Sir Peter MacCallum Department of Oncology - Research Publications

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    Gelfoam slurry tract occlusion after computed tomography-guided percutaneous lung biopsy: Does it prevent major pneumothorax?
    Sum, R ; Lau, T ; Paul, E ; Lau, K (WILEY, 2021-06-13)
    INTRODUCTION: Computed tomography (CT)-guided lung biopsy is a frequently performed procedure in the diagnostic workup for suspicious lung nodules that can be complicated by pneumothorax. This retrospective study assessed the efficacy of biopsy tract occlusion with a gelatin sponge slurry for preventing post-biopsy pneumothorax. METHODS: Retrospective analysis was conducted on consecutive adult patients who underwent CT-guided lung biopsy over a 10-year period. Age, gender, existing chronic obstructive pulmonary disease (COPD), evidence of emphysema on CT, location of the lesion and the presence of pneumothorax on post-procedure CT and 4-h chest radiograph were recorded. RESULTS: Two hundred and ninety-six patients were included (126 patients in the non-gelfoam group and 170 in the gelfoam group). When gelfoam was used, risk of developing an immediate pneumothorax was lower (P = 0.032). Patients with emphysema were 2.4 times more likely to develop a delayed pneumothorax without gelfoam (P = 0.034). There was a significantly higher risk of both immediate and delayed pneumothorax in non-peripheral lesions without gelfoam (P = 0.001 and P = 0.002, respectively). The frequency of requiring a chest tube to treat a pneumothorax was 86% lower when gelfoam was used (P = 0.012). CONCLUSION: Gelfoam is effective in preventing immediate pneumothorax. In patients with emphysema, there was a significantly higher risk of delayed pneumothorax without gelfoam. Additionally, non-peripheral lesions were more likely to develop pneumothorax when gelfoam was not used. The use of gelfoam was especially important in preventing the development of major pneumothoraces that would require drainage with a chest tube.
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    Glial Hedgehog signalling and lipid metabolism regulate neural stem cell proliferation in Drosophila
    Dong, Q ; Zavortink, M ; Froldi, F ; Golenkina, S ; Lam, T ; Cheng, LY (WILEY, 2021-03-10)
    The final size and function of the adult central nervous system (CNS) are determined by neuronal lineages generated by neural stem cells (NSCs) in the developing brain. In Drosophila, NSCs called neuroblasts (NBs) reside within a specialised microenvironment called the glial niche. Here, we explore non-autonomous glial regulation of NB proliferation. We show that lipid droplets (LDs) which reside within the glial niche are closely associated with the signalling molecule Hedgehog (Hh). Under physiological conditions, cortex glial Hh is autonomously required to sustain niche chamber formation. Upon FGF-mediated cortex glial overgrowth, glial Hh non-autonomously activates Hh signalling in the NBs, which in turn disrupts NB cell cycle progression and its ability to produce neurons. Glial Hh's ability to signal to NB is further modulated by lipid storage regulator lipid storage droplet-2 (Lsd-2) and de novo lipogenesis gene fatty acid synthase 1 (Fasn1). Together, our data suggest that glial-derived Hh modified by lipid metabolism mechanisms can affect the neighbouring NB's ability to proliferate and produce neurons.
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    Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion-Positive NSCLC.
