by glucose fluctuations. Laboratory studies suggest that cognition is reduced when glucose is very low (hypoglycemia) and very high (hyperglycemia). Until recently, technological limitations prevented researchers from understanding how naturally-occurring glucose fluctuations impact cognitive fluctuations. This study leveraged advances in continuous glucose monitoring (CGM) and cognitive ecological momentary assessment (EMA) to characterize dynamic, within-person associations between glucose and cognition in naturalistic environments. Using CGM and EMA, we obtained intensive longitudinal measurements of glucose and cognition (processing speed, sustained attention) in 200 adults with T1D. First, we used hierarchical Bayesian modeling to estimate dynamic, within-person associations between glucose and cognition. Consistent with laboratory studies, we hypothesized that cognitive performance would be reduced at low and high glucose, reflecting cognitive vulnerability to glucose fluctuations. Second, we used data-driven lasso regression to identify clinical characteristics that predicted individual differences in cognitive vulnerability to glucose fluctuations. Large glucose fluctuations were associated with slower and less accurate processing speed, although slight glucose elevations (relative to person-level means) were associated with faster processing speed. Glucose fluctuations were not related to sustained attention. Seven clinical characteristics predicted individual differences in cognitive vulnerability to glucose fluctuations: age, time in hypoglycemia, lifetime severe hypoglycemic events, microvascular complications, glucose variability, fatigue, and neck circumference. Results establish the impact of glucose on processing speed in naturalistic environments, suggest that minimizing glucose fluctuations is important for optimizing processing speed, and identify several clinical characteristics that may exacerbate cognitive vulnerability to glucose fluctuations.

Published
2024

3. Revival of the magnetar PSR J1622-4950: observations with MeerKAT, Parkes, XMM-Newton, Swift, Chandra, and NuSTAR

Author

Camilo, F., Scholz, P., Serylak, M., Buchner, S., Merryfield, M., Kaspi, V. M., Archibald, R. F., Bailes, M., Jameson, A., van Straten, W., Sarkissian, J., Reynolds, J. E., Johnston, S., Hobbs, G., Abbott, T. D., Adam, R. M., Adams, G. B., Alberts, T., Andreas, R., Asad, K. M. B., Baker, D. E., Baloyi, T., Bauermeister, E. F., Baxana, T., Bennett, T. G. H., Bernardi, G., Booisen, D., Booth, R. S., Botha, D. H., Boyana, L., Brederode, L. R. S., Burger, J. P., Cheetham, T., Conradie, J., Conradie, J. P., Davidson, D. B., de Bruin, G., de Swardt, B., de Villiers, C., de Villiers, D. I. L., de Villiers, M. S., de Villiers, W., de Waal, C., Dikgale, M. A., Toit, G. du, Toit, L. J. du, Esterhuyse, S. W. P., Fanaroff, B., Fataar, S., Foley, A. R., Foster, G., Fourie, D., Gamatham, R., Gatsi, T., Geschke, R., Goedhart, S., Grobler, T. L., Gumede, S. C., Hlakola, M. J., Hokwana, A., Hoorn, D. H., Horn, D., Horrell, J., Hugo, B., Isaacson, A., Jacobs, O., van Rensburg, J. P. Jansen, Jonas, J. L., Jordaan, B., Joubert, A., Joubert, F., Jozsa, G. I. G., Julie, R., Julius, C. C., Kapp, F., Karastergiou, A., Karels, F., Kariseb, M., Karuppusamy, R., Kasper, V., Knox-Davies, E. C., Koch, D., Kotze, P. P. A., Krebs, A., Kriek, N., Kriel, H., Kusel, T., Lamoor, S., Lehmensiek, R., Liebenberg, D., Liebenberg, I., Lord, R. T., Lunsky, B., Mabombo, N., Macdonald, T., Macfarlane, P., Madisa, K., Mafhungo, L., Magnus, L. G., Magozore, C., Mahgoub, O., Main, J. P. L., Makhathini, S., Malan, J. A., Malgas, P., Manley, J. R., Manzini, M., Marais, L., Marais, N., Marais, S. J., Maree, M., Martens, A., Matshawule, S. D., Matthysen, N., Mauch, T., Nally, L. D. Mc, Merry, B., Millenaar, R. P., Mjikelo, C., Mkhabela, N., Mnyandu, N., Moeng, I. T., Mokone, O. J., Monama, T. E., Montshiwa, K., Moss, V., Mphego, M., New, W., Ngcebetsha, B., Ngoasheng, K., Niehaus, H., Ntuli, P., Nzama, A., Obies, F., Obrocka, M., Ockards, M. T., Olyn, C., Oozeer, N., Otto, A. J., Padayachee, Y., Passmoor, S., Patel, A. A., Paula, S., Peens-Hough, A., Pholoholo, B., Prozesky, P., Rakoma, S., Ramaila, A. J. T., Rammala, I., Ramudzuli, Z. R., Rasivhaga, M., Ratcliffe, S., Reader, H. C., Renil, R., Richter, L., Robyntjies, A., Rosekrans, D., Rust, A., Salie, S., Sambu, N., Schollar, C. T. G., Schwardt, L., Seranyane, S., Sethosa, G., Sharpe, C., Siebrits, R., Sirothia, S. K., Slabber, M. J., Smirnov, O., Smith, S., Sofeya, L., Songqumase, N., Spann, R., Stappers, B., Steyn, D., Steyn, T. J., Strong, R., Struthers, A., Stuart, C., Sunnylall, P., Swart, P. S., Taljaard, B., Tasse, C., Taylor, G., Theron, I. P., Thondikulam, V., Thorat, K., Tiplady, A., Toruvanda, O., van Aardt, J., van Balla, T., Heever, L. van den, van der Byl, A., van der Merwe, C., van der Merwe, P., van Niekerk, P. C., van Rooyen, R., van Staden, J. P., van Tonder, V., van Wyk, R., Wait, I., Walker, A. L., Wallace, B., Welz, M., Williams, L. P., Xaia, B., Young, N., and Zitha, S.

