Sir Peter MacCallum Department of Oncology - Research Publications
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ItemEducation in youth-friendly genetic counseling(WILEY, 2021-03-31)Genetic counselors have long recognized the challenges of working with adolescents and young adults (AYA) and their families. In 2010, a framework of Youth-friendly Genetic Counseling was developed by an expert reference group with the aim to improve both care for AYAs and the experience of health professionals delivering that care. Subsequently, an education workshop was developed aimed to upskill genetic health professionals in youth-friendly genetic counseling. The workshop was piloted with genetic counselors in Australia and New Zealand. A purpose designed, pre- and post-workshop survey and post-workshop focus group was utilized for evaluation. Mean confidence scores increased pre- and post-workshop. Participants also demonstrated increases in knowledge regarding: adolescent development; developmental theory; social factors impacting on health; the needs of young people; practice challenges; youth-friendly engagement, communication, consent and confidentiality; practice approaches; principles of adolescent healthcare; ethical issues; and available services and resources. Focus group data revealed several themes relating to practice challenges, learning gains, barriers, and enablers to clinical translation and workshop feedback. Results demonstrate utility of the workshop in up-skilling genetic health professionals in the provision of youth-friendly genetic counseling. Consideration of adaptation and sustainability, by embedding this theoretical and skills-based workshop as a module within genetic counseling education, is required to ensure practice competence and the best health outcomes for young people and their families.
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ItemUtility of Ga-68-DOTA-Exendin-4 positron emission tomography-computed tomography imaging in distinguishing between insulinoma and nesidioblastosis in patients with confirmed endogenous hyperinsulinaemic hypoglycaemia(WILEY, 2021-10-01)BACKGROUND: Because management is very different, it is important to differentiate between small focal insulinomas and diffuse pancreatic dysplasia (nesidioblastosis) in patients with confirmed endogenous hyperinsulinaemic hypoglycaemia (EHH). Most insulinomas highly express glucagon-like peptide-1 receptors enabling positron emission tomography-computed tomography imaging with its radiolabelled analogue; 68 Ga-DOTA-Exendin-4 (Exendin). AIM: To determine: (i) the utility of Exendin in EHH patients in a clinical setting; and (ii) whether the degree of Exendin uptake differentiates non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) from post-gastric bypass hypoglycaemia (PGBH). METHODS: This retrospective study reviewed the clinical, biochemistry and prior imaging findings in confirmed EHH patients referred for Exendin. Accuracy of Exendin was based on surgical findings and treatment outcomes. Finally, average Exendin uptake (SUVmax) of five PGBH studies was compared with the SUVmax of a key NIPHS case report. RESULTS: Twenty of 25 consecutive patients had confirmed EHH. Exendin located insulinomas in eight of nine patients enabling successful surgical excision with rapid and durable cure. Exendin correctly identified diffuse nesidioblastosis in two of three cases requiring partial pancreatectomy for hypoglycaemia control. All three relapsed within 1.7 years with one needing completion pancreatectomy. Establishing the cause in the remainder relied on other investigations, clinical correlation and response to empirical treatment. Finally, Exendin SUVmax could not distinguish between NIPHS and PGBH. CONCLUSION: In EHH patients, Exendin accurately identifies the site of insulinoma and thereby differentiates it from nesidioblastosis but negative findings should not be ignored. Exendin is unlikely to differentiate between normal pancreatic uptake, NIPHS and PGBH.
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ItemHOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma-induced apoptosis(WILEY, 2021-09-01)The success of cancer immunotherapy is limited to a subset of patients, highlighting the need to identify the processes by which tumors evade immunity. Using CRISPR/Cas9 screening, we reveal that melanoma cells lacking HOIP, the catalytic subunit of LUBAC, are highly susceptible to both NK and CD8+ T-cell-mediated killing. We demonstrate that HOIP-deficient tumor cells exhibit increased sensitivity to the combined effect of the inflammatory cytokines, TNF and IFN-γ, released by NK and CD8+ T cells upon target recognition. Both genetic deletion and pharmacological inhibition of HOIP augment tumor cell sensitivity to combined TNF and IFN-γ. Together, we unveil a protective regulatory axis, involving HOIP, which limits a transcription-dependent form of cell death that engages both intrinsic and extrinsic apoptotic machinery upon exposure to TNF and IFN-γ. Our findings highlight HOIP inhibition as a potential strategy to harness and enhance the killing capacity of TNF and IFN-γ during immunotherapy.