    Drilon, A ; Chiu, C-H ; Fan, Y ; Cho, BC ; Lu, S ; Ahn, M-J ; Krebs, MG ; Liu, SV ; John, T ; Otterson, GA ; Tan, DSW ; Patil, T ; Dziadziuszko, R ; Massarelli, E ; Seto, T ; Doebele, RC ; Pitcher, B ; Kurtsikidze, N ; Heinzmann, S ; Siena, S (Elsevier BV, 2022-06)
    Introduction: Entrectinib is an approved tyrosine kinase inhibitor (TKI) for ROS1 fusion-positive NSCLC. An updated integrated analysis of entrectinib from the ALKA-372-001, STARTRK-1, and STARTRK-2 trials is presented, with substantially longer follow-up, more patients, and the first description of the median overall survival (OS). An exploratory analysis of entrectinib in ROS1 fusion-positive NSCLC with the central nervous system (CNS)-only progression post-crizotinib is reported. Methods: Adults with ROS1 fusion-positive, locally advanced or metastatic NSCLC who received at least one dose of entrectinib and had 12 months or longer of follow-up were included in the analysis. Co-primary end points were confirmed objective response rate (ORR) and duration of response (DoR) by blinded independent central review. The data cutoff was on August 31, 2020. Results: The efficacy-assessable population comprised 168 ROS1 TKI-naïve patients. The median survival follow-up was 29.1 months (interquartile range, 21.8-35.9). The ORR was 68% (95% confidence interval [CI]: 60.2-74.8); the median DoR was 20.5 months. The median progression-free survival (PFS) was 15.7 months and the median OS was 47.8 months. In the 25 patients with measurable baseline CNS metastases, the intracranial ORR was 80% (95% CI: 59.3-93.2), median intracranial DoR was 12.9 months, and median intracranial PFS was 8.8 months. Among 18 patients with CNS-only progression on previous crizotinib treatment, two achieved a partial response (11%) and four had stable disease (22%). In seven patients with measurable CNS disease from this cohort, the intracranial ORR was 14% (1 partial response). Conclusions: Entrectinib is active and achieves prolonged survival in ROS1 TKI-naïve patients with ROS1 fusion-positive NSCLC. Modest activity is seen in patients with CNS-only progression post-crizotinib.
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    Aurora Kinase A Is an Independent Predictor of Invasive Recurrence in Breast Ductal Carcinoma in situ
    Miligy, IM ; Toss, MS ; Gorringe, KL ; Ellis, IO ; Green, AR ; Rakha, EA (KARGER, 2022-05-09)
    INTRODUCTION: Aurora Kinase A (AURKA/STK15) has a role in centrosome duplication and is a regulator of mitotic cell proliferation. It is over-expressed in breast cancer and other cancers, however; its role in ductal carcinoma in situ (DCIS) remains to be defined. This study aims to characterize AURKA protein expression in DCIS and evaluate its prognostic significance. METHODS: AURKA was assessed immunohistochemically in a large well-characterized cohort of DCIS (n = 776 pure DCIS and 239 DCIS associated with invasive breast cancer [DCIS-mixed]) with long-term follow-up data (median = 105 months) and basic molecular characterization. RESULTS: High AURKA expression was observed in 15% of DCIS cases and was associated with features of aggressiveness including larger tumour size, high nuclear grade, hormone receptor negativity, HER2 positivity, and high Ki67 proliferation index. AURKA expression was higher in DCIS associated with invasive breast cancer than in pure DCIS (p < 0.0001). In the DCIS-mixed cohort, the invasive component showed higher AURKA expression than the DCIS component (p < 0.0001). Outcome analysis revealed that AURKA was a predictor of invasive recurrence (p = 0.002). CONCLUSION: High AURKA expression is associated with poor prognosis in DCIS and might be a potential marker to predict DCIS progression to invasive disease.
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    Effectiveness of the conservation areas on the Mornington Peninsula for the common resident shorebird species using citizen science data
    Wijewardhana, UA ; Apputhurai, P ; Jayawardana, M ; Meyer, D ; Zhang, Y (PUBLIC LIBRARY SCIENCE, 2022-05-04)
    Conservation areas are critical for biodiversity conservation, but few citizen science studies have evaluated their efficiency. In the absence of thorough survey data, this study assessed which species benefit most from conservation areas using citizen science bird counts extracted from the Atlas of Living Australia. This was accomplished by fitting temporal models using citizen science data taken from ALA for the years 2010-2019 using the INLA approach. The trends for six resident shorebird species were compared to those for the Australian Pied Oystercatcher, with the Black-fronted Dotterel, Red-capped Dotterel, and Red-kneed Dotterel exhibiting significantly steeper increasing trends. For the Black-fronted Dotterel, Masked Lapwing, and Red-kneed Dotterel, steeper rising trends were recorded in conservation areas than in other locations. The Dotterel species' conservation status is extremely favourable. This study demonstrates that, with some limits, statistical models can be used to track the persistence of resident shorebirds and to investigate the factors affecting these data.