Subjects
Astrophysics - High Energy Astrophysical Phenomena
Abstract

New radio (MeerKAT and Parkes) and X-ray (XMM-Newton, Swift, Chandra, and NuSTAR) observations of PSR J1622-4950 indicate that the magnetar, in a quiescent state since at least early 2015, reactivated between 2017 March 19 and April 5. The radio flux density, while variable, is approximately 100x larger than during its dormant state. The X-ray flux one month after reactivation was at least 800x larger than during quiescence, and has been decaying exponentially on a 111+/-19 day timescale. This high-flux state, together with a radio-derived rotational ephemeris, enabled for the first time the detection of X-ray pulsations for this magnetar. At 5%, the 0.3-6 keV pulsed fraction is comparable to the smallest observed for magnetars. The overall pulsar geometry inferred from polarized radio emission appears to be broadly consistent with that determined 6-8 years earlier. However, rotating vector model fits suggest that we are now seeing radio emission from a different location in the magnetosphere than previously. This indicates a novel way in which radio emission from magnetars can differ from that of ordinary pulsars. The torque on the neutron star is varying rapidly and unsteadily, as is common for magnetars following outburst, having changed by a factor of 7 within six months of reactivation., Comment: Published in ApJ (2018 April 5); 13 pages, 4 figures

Published
2018
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6. Design of aging intervention studies: the NIA interventions testing program

Author

Nadon, N., Strong, R., Miller, R., Nelson, J., Javors, M., Sharp, Z., Peralba, J., and Harrison, D.

Abstract

Abstract: The field of biogerontology has made great strides towards understanding the biological processes underlying aging, and the time is ripe to look towards applying this knowledge to the pursuit of aging interventions. Identification of safe, inexpensive, and non-invasive interventions that slow the aging process and promote healthy aging could have a significant impact on quality of life and health care expenditures for the aged. While there is a plethora of supplements and interventions on the market that purport to slow aging, the evidence to validate such claims is generally lacking. Here we describe the development of an aging interventions testing program funded by the National Institute on Aging (NIA) to test candidate interventions in a model system. The development of this program highlights the challenges of long-term intervention studies and provides approaches to cope with the stringent requirements of a multi-site testing program.

Published
2024
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11. Systems-Level Change to Alleviate Barriers to Cancer Clinical Trial Access for Adolescents and Young Adults in Australia.

Author

Ellis J.A., Malalasekera V.S., Allan C., Choong P.F., Hansford J.R., Hehir R., Morello N., O'Callaghan S., Orme L., Phillipson N., Rosenthal M.A., Sawyer S., Strong R., Super L., Watt A., Williams C., Woollett A., Robertson A., Lewin J., Ellis J.A., Malalasekera V.S., Allan C., Choong P.F., Hansford J.R., Hehir R., Morello N., O'Callaghan S., Orme L., Phillipson N., Rosenthal M.A., Sawyer S., Strong R., Super L., Watt A., Williams C., Woollett A., Robertson A., and Lewin J.

