Sir Peter MacCallum Department of Oncology - Research Publications

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    A CAF01-adjuvanted whole asexual blood-stage liposomal malaria vaccine induces a CD4+ T-cell-dependent strain-transcending protective immunity in rodent models
    Okoth, WA ; Ho, M-F ; Zaman, M ; Cooper, E ; Som, P ; Burgess, M ; Walton, M ; Nevagi, RJ ; Beattie, L ; Murphy, D ; Stanisic, DI ; Good, MF ; Miller, LH (AMER SOC MICROBIOLOGY, 2023-12-19)
    Malaria is a devastating disease that has claimed many lives, especially children <5 years of age in Sub-Saharan Africa, as documented in World Malaria Reports by WHO. Even though vector control and chemoprevention tools have helped with elimination efforts in some, if not all, endemic areas, these efforts have been hampered by serious issues (including drug and insecticide resistance and disruption to social cohesion caused by the COVID-19 pandemic). Development of an effective malaria vaccine is the alternative preventative tool in the fight against malaria. Vaccines save millions of lives each year and have helped in elimination and/or eradication of global diseases. Development of a highly efficacious malaria vaccine that will ensure long-lasting protective immunity will be a "game-changing" prevention strategy to finally eradicate the disease. Such a vaccine will need to counteract the significant obstacles that have been hampering subunit vaccine development to date, including antigenic polymorphism, sub-optimal immunogenicity, and waning vaccine efficacy.
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    Approach to diagnostic evaluation and prevention of invasive fungal disease in patients prior to allogeneic hematopoietic stem cell transplant
    O'Keeffe, JC ; Singh, N ; Slavin, MA (WILEY, 2023-11)
    In recent years, advancements in the treatment landscape for hematological malignancies, such as acute myeloid leukemia and acute lymphoblastic leukemia, have significantly improved disease prognosis and overall survival. However, the treatment landscape is changing and the emergence of targeted oral therapies and immune-based treatments has brought forth new challenges in evaluating and preventing invasive fungal diseases (IFDs). IFD disproportionately affects immunocompromised hosts, particularly those undergoing therapy for acute leukemia and allogeneic hematopoietic stem cell transplant. This review aims to provide a comprehensive overview of the pretransplant workup, identification, and prevention of IFD in patients with hematological malignancy. The pretransplant period offers a critical window to assess each patient's risk factors and implement appropriate prophylactic measures. Risk assessment includes evaluation of disease, host, prior treatments, and environmental factors, allowing a dynamic evaluation that considers disease progression and treatment course. Diagnostic screening, involving various biomarkers and radiological modalities, plays a crucial role in early detection of IFD. Antifungal prophylaxis choice is based on available evidence as well as individual risk assessment, potential for drug-drug interactions, toxicity, and patient adherence. Therapeutic drug monitoring ensures effective antifungal stewardship and optimal treatment. Patient education and counselling are vital in minimizing environmental exposures to fungal pathogens and promoting medication adherence. A well-structured and individualized approach, encompassing risk assessment, prophylaxis, surveillance, and patient education, is essential for effectively preventing IFD in hematological malignancies, ultimately leading to improved patient outcomes and overall survival.
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    Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.