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    Management of Patients with Advanced Prostate Cancer: Report from the Advanced Prostate Cancer Consensus Conference 2021.
    Gillessen, S ; Armstrong, A ; Attard, G ; Beer, TM ; Beltran, H ; Bjartell, A ; Bossi, A ; Briganti, A ; Bristow, RG ; Bulbul, M ; Caffo, O ; Chi, KN ; Clarke, CS ; Clarke, N ; Davis, ID ; de Bono, JS ; Duran, I ; Eeles, R ; Efstathiou, E ; Efstathiou, J ; Ekeke, ON ; Evans, CP ; Fanti, S ; Feng, FY ; Fizazi, K ; Frydenberg, M ; George, D ; Gleave, M ; Halabi, S ; Heinrich, D ; Higano, C ; Hofman, MS ; Hussain, M ; James, N ; Jones, R ; Kanesvaran, R ; Khauli, RB ; Klotz, L ; Leibowitz, R ; Logothetis, C ; Maluf, F ; Millman, R ; Morgans, AK ; Morris, MJ ; Mottet, N ; Mrabti, H ; Murphy, DG ; Murthy, V ; Oh, WK ; Ost, P ; O'Sullivan, JM ; Padhani, AR ; Parker, C ; Poon, DMC ; Pritchard, CC ; Rabah, DM ; Rathkopf, D ; Reiter, RE ; Rubin, M ; Ryan, CJ ; Saad, F ; Sade, JP ; Sartor, O ; Scher, HI ; Shore, N ; Skoneczna, I ; Small, E ; Smith, M ; Soule, H ; Spratt, DE ; Sternberg, CN ; Suzuki, H ; Sweeney, C ; Sydes, MR ; Taplin, M-E ; Tilki, D ; Tombal, B ; Türkeri, L ; Uemura, H ; Uemura, H ; van Oort, I ; Yamoah, K ; Ye, D ; Zapatero, A ; Omlin, A (Elsevier BV, 2022-07)
    BACKGROUND: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence. OBJECTIVE: To present the voting results from APCCC 2021. DESIGN, SETTING, AND PARTICIPANTS: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process. RESULTS AND LIMITATIONS: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material. CONCLUSIONS: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making.
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    Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048
    Rischin, D ; Harrington, KJ ; Greil, R ; Soulieres, D ; Tahara, M ; de Castro Jr, G ; Psyrri, A ; Brana, I ; Neupane, P ; Bratland, A ; Fuereder, T ; Hughes, BGM ; Mesia, R ; Ngamphaiboon, N ; Rordorf, T ; Ishak, WZW ; Hong, R-L ; Mendoza, RG ; Jia, L ; Chirovsky, D ; Norquist, J ; Jin, F ; Burtness, B (ELSEVIER, 2022-05-01)
    OBJECTIVES: To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031). MATERIALS AND METHODS: HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer-specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing. RESULTS: Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, -3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, -3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95-2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94-2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores. CONCLUSIONS: Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC.
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    The Role of Voriconazole in the Current Era of Oral Triazoles: Current Usage and Therapeutic Level Attainment of Voriconazole at a Major Tertiary Cancer Center
    Lindsay, J ; Krantz, E ; Morris, J ; Sweet, A ; Tverdek, F ; Joshi, A ; Yeh, RF ; Hill, JA ; Slavin, MA ; Pergam, SA ; Liu, C (Elsevier BV, 2022-03)
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    Better Understanding the Timing Of Androgen Deprivation Trial Outcomes: Impacts of Prior Androgen Deprivation Therapy.