Abstract

Purpose: International data demonstrate association between clinical trial participation and reduced cancer mortality. Adolescents and young adults (AYA) have low clinical trial enrollment rates. We established a program to understand local barriers and develop targeted solutions that lead to greater AYA clinical trial participation. Method(s): A steering committee (SC) with expertise in adult and pediatric oncology, research ethics, and consumer representation was formed. The SC mapped barriers related to AYA trial access and established working groups (WGs) around three themes. Result(s): The Regulatory Awareness WG identified a lack of understanding of processes that support protocol approval for clinical trials across the AYA age range. A guideline to raise awareness was developed. The Access WG identified challenges for young adults (18-25 years) to access a pediatric hospital to enroll in a pediatric trial. A procedure was developed to streamline applications for access. The first six applications using this procedure have been successful. The Availability WG identified lack of pediatric-Adult oncology reciprocal relationships as a barrier to awareness of open trials, and future collaboration. An AYA Craft Group Framework was established to grow relationships within tumor streams across institutions; two craft groups are now operating locally. An additional achievement was a successful request to the Therapeutic Goods Administration for Australian adoption of the Food and Drug Administration Guidance on Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials. Conclusion(s): This multipronged approach to improving AYA clinical trial access has relevance for other health environments. Our knowledge products are available as an online toolkit. Copyright © Justine A. Ellis et al., 2022; Published by Mary Ann Liebert, Inc. 2022.

Published
2022

12. A phase ii study of continuous low dose panobinostat in paediatric patients with malignant rhabdoid tumours and atypical teratoid rhabdoid tumours.

Author

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., 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., and Ashley D.

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. METHOD(S): 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. RESULT(S): 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. CONCLUSION(S): Treatment with low dose panobinostat is well tolerated in infants and

Published
2022

13. Systems-Level Change to Alleviate Barriers to Cancer Clinical Trial Access for Adolescents and Young Adults in Australia

Author

Ellis, JA, Malalasekera, VS, Allan, C, Choong, PF, Hansford, JR, Hehir, R, Morello, N, O'Callaghan, S, Orme, L, Phillipson, N, Rosenthal, MA, Sawyer, S, Strong, R, Super, L, Watt, A, Williams, C, Woollett, A, Robertson, A, Lewin, J, Ellis, JA, Malalasekera, VS, Allan, C, Choong, PF, Hansford, JR, Hehir, R, Morello, N, O'Callaghan, S, Orme, L, Phillipson, N, Rosenthal, MA, Sawyer, S, Strong, R, Super, L, Watt, A, Williams, C, Woollett, A, Robertson, A, and Lewin, J

Abstract

Purpose: International data demonstrate association between clinical trial participation and reduced cancer mortality. Adolescents and young adults (AYA) have low clinical trial enrollment rates. We established a program to understand local barriers and develop targeted solutions that lead to greater AYA clinical trial participation. Methods: A steering committee (SC) with expertise in adult and pediatric oncology, research ethics, and consumer representation was formed. The SC mapped barriers related to AYA trial access and established working groups (WGs) around three themes. Results: The Regulatory Awareness WG identified a lack of understanding of processes that support protocol approval for clinical trials across the AYA age range. A guideline to raise awareness was developed. The Access WG identified challenges for young adults (18-25 years) to access a pediatric hospital to enroll in a pediatric trial. A procedure was developed to streamline applications for access. The first six applications using this procedure have been successful. The Availability WG identified lack of pediatric-adult oncology reciprocal relationships as a barrier to awareness of open trials, and future collaboration. An AYA Craft Group Framework was established to grow relationships within tumor streams across institutions; two craft groups are now operating locally. An additional achievement was a successful request to the Therapeutic Goods Administration for Australian adoption of the Food and Drug Administration Guidance on Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials. Conclusion: This multipronged approach to improving AYA clinical trial access has relevance for other health environments. Our knowledge products are available as an online toolkit.

Published
2022

14. A PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMOURS AND ATYPICAL TERATOID RHABDOID TUMOURS

Author

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, 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, and Ashley, D

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 a

Published
2022

25. Obituaries

Author

Elder, William H., Schorger, A. W., Palmer, T. S., Jewett, Stanley G., Strong, R. M., and Murphy, Robert Cushman

Published
1951
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32. DOPAL initiates αSynuclein-mediated impaired proteostasis in neuronal projections leading to enhanced vulnerability in Parkinson’s disease

Author

Masato, A., primary, Plotegher, N., additional, Thor, A., additional, Adams, S., additional, Sandre, M., additional, Cogo, S., additional, De Lazzari, F., additional, Fontana, C. M., additional, Martinez, P. A., additional, Strong, R., additional, Bellucci, A., additional, Bisaglia, M., additional, Greggio, E., additional, Valle, L. Dalla, additional, Boassa, D., additional, and Bubacco, L., additional

Published
2021
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33. Systems-Level Change to Alleviate Barriers to Cancer Clinical Trial Access for Adolescents and Young Adults in Australia.

Author

Ellis J.A., Malalasekera V.S., Allan C., Choong P.F., Hansford J.R., Hehir R., Morello N., O'Callaghan S., Orme L., Phillipson N., Rosenthal M.A., Sawyer S., Strong R., Super L., Watt A., Williams C., Woollett A., Robertson A., Lewin J., Ellis J.A., Malalasekera V.S., Allan C., Choong P.F., Hansford J.R., Hehir R., Morello N., O'Callaghan S., Orme L., Phillipson N., Rosenthal M.A., Sawyer S., Strong R., Super L., Watt A., Williams C., Woollett A., Robertson A., and Lewin J.