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ItemAssessing the acceptability, feasibility, and usefulness of a psychosocial screening tool to patients and clinicians in a clinical genetics service in Australia(WILEY, 2021-11-17)Increasing demand for clinical genetic services may impact the resources and quality of genetic counseling, potentially impacting patient outcomes. Using a psychosocial screening tool may aid the provision of genetic counseling by reliably identifying patients' psychosocial needs. The Genetic Psychosocial Risk Instrument (GPRI) is a validated genetic-specific screening tool designed to identify psychological risk factors that predict distress in patients having genetic testing. This questionnaire-based study investigated the perceived acceptability, feasibility, and usefulness of the GPRI in patients and clinicians in routine clinical genetic practice. From December 2018 to January 2019, 154 patients attending an Australian clinical genetic service were invited to complete a paper-based survey that included the GPRI. The GPRI was scored and provided to the clinician for use in the appointment. In February 2019, clinicians completed an anonymous online survey regarding acceptability, feasibility, and usefulness of the GPRI. Descriptive statistics, chi-squared, t tests, and regression analyses were used to analyze the patient data, and descriptive statistics were employed for clinician surveys. A total of 145 patients participated (94% response rate). The average GPRI score was 46.3 (95% CI 43.6-49.0) with 41% of patients meeting the 50-point threshold indicating high risk for psychological distress. The GPRI was highly acceptable to patients, regardless of their level of psychosocial risk. Fourteen clinicians participated (54% response rate): 85% found the GPRI not too time consuming, and 86% believed it improved patient care by identifying patient needs. All were willing to use the GPRI routinely. The use of the GPRI is highly acceptable to patients and clinicians in this setting, assisting in identifying patients at risk for distress, prompting clinicians to address concerns, provide psychosocial support, and consider ongoing referral. As 41% of patients' scores indicated a high risk of distress, the GPRI is an important tool for potentially enhancing overall patient outcomes.
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ItemIL-15 Preconditioning Augments CAR T Cell Responses to Checkpoint Blockade for Improved Treatment of Solid Tumors(CELL PRESS, 2020-11-04)Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their US Food and Drug Administration (FDA) approval. However, the efficacy of CAR T cells in solid tumors is limited by tumor-induced immunosuppression, leading to the development of combination approaches, such as adjuvant programmed cell death 1 (PD-1) blockade. Current FDA-approved methods for generating CAR T cells utilize either anti-CD3 and interleukin (IL)-2 or anti-CD3/CD28 beads, which can generate a T cell product with an effector/exhausted phenotype. Whereas different cytokine preconditioning milieu, such as IL-7/IL-15, have been shown to promote T cell engraftment, the impact of this approach on CAR T cell responses to adjuvant immune-checkpoint blockade has not been assessed. In the current study, we reveal that the preconditioning of CAR T cells with IL-7/IL-15 increased CAR T cell responses to anti-PD-1 adjuvant therapy. This was associated with the emergence of an intratumoral CD8+CD62L+TCF7+IRF4- population that was highly responsive to anti-PD-1 therapy and mediated the vast majority of transcriptional and epigenetic changes in vivo following PD-1 blockade. Our data indicate that preservation of CAR T cells in a TCF7+ phenotype is crucial for their responsiveness to adjuvant immunotherapy approaches and should be a key consideration when designing clinical protocols.
