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Computed tomography (CT) is a commonly used imaging modality in Emergency Departments (EDs), however its use is questionable in many low yield settings. The Emergency CT Head score (ECHS) is a recently published clinical tool that assists in stratifying the need for CT brain (CTB) for patients presenting without a history of trauma. We sought to validate this tool in an Australian ED setting.We prospectively evaluated 412 patients who received CTB without a history of trauma at a large Australian ED. We assessed them for the 4 main ECHS data points: focal neurological deficit on physical examination, new acute onset headache, transient neurological deficit, and a combination of new onset seizures with an altered conscious state. We examined their association with acute and chronic CTB findings. We then applied the ECHS to our data, calculating its sensitivity and its appropriateness at this single site via the calculation of a receiver operating curve (ROC).10.2% of all CTB performed were positive for an acute or chronic abnormality. Only sex (male) and focal motor deficit were independent predictors of positive CTB at univariate analysis. The ECHS did not perform as anticipated in our population, with a ROC area under the curve of 0.498. An ECHS score of0, which has been proposed as the threshold to not require imaging, had sensitivity of only 83.3% in our population.Further research and validation is required in order to safely implement the ECHS clinical score in the Australian ED setting.

Background A large number of CT brain (CTB) scans are ordered in the ED for older patients with a confirmed or possible head strike but no ongoing symptoms of a head injury. This study aimed to evaluate the effect of the Canadian CT head rule supplemented by the original published minimum inclusion criteria to assist clinician assessment of the need for CTB following minimal trauma fall in patients presenting from residential aged care facilities to a major metropolitan emergency department (ED). Methods This study was conducted as a pre- and post-intervention retrospective audit. The intervention involved implementation of a decision support tool to help clinicians assess patients presenting to the ED following a fall. The tool integrated the Canadian CT Head Rule (CCHR) in conjunction with a simplified set of inclusion criteria to help clinicians define a minimum threshold for a “minor head injury”. Outcome data pertaining to CT brain ordering practices and results were compared over symmetrical 3-month time periods pre- and post-intervention in 2 consecutive years. Results The study included 233 patients in the pre-intervention arm and 241 in the post-intervention arm. Baseline demographics and clinical characteristics were similar in both groups. There was a 20% reduction in the total number of CTB scans ordered following tool implementation, with 134 (57.0%) scans in the pre-intervention group and 90 (37.3%) in the post-intervention group (p p = 0.52). No variation was observed in medical management between groups, and no patients in either group underwent neurosurgical intervention. Conclusions Use of the CCHR supplemented by the original published minimum inclusion criteria appeared to safely reduce the number of CTB scans performed in residential aged care facility residents presenting to an ED after a fall, with no associated adverse outcomes. A larger study across multiple centres is required to determine widespread efficacy and safety of this tool.

ObjectivesTo determine the negative predictive value (NPV) of the FebriDx point-of-care host response device in patients presenting with symptoms suggestive of COVID-19 infection in a mostly immunised Australian emergency department (ED) population during the late 2021 phase of the COVID-19 pandemic.DesignObservational diagnostic accuracy study comparing FebriDx point-of-care test to SARS-CoV-2 PCR.SettingAn ED in Melbourne, Australia, with 63 000 annual presentations in 2021.ParticipantsPatients aged 16 and over who met the Victorian Department of Health case definition for suspected COVID-19 infection PCR testing. Patients meeting any of the following criteria were excluded: 14 days prior to testing; current immunosuppressive or interferon therapy; live immunisation within the last 30 days; fever lasting>7 days; antibiotic or antiviral use in the preceding 14 days; experience of major trauma, major surgical intervention or severe burns within the last 30 days.Primary and secondary outcome measuresCOVID-19 PCR results (detected, not detected) and FebriDx results (bacterial positive, viral negative, viral positive).Results94 participants were enrolled (female: 46; male: 48), 34% of participants (tested positive for COVID-19 according to PCR results, with a background incidence among all adult ED attenders of 2.5%. The sensitivity of FebriDx for detection of COVID-19 was 56% (95% CI 40% to 100%) and specificity was 92% (95% CI 84% to 100%). For the population tested, this resulted in an NPV of 80% (95% CI 71% to 100%) and a positive predictive value of 78% (95% CI 60% to 100%).ConclusionsIn the context of a population with low COVID-19 infection rates, an evolved variant of COVID-19 and a very high community COVID-19 vaccination rate, FebriDx demonstrated reduced sensitivity and NPV relative to results from earlier international tests. These contextual factors should be considered during any attempt to generalise the current results.Trial registration numberACTRN12620001029987 (Australian Clinical Trials).