    Stensland, KD ; Devasia, T ; Caram, MEV ; Chapman, C ; Zaslavsky, A ; Morgan, TM ; Hollenbeck, BK ; Sparks, JB ; Burns, J ; Vedapudi, V ; Duchesne, GM ; Tsodikov, A ; Skolarus, TA (Oxford University Press (OUP), 2022-05-02)
    BACKGROUND: The Timing Of Androgen Deprivation (TOAD) trial found an overall survival benefit for immediate vs delayed androgen deprivation therapy (ADT) for prostate-specific antigen (PSA)-relapsed or noncurable prostate cancer. However, broad eligibility criteria allowed entry of a heterogeneous participant group, including those with prior ADT exposure, raising concerns about subsequent androgen sensitivity. For these reasons, we completed previously specified subgroup analyses to assess if prior ADT was associated with ADT timing efficacy after PSA relapse. METHODS: We examined TOAD trial patient-level data for participants with PSA relapse after local therapy. We performed Kaplan-Meier analyses for overall survival stratified by prior ADT and randomized treatment arm (immediate or delayed ADT). We compared group characteristics using Mann-Whitney U and Fisher exact tests. All hypothesis tests were 2-sided. RESULTS: We identified 261 patients with PSA relapse, 125 of whom received prior ADT. Patients with prior ADT had higher PSA at presentation (12.1 vs 9.0 ng/mL; P < .001), more cT3 disease (38.4% vs 25.0%; P = .007), and more likely received radiotherapy as local treatment (80.0% vs 47.8%; P < .001) but were otherwise similar to patients without prior ADT exposure. Within this prior ADT group, those who received immediate ADT (n = 56) had improved overall survival compared with those who received delayed ADT (n = 69; P = .02). This benefit was not observed in the group with no prior ADT (P = .98). CONCLUSIONS: The survival benefit demonstrated in the TOAD trial may be driven by patients who received ADT prior to trial entry. We provide possible explanations for this finding with implications for treatment of PSA-relapsed prostate cancer and future study planning.
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    Investigation of Intervention Solutions to Enhance Adherence to Oral Anticancer Medicines in Adults: Overview of Reviews.
    Dang, TH ; Forkan, ARM ; Wickramasinghe, N ; Jayaraman, PP ; Alexander, M ; Burbury, K ; Schofield, P (JMIR Publications Inc., 2022-04-27)
    BACKGROUND: Adherence to anticancer medicines is critical for the success of cancer treatments; however, nonadherence remains challenging, and there is limited evidence of interventions to improve adherence to medicines in patients with cancer. OBJECTIVE: This overview of reviews aimed to identify and summarize available reviews of interventions to improve adherence to oral anticancer medicines in adult cancer survivors. METHODS: A comprehensive search of 7 electronic databases was conducted by 2 reviewers who independently conducted the study selection, quality assessment using the A Measurement Tool to Assess Systematic Reviews 2, and data extraction. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 checklist was adapted to report the results. RESULTS: A total of 29 reviews were included in the narrative synthesis. The overall quality of the systematic reviews was low. The 4 main strategies to promote adherence were focused on education, reminders, behavior and monitoring, and multicomponent approaches. Digital technology-based interventions were reported in most reviews (27/29, 93%). A few interventions applied theories (10/29, 34%), design frameworks (2/29, 7%), or engaged stakeholders (1/29, 3%) in the development processes. The effectiveness of interventions was inconsistent between and within reviews. However, interventions using multiple strategies to promote adherence were more likely to be effective than single-strategy interventions (12/29, 41% reviews). Unidirectional communication (7/29, 24% reviews) and technology alone (11/29, 38% reviews) were not sufficient to demonstrate improvement in adherence outcomes. Nurses and pharmacists played a critical role in promoting patient adherence to oral cancer therapies, especially with the support of digital technologies (7/29, 24% reviews). CONCLUSIONS: Multicomponent interventions are potentially effective in promoting patient adherence to oral anticancer medicines. The seamless integration of digital solutions with direct clinical contacts is likely to be effective in promoting adherence. Future research for developing comprehensive digital adherence interventions should be evidence-based, theory-based, and rigorously evaluated.