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ItemConserved Tao Kinase Activity Regulates Dendritic Arborization, Cytoskeletal Dynamics, and Sensory Function in Drosophila(SOC NEUROSCIENCE, 2020-02-26)Dendritic arborization is highly regulated and requires tight control of dendritic growth, branching, cytoskeletal dynamics, and ion channel expression to ensure proper function. Abnormal dendritic development can result in altered network connectivity, which has been linked to neurodevelopmental disorders, including autism spectrum disorders (ASDs). How neuronal growth control programs tune dendritic arborization to ensure function is still not fully understood. Using Drosophila dendritic arborization (da) neurons as a model, we identified the conserved Ste20-like kinase Tao as a negative regulator of dendritic arborization. We show that Tao kinase activity regulates cytoskeletal dynamics and sensory channel localization required for proper sensory function in both male and female flies. We further provide evidence for functional conservation of Tao kinase, showing that its ASD-linked human ortholog, Tao kinase 2 (Taok2), could replace Drosophila Tao and rescue dendritic branching, dynamic microtubule alterations, and behavioral defects. However, several ASD-linked Taok2 variants displayed impaired rescue activity, suggesting that Tao/Taok2 mutations can disrupt sensory neuron development and function. Consistently, we show that Tao kinase activity is required in developing and as well as adult stages for maintaining normal dendritic arborization and sensory function to regulate escape and social behavior. Our data suggest an important role for Tao kinase signaling in cytoskeletal organization to maintain proper dendritic arborization and sensory function, providing a strong link between developmental sensory aberrations and behavioral abnormalities relevant for Taok2-dependent ASDs.SIGNIFICANCE STATEMENT Autism spectrum disorders (ASDs) are linked to abnormal dendritic arbors. However, the mechanisms of how dendritic arbors develop to promote functional and proper behavior are unclear. We identified Drosophila Tao kinase, the ortholog of the ASD risk gene Taok2, as a regulator of dendritic arborization in sensory neurons. We show that Tao kinase regulates cytoskeletal dynamics, controls sensory ion channel localization, and is required to maintain somatosensory function in vivo Interestingly, ASD-linked human Taok2 mutations rendered it nonfunctional, whereas its WT form could restore neuronal morphology and function in Drosophila lacking endogenous Tao. Our findings provide evidence for a conserved role of Tao kinase in dendritic development and function of sensory neurons, suggesting that aberrant sensory function might be a common feature of ASDs.
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ItemSUBA-Itraconazole for Primary Antifungal Prophylaxis After Allogeneic Hematopoietic Cell Transplantation(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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ItemImpact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG03.01) randomized clinical trial.(Oxford University Press (OUP), 2021)BACKGROUND: Lymphopenia may lead to worse outcomes for glioblastoma patients. This study is a secondary analysis of the CCTG CE.6 trial evaluating the impact of chemotherapy and radiation on lymphopenia, and effects of lymphopenia on overall survival (OS). METHODS: CCTG CE.6 randomized elderly glioblastoma patients (≥ 65 years) to short-course radiation alone (RT) or short-course radiation with temozolomide (RT + TMZ). Lymphopenia (mild-moderate: grade 1-2; severe: grade 3-4) was defined per CTCAE v3.0, and measured at baseline, 1 week and 4 weeks post-RT. Preselected key factors for analysis included age, sex, ECOG, resection extent, MGMT methylation, Mini-Mental State Examination, and steroid use. Multinomial logistic regression and multivariable Cox regression models were used to identify lymphopenia-associated factors and association with survival. RESULTS: Five hundred and sixty-two patients were analyzed (281 RT vs 281 RT+TMZ). At baseline, both arms had similar rates of mild-moderate (21.4% vs 21.4%) and severe (3.2% vs 2.9%) lymphopenia. However, at 4 weeks post-RT, RT+TMZ was more likely to develop lymphopenia (mild-moderate: 27.9% vs 18.2%; severe: 9.3% vs 1.8%; p<0.001). Developing any lymphopenia post-RT was associated with baseline lymphopenia (P < .001). Baseline lymphopenia (hazard ratio [HR] 1.3) was associated with worse OS (HR: 1.30, 95% confidence interval [CI] 1.05-1.62; P = .02), regardless of MGMT status. CONCLUSIONS: Development of post-RT lymphopenia is associated with addition of TMZ and baseline lymphopenia and not with RT alone in patients treated with short-course radiation. However, regardless of MGMT status, only baseline lymphopenia is associated with worse OS, which may be considered as a prognostic biomarker for elderly glioblastoma patients.
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ItemTissue-specific tumour microenvironments are an emerging determinant of immunotherapy responses(AME PUBL CO, 2020-08-01)