Introduction: Despite recent advances in the therapy of diffuse large B cell lymphoma (DLBCL), many patients are still not cured, and therefore new therapeutic combinations are needed. The anti-apoptotic B cell lymphoma 2 (BCL-2) gene is commonly dysregulated in DLBCL due to various mechanisms such as chromosomal translocation t(14;18)(q32.3;q21.3), copy number alterations and gene amplifications; however, targeting BCL-2 with a selective inhibitor, venetoclax, led to response in only a minority of patients. Thus, we sought to identify a novel combination partner for venetoclax to improve response to therapy. Previously with dynamic BH3 profiling, we found that DNA hypomethylating agents (HMA) could increase BCL2 dependence in DLBCL cells. Here, we investigate the activity of the HMA decitabine with venetoclax in DLBCL. Methods: We utilized BH3 profiling, a functional assay to assess the mitochondrial priming of cells for apoptosis and the dependence of cells on various anti-apoptotic BCL-2 family proteins. Other standard techniques included Western blot, cell cycle (BrdU/7-AAD), CellTiter-Glo, and Seahorse XF cell mito stress test. The DLBCL cell lines (TMD8, HBL1, OCI-Ly3, OCI-Ly1, Karpas 422, SUDHL4, Toledo, OCI-Ly7) and double hit lymphoma (DHL) patient-derived xenograft cell lines were used to investigate the in vitro anti-cancer activity of decitabine and venetoclax. Results: Through BH3 profiling, we found heterogenous dependence of DLBCL, consistent with the variable expression of multiple anti-apoptotic proteins in DLBCL assessed by Western blot. DLBCL cells were less sensitive to single BH3 mimetic treatment (venetoclax, S63 (MCL-1i) and A133 (BCL-xLi)). Using dynamic BH3 profiling (which assesses the change in priming induced by ex vivo drug treatment), we found that decitabine primes DLBCL cells for apoptosis and increases BCL-2 dependence. Consequently, decitabine increases the sensitivity of DLBCL cells to venetoclax, as the combination of decitabine and venetoclax synergistically induces apoptosis and suppresses cell proliferation. Decitabine has previously been shown to increase TGF-β signaling in DLBCL by restoring the expression of a downstream target, SMAD1. Interestingly, we found that inhibition of TGF-β signaling only partially antagonizes the anti-cancer activity of decitabine, implicating other anti-cancer mechanisms of decitabine. Indeed, we found that decitabine also induces DNA damage and leads to cell cycle arrest in DLBCL cells. Furthermore, decitabine promotes activation of the key apoptotic effector proteins, BAK and BAX. Additionally, we found that this combination also suppresses oxidative phosphorylation, thus restricting the energy supply for DLBCL cells. Conclusions: The HMA decitabine sensitizes DLBCL cells to venetoclax in vitro through increasing apoptotic priming and BCL-2 dependence. This combination is worthy of further study in in vivo model systems. Citation Format: Matthew S. Davids, Fen Zhu, Stephen J. Chong, Jennifer Crombie, Liam Hackett, May C. Collins. Decitabine sensitizes diffuse large B cell lymphoma cells to venetoclax [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5377.

Introduction: BCL2 family protein dysfunction is an important mediator of chemoresistance in lymphoid malignancies. Venetoclax (VEN), a BH3 mimetic that selectively targets the anti-apoptotic protein BCL2, is FDA approved for treatment of chronic lymphocytic leukemia (CLL), with clinical trials underway for other lymphoid malignancies. Despite the clinical efficacy of VEN monotherapy, complete remission and progression free rates are still relatively low, thereby indicating the existence of inherent or acquired mechanisms of resistance. Preclinically, increases in anti-apoptotic BCL2 and MCL1 phosphorylation (BCL2-P/MCL1-P) and MCL1 protein level have been implicated in chemoresistance. We therefore question if phosphorylation of these proteins may drive VEN resistance and if removing this modification may re-sensitize resistant cells to VEN induced cell death. Methodology: BH3 profiling (a functional assay that assesses mitochondrial apoptotic priming and anti-apoptotic protein dependence), western blot and cell death assays were performed. Result: We report that VEN acquired resistant DLBCL cell line (OCI-Ly1R) has increased BCL2-P, MCL1-P and MCL1 protein levels as compared to sensitive parental cell line (OCI-Ly1S), while inherently resistant DHL cell line (Su-DHL4) possesses higher MCL1-P and MCL1 protein levels as compared to OCI-Ly1S. We further show that this increase in phosphorylation status contributes to the induction of VEN resistance. Using BH3 profiling, we demonstrate that anti-apoptotic protein phosphorylation-driven VEN resistance involves a change in sensitivity to pro-apoptotic proteins, with an increase in sensitivity to MCL1 inhibition and reciprocal decrease in sensitivity to BCL2 inhibition. We further show that BCL2 and MCL1 dephosphorylation by PP2A activating drugs (PADs) re-sensitizes resistant cells to VEN treatment. Mechanistically, PADs such as the fingolimod (FTY720) not only dephosphorylate BCL2-P and MCL1-P, but also dissociate BAX from BCL2 and destabilize MCL1 protein. These changes lead to the rewiring of cellular sensitivity to BCL2 inhibition, thereby re-sensitizing both VEN acquired and inherent resistant cells to VEN induced cell death. Importantly, the PP2A activating effects of FTY720 were recapitulated in primary cells from the peripheral blood of 16 CLL patients, where FTY720 treatment also reduced BCL2-P, MCL1-P and MCL1 protein levels and dissociated BAX from BCL2. This led to an increased sensitivity to BCL2 inhibition and enhanced cell death upon combined treatment with FTY720 and VEN. Conclusion: Our work defines a new targetable mechanism of VEN resistance in lymphoid malignancies due to the phosphorylation of anti-apoptotic BCL2 family proteins. PADs re-sensitize resistant malignant cells to VEN treatment via dephosphorylation of anti-apoptotic proteins, suggesting a promising combination approach to explore further. Citation Format: Stephen J. Chong, Fen Zhu, Jolin X. Lai, Liam Hackett, Mary C. Collins, Shazib Pervaiz, Jean-Philippe Coppe, Matthew S. Davids. Targeting BCL2 family protein phosphorylation in venetoclax resistant lymphoid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3959.