    Saner, FAM ; Takahashi, K ; Budden, T ; Pandey, A ; Ariyaratne, D ; Zwimpfer, TA ; Meagher, NS ; Fereday, S ; Twomey, L ; Pishas, KI ; Hoang, T ; Bolithon, A ; Traficante, N ; Alsop, K ; Christie, EL ; Kang, E-Y ; Nelson, GS ; Ghatage, P ; Lee, C-H ; Riggan, MJ ; Alsop, J ; Beckmann, MW ; Boros, J ; Brand, AH ; Brooks-Wilson, A ; Carney, ME ; Coulson, P ; Courtney-Brooks, M ; Cushing-Haugen, KL ; Cybulski, C ; El-Bahrawy, MA ; Elishaev, E ; Erber, R ; Gayther, SA ; Gentry-Maharaj, A ; Blake Gilks, C ; Harnett, PR ; Harris, HR ; Hartmann, A ; Hein, A ; Hendley, J ; AOCS Group, ; Hernandez, BY ; Jakubowska, A ; Jimenez-Linan, M ; Jones, ME ; Kaufmann, SH ; Kennedy, CJ ; Kluz, T ; Koziak, JM ; Kristjansdottir, B ; Le, ND ; Lener, M ; Lester, J ; Lubiński, J ; Mateoiu, C ; Orsulic, S ; Ruebner, M ; Schoemaker, MJ ; Shah, M ; Sharma, R ; Sherman, ME ; Shvetsov, YB ; Singh, N ; Rinda Soong, T ; Steed, H ; Sukumvanich, P ; Talhouk, A ; Taylor, SE ; Vierkant, RA ; Wang, C ; Widschwendter, M ; Wilkens, LR ; Winham, SJ ; Anglesio, MS ; Berchuck, A ; Brenton, JD ; Campbell, I ; Cook, LS ; Doherty, JA ; Fasching, PA ; Fortner, RT ; Goodman, MT ; Gronwald, J ; Huntsman, DG ; Karlan, BY ; Kelemen, LE ; Menon, U ; Modugno, F ; Pharoah, PDP ; Schildkraut, JM ; Sundfeldt, K ; Swerdlow, AJ ; Goode, EL ; DeFazio, A ; Köbel, M ; Ramus, SJ ; Bowtell, DDL ; Garsed, DW (Cold Spring Harbor Laboratory, 2023-11-10)
    BACKGROUND: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. PATIENTS AND METHODS: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. RESULTS: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
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    The Feasibility of Quality Assurance in the TOPGEAR International Phase 3 Clinical Trial of Neoadjuvant Chemoradiation Therapy for Gastric Cancer (an Intergroup Trial of the AGITG/TROG/NHMRC CTC/EORTC/CCTG)
    Lukovic, J ; Moore, AJ ; Lee, MT ; Willis, D ; Ahmed, S ; Akra, M ; Hortobagyi, E ; Kron, T ; Joon, DL ; Liu, A ; Ryan, J ; Thomas, M ; Wall, K ; Ward, I ; Wiltshire, KL ; O'Callaghan, CJ ; Wong, RKS ; Ringash, JG ; Haustermans, K ; Leong, T (ELSEVIER SCIENCE INC, 2023-12-01)
    PURPOSE: The TOPGEAR phase 3 trial hypothesized that adding preoperative chemoradiation therapy (CRT) to perioperative chemotherapy will improve survival in patients with gastric cancer. Owing to the complexity of gastric irradiation, a comprehensive radiation therapy quality assurance (RTQA) program was implemented. Our objective is to describe the RTQA methods and outcomes. METHODS AND MATERIALS: RTQA was undertaken in real time before treatment for the first 5 patients randomized to CRT from each center. Once acceptable quality was achieved, RTQA was completed for one-third of subsequent cases. RTQA consisted of evaluating (1) clinical target volume and organ-at-risk contouring and (2) radiation therapy planning parameters. Protocol violations between high- (20+ patients enrolled) and low-volume centers were compared using the Fisher exact test. RESULTS: TOPGEAR enrolled 574 patients, of whom 286 were randomized to receive preoperative CRT and 203 (71%) were included for RTQA. Of these, 67 (33%) and 136 (67%) patients were from high- and low-volume centers, respectively. The initial RTQA pass rate was 72%. In total, 28% of cases required resubmission. In total, 200 of 203 cases (99%) passed RTQA before treatment. Cases from low-volume centers required resubmission more often (44/136 [33%] vs 13/67 [18%]; P = .078). There was no change in the proportion of cases requiring resubmission over time. Most cases requiring resubmission had multiple protocol violations. At least 1 aspect of the clinical target volume had to be adjusted in all cases. Inadequate coverage of the duodenum was most common (53% major violation, 25% minor violation). For the remaining cases, the resubmission process was triggered secondary to poor contour/plan quality. CONCLUSIONS: In a large multicenter trial, RTQA is feasible and effective in achieving high-quality treatment plans. Ongoing education should be performed to ensure consistent quality during the entire study period.
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    Vasculature is getting Hip(po): Hippo in vascular development and disease
    Kobayashi, S ; Cox, AG ; Harvey, KF ; Hogan, BM (CELL PRESS, 2023-12-04)
    The Hippo signaling pathway regulates developmental organ growth, regeneration, and cell fate decisions. Although the role of the Hippo pathway, and its transcriptional effectors YAP and TAZ, has been well documented in many cell types and species, only recently have the roles for this pathway come to light in vascular development and disease. Experiments in mice, zebrafish, and in vitro have uncovered roles for the Hippo pathway, YAP, and TAZ in vasculogenesis, angiogenesis, and lymphangiogenesis. In addition, the Hippo pathway has been implicated in vascular cancers and cardiovascular diseases, thus identifying it as a potential therapeutic target for the treatment of these conditions. However, despite recent advances, Hippo's role in the vasculature is still underappreciated compared with its role in epithelial tissues. In this review, we appraise our current understanding of the Hippo pathway in blood and lymphatic vessel development and highlight the current knowledge gaps and opportunities for further research.