Abstract

Purpose: International data demonstrate association between clinical trial participation and reduced cancer mortality. Adolescents and young adults (AYA) have low clinical trial enrollment rates. We established a program to understand local barriers and develop targeted solutions that lead to greater AYA clinical trial participation. Method(s): A steering committee (SC) with expertise in adult and pediatric oncology, research ethics, and consumer representation was formed. The SC mapped barriers related to AYA trial access and established working groups (WGs) around three themes. Result(s): The Regulatory Awareness WG identified a lack of understanding of processes that support protocol approval for clinical trials across the AYA age range. A guideline to raise awareness was developed. The Access WG identified challenges for young adults (18-25 years) to access a pediatric hospital to enroll in a pediatric trial. A procedure was developed to streamline applications for access. The first six applications using this procedure have been successful. The Availability WG identified lack of pediatric-adult oncology reciprocal relationships as a barrier to awareness of open trials, and future collaboration. An AYA Craft Group Framework was established to grow relationships within tumor streams across institutions; two craft groups are now operating locally. An additional achievement was a successful request to the Therapeutic Goods Administration for Australian adoption of the Food and Drug Administration Guidance on Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials. Conclusion(s): This multipronged approach to improving AYA clinical trial access has relevance for other health environments. Our knowledge products are available as an online toolkit.

Published
2021

34. A phase II study of continuous low dose panobinostat in paediatric patients with malignant rhabdoid tumors/atypical teratoid rhabdoid tumors.

Author

Wood P., Strong R., Kinross K., Carr M., Jones J., Wong L., Ziegler D., Cain J., Hansford J., Michael M., Ashley D., Waldeck K., Gottardo N., Desai J., Wood P., Strong R., Kinross K., Carr M., Jones J., Wong L., Ziegler D., Cain J., Hansford J., Michael M., Ashley D., Waldeck K., Gottardo N., and Desai J.

Abstract

BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens. METHOD(S): Following cycles of 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 following 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. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2. RESULT(S): Six patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44-327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC. CONCLUSION(S): Treatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.

Published
2021

35. Increasing access to clinical trials for adolescents and young adults (AYA)with cancer.

Author

Watt A., Super L., Williams C., Robertson A., Lewin J., Ellis J., Woollett A., Allan C., Ball N., Choong P., Conyers R., Hansford J., Hehir R., Morello N., O'Callaghan S., Orme L., Sawyer S., Strong R., Watt A., Super L., Williams C., Robertson A., Lewin J., Ellis J., Woollett A., Allan C., Ball N., Choong P., Conyers R., Hansford J., Hehir R., Morello N., O'Callaghan S., Orme L., Sawyer S., and Strong R.

Abstract

Aims: International data demonstrate strong correlation between clinical trial participation and improved cancer survival. Adolescents and young adults (AYA) have low enrolment rates onto clinical trials and considerable international effort has worked to understand barriers to AYA trial access. In 2018, the Victorian Comprehensive Cancer Centre (VCCC) established a programof work to understand local barriers to AYA trial access, with the aim of developing targeted solutions that lead to greater AYA trial participation. Method(s): A steering committee (SC) was assembled, including expertise in adult and paediatric oncology, research ethics and governance, and consumer representation. The SC mapped Victorian barriers related to AYA trial access, and establishedWorking Groups (WG) around three themes: Ethics and Governance, Access, and Availability. EachWGwas tasked with identifying solutions to their assigned barriers. Result(s): Identified ethics barriers for AYA trials in Victoria were found to be perceived. A guideline document was produced to raise awareness of current processes that support the approval of protocols with age eligibility less than or equal to 18 years. The AccessWGidentified the most significant barrier was young adult (18-25 years) access to a paediatric hospital to enrol in a paediatric trial. A procedure has been written to streamline applications to Hospital Executive for young adult access (pending Executive approval). The availability WG identified a lack of reciprocal relationships between paediatric and adult oncology as a key barrier to awareness of open trials, and to future research collaboration. An 'AYA Craft Group' Framework has been established to support growth of such relationships within relevant tumour streams across institutions. Conclusion(s): A multi-pronged approach to improving AYA cancer clinical trial accrual has been developed. Although our program of work is Victorian based, the AYA trial equity issue should be on the

Published
2021

41. A PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMORS/ATYPICAL TERATOID RHABDOID TUMORS

Author

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, 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, and Ashley, D

Abstract

BACKGROUND

Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens.

METHODS

Following cycles of 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 following 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. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2.

RESULTS

Six patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44–327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC.

CONCLUSIONS

Treatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.

Published
2020

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