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    A MXI1-NUTM1 fusion protein with MYC-like activity suggests a novel oncogenic mechanism in a subset ofNUTM1-rearranged tumors
    McEvoy, CR ; Holliday, H ; Thio, N ; Mitchell, C ; Choong, DY ; Yellapu, B ; Leong, HS ; Xu, H ; Lade, S ; Browning, J ; Takano, EA ; Byrne, DJ ; Gill, AJ ; Duong, CP ; Li, J ; Fellowes, AP ; Fox, SB ; Swarbrick, A ; Prall, OWJ (ELSEVIER SCIENCE INC, 2021-01)
    Most NUTM1-rearranged neoplasms (NRNs) have fusions between NUTM1 and BRD (bromodomain-containing) family members and are termed NUT carcinomas (NCs) because they show some squamous differentiation. However, some NRNs are associated with fusions between NUTM1 and members of the MAD (MAX dimerization) gene family of MYC antagonists. Here we describe a small round cell malignancy from the gastro-esophageal junction with a previously unreported fusion between NUTM1 and the MAD family member MXI1. In contrast to NCs, the MXI1-NUTM1 tumor did not show squamous differentiation and did not express MYC, TP63 or SOX2, genes known to be targets of BRD-NUTM1 proteins and critical for NC oncogenesis. Transcriptome analysis showed paradoxical enrichment of MYC target genes in the MXI1-NUTM1 tumor despite the lack of MYC expression. When expressed in vitro MXI1-NUTM1 partially phenocopied MYC, enhancing cell proliferation and cooperating with oncogenic HRAS to produce anchorage-independent cell growth. These data provide evidence that MAD family members, which are normally repressors of MYC activity, can be converted into MYC-like mimics by fusion to NUTM1. The pathological features and novel oncogenic mechanism of the MXI1-NUTM1 tumor show that identification of NUTM1 fusion partners can be important for accurate diagnostic classification of some NRN subtypes, and potentially may guide therapeutic options.
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    SCORE: a randomised controlled trial evaluating shared care (general practitioner and oncologist) follow-up compared to usual oncologist follow-up for survivors of colorectal cancer
    Jefford, M ; Emery, JD ; Martin, AJ ; Lourenco, RDA ; Lisy, K ; Grunfeld, E ; Mohamed, MA ; King, D ; Tebbutt, NC ; Lee, M ; Mehrnejad, A ; Burgess, A ; Marker, J ; Eggins, R ; Carrello, J ; Thomas, H ; Schofield, P (ELSEVIER, 2023-12)
    BACKGROUND: SCORE is the first randomised controlled trial (RCT) to examine shared oncologist and general practitioner (GP) follow-up for survivors of colorectal cancer (CRC). SCORE aimed to show that shared care (SC) was non-inferior to usual care (UC) on the EORTC QLQ-C30 Global Health Status/Quality of Life (GHQ-QoL) scale to 12 months. METHODS: The study recruited patients from five public hospitals in Melbourne, Australia between February 2017 and May 2021. Patients post curative intent treatment for stage I-III CRC underwent 1:1 randomisation to SC and UC. SC replaced two oncologist visits with GP visits and included a survivorship care plan and primary care management guidelines. Assessments were at baseline, 6 and 12 months. Difference between groups on GHQ-QoL to 12 months was estimated from a mixed model for repeated measures (MMRM), with a non-inferiority margin (NIM) of -10 points. Secondary endpoints included quality of life (QoL); patient perceptions of care; costs and clinical care processes (CEA tests, recurrences). Registration ACTRN12617000004369p. FINDINGS: 150 consenting patients were randomised to SC (N = 74) or UC (N = 76); 11 GPs declined. The mean (SD) GHQ-QoL scores at 12 months were 72 (20.2) for SC versus 73 (17.2) for UC. The MMRM mean estimate of GHQ-QoL across the 6 month and 12 month follow-up was 69 for SC and 73 for UC, mean difference -4.0 (95% CI: -9.0 to 0.9). The lower limit of the 95% CI did not cross the NIM. There was no clear evidence of differences on other QoL, unmet needs or satisfaction scales. At 12 months, the majority preferred SC (40/63; 63%) in the SC group, with equal preference for SC (22/62; 35%) and specialist care (22/62; 35%) in UC group. CEA completion was higher in SC. Recurrences similar between arms. Patients in SC on average incurred USD314 less in health costs versus UC patients. INTERPRETATION: SC seems to be an appropriate and cost-effective model of follow-up for CRC survivors. FUNDING: Victorian Cancer Agency and Cancer Australia.
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    Type of anesthesia for cancer resection surgery: No differential impact on cancer recurrence in mouse models of breast cancer
    Dubowitz, J ; Ziegler, AI ; Beare, R ; Jost-Brinkmann, F ; Walker, AK ; Gillis, RD ; Chang, A ; Chung, N-C ; Martin, OA ; Hollande, F ; Riedel, B ; Sloan, EK ; Faisal, SM (PUBLIC LIBRARY SCIENCE, 2023-11-27)
    BACKGROUND: Surgery is essential for curative treatment of solid tumors. Evidence from recent retrospective clinical analyses suggests that use of propofol-based total intravenous anesthesia during cancer resection surgery is associated with improved overall survival compared to inhaled volatile anesthesia. Evaluating these findings in prospective clinical studies is required to inform definitive clinical guidelines but will take many years and requires biomarkers to monitor treatment effect. Therefore, we examined the effect of different anesthetic agents on cancer recurrence in mouse models of breast cancer with the overarching goal of evaluating plausible mechanisms that could be used as biomarkers of treatment response. METHODS: To test the hypothesis that volatile anesthesia accelerates breast cancer recurrence after surgical resection of the primary tumor, we used three mouse models of breast cancer. We compared volatile sevoflurane anesthesia with intravenous propofol anesthesia and used serial non-invasive bioluminescent imaging to track primary tumor recurrence and metastatic recurrence. To determine short-term perioperative effects, we evaluated the effect of anesthesia on vascular integrity and immune cell changes after surgery in animal models. RESULTS: Survival analyses found that the kinetics of cancer recurrence and impact on survival were similar regardless of the anesthetic agent used during cancer surgery. Vascular permeability, immune cell infiltration and cytokine profiles showed no statistical difference after resection with inhaled sevoflurane or intravenous propofol anesthesia. CONCLUSIONS: These preclinical studies found no evidence that choice of anesthetic agent used during cancer resection surgery affected either short-term perioperative events or long-term cancer outcomes in mouse models of breast cancer. These findings raise the possibility that mouse models do not recapitulate perioperative events in cancer patients. Nonetheless, the findings suggest that future evaluation of effects of anesthesia on cancer outcomes should focus on cancer types other than breast cancer.
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    Australia and New Zealand consensus position statement: use of COVID-19 therapeutics in patients with haematological malignancies
    Campbell, A ; Teh, B ; Mulligan, S ; Ross, DM ; Weinkove, R ; Gilroy, N ; Gangatharan, S ; Prince, HM ; Szer, J ; Trotman, J ; Lane, S ; Dickinson, M ; Quach, H ; Enjeti, AK ; Ku, M ; Gregory, G ; Hapgood, G ; Ho, PJ ; Cochrane, T ; Cheah, C ; Greenwood, M ; Latimer, M ; Berkahn, L ; Wight, J ; Armytage, T ; Diamond, P ; Tam, CS ; Hamad, N (Wiley, 2023-02)
    Despite widespread vaccination rates, we are living with high transmission rates of SARS-CoV-2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 management in patients with haematological disorders. It is our recommendation that both patients with haematological malignancies and treating specialists be educated regarding the preventive and treatment options available and that patients continue to receive adequate vaccinations, keeping in mind the suboptimal vaccine responses that occur in haematology patients, in particular, those with B-cell malignancies and on B-cell-targeting or depleting therapy. Patients with haematological malignancies should receive treatment for COVID-19 in accordance with the severity of their symptoms, but even mild infections should prompt early treatment with antiviral agents. The issue of de-isolation following COVID-19 infection and optimal time to treatment for haematological malignancies is discussed but remains an area with evolving data. This position statement is to be used in conjunction with advice from infectious disease, respiratory and intensive care specialists, and current guidelines from the National COVID-19 Clinical Evidence Taskforce and the New Zealand Ministry of Health and Cancer Agency Te Aho o Te Kahu COVID-19 Guidelines.
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    Robotic pelvic sidewall resection with en bloc sciatic nerve excision - a video vignette
    Rajkomar, A ; Larach, T ; Mohan, H ; Kelly, B ; Heriot, A ; Warrier, SK (Wiley, 2023-04)