Medical Biology - Research Publications
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Item[18F]FDG-PET-CT compared with CT for persistent or recurrent neutropenic fever in high-risk patients (PIPPIN): a multicentre, open-label, phase 3, randomised, controlled trial(ELSEVIER SCI LTD, 2022-08)BACKGROUND: Management of neutropenic fever in high-risk haematology patients is challenging; there are often few localising clinical features, and diagnostic tests have poor sensitivity and specificity. We aimed to compare how [18F]flurodeoxyglucose ([18F]FDG)-PET-CT scans and conventional CT scans affected the guidance of antimicrobial management and the outcomes of patients with persistent or recurrent neutropenic fever. METHODS: We did a multicentre, open-label, phase 3, randomised, controlled trial in two tertiary referral hospitals in Australia. We recruited adults aged 18 years or older who were receiving conditioning chemotherapy for haematopoietic stem-cell transplantation or chemotherapy for acute leukaemia and had persistent (>72 h) or recurrent (new fever beyond 72 h of initial onset interspersed with >48 h defervescence) neutropenic fever. Exclusion criteria were pregnancy, allergy to iodinated contrast, or estimated glomerular filtration rate of less than 30 mL/min. Patients were randomly assigned by computer-generated randomisation chart (1:1) to [18F]FDG-PET-CT or conventional CT. Masking was not possible because of the nature of the investigation. Scans were done within 3 days of random assignment. The primary endpoint was a composite of starting, stopping, or changing the spectrum (broadening or narrowing) of antimicrobial therapy-referred to here as antimicrobial rationalisation-within 96 h of the assigned scan, analysed per protocol. This trial is registered with clinicaltrials.gov, NCT03429387, and is complete. FINDINGS: Between Jan 8, 2018, and July 23, 2020, we assessed 316 patients for eligibility. 169 patients were excluded and 147 patients were randomly assigned to either [18F]FDG-PET-CT (n=73) or CT (n=74). Nine patients did not receive a scan per protocol, and two participants in each group were excluded for repeat entry into the study. 65 patients received [18F]FDG-PET-CT (38 [58%] male; 53 [82%] White) and 69 patients received CT (50 [72%] male; 58 [84%] White) per protocol. Median follow up was 6 months (IQR 6-6). Antimicrobial rationalisation occurred in 53 (82%) of 65 patients in the [18F]FDG-PET-CT group and 45 (65%) of 69 patients in the CT group (OR 2·36, 95% CI 1·06-5·24; p=0·033). The most frequent component of antimicrobial rationalisation was narrowing spectrum of therapy, in 28 (43%) of 65 patients in the [18F]FDG-PET-CT group compared with 17 (25%) of 69 patients in the CT group (OR 2·31, 95% CI 1·11-4·83; p=0·024). INTERPRETATION: [18F]FDG-PET-CT was associated with more frequent antimicrobial rationalisation than conventional CT. [18F]FDG-PET-CT can support decision making regarding antimicrobial cessation or de-escalation and should be considered in the management of patients with haematological diseases and persistent or recurrent high-risk neutropenic fever after chemotherapy or transplant conditioning. FUNDING: National Health and Medical Research Council Centre of Research Excellence (APP1116876), Melbourne Health foundation, Gilead Research Fellowship grants supported this study.
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ItemProcalcitonin and Interleukin-10 May Assist in Early Prediction of Bacteraemia in Children With Cancer and Febrile Neutropenia(FRONTIERS MEDIA SA, 2021-05-20)OBJECTIVES: Febrile neutropenia (FN) causes treatment disruption and unplanned hospitalization in children with cancer. Serum biomarkers are infrequently used to stratify these patients into high or low risk for serious infection. This study investigated plasma abundance of cytokines in children with FN and their ability to predict bacteraemia. METHODS: Thirty-three plasma cytokines, C-reactive protein (CRP) and procalcitonin (PCT) were measured using ELISA assays in samples taken at FN presentation (n = 79) and within 8-24 h (Day 2; n = 31). Optimal thresholds for prediction of bacteraemia were identified and the predictive ability of biomarkers in addition to routinely available clinical variables was assessed. RESULTS: The median age of included FN episodes was 6.0 years and eight (10%) had a bacteraemia. On presentation, elevated PCT, IL-10 and Mip1-beta were significantly associated with bacteraemia, while CRP, IL-6 and IL-8 were not. The combination of PCT (≥0.425 ng/ml) and IL-10 (≥4.37 pg/ml) had a sensitivity of 100% (95% CI 68.8-100%) and specificity of 89% (95% CI 80.0-95.0%) for prediction of bacteraemia, correctly identifying all eight bacteraemia episodes and classifying 16 FN episodes as high-risk. There was limited additive benefit of incorporating clinical variables to this model. On Day 2, there was an 11-fold increase in PCT in episodes with a bacteraemia which was significantly higher than that observed in the non-bacteraemia episodes. CONCLUSION: Elevated PCT and IL-10 accurately identified all bacteraemia episodes in our FN cohort and may enhance the early risk stratification process in this population. Prospective validation and implementation is required to determine the impact on health service utilisation.
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ItemPseudotumor presentation of CMV disease: Diagnostic dilemma and association with immunomodulating therapy(WILEY, 2021-06)Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in the immunocompromised host. Atypical presentations which include pseudotumors or "cancer mimics" have been described. The etiology of these lesions remains unclear. The authors describe two previously unpublished cases that have arisen in the context of newer immunomodulating therapy and review the existing non-HIV-associated CMV pseudotumors described in the literature.
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ItemSuccessful identification of predictive profiles for infection utilising systems-level immune analysis: a pilot study in patients with relapsed and refractory multiple myeloma(WILEY, 2021)OBJECTIVES: Patients with multiple myeloma (MM) are at increased risk for infection. Clinical assessment of infection risk is increasingly challenging in the era of immune-based therapy. A pilot systems-level immune analysis study to identify predictive markers for infection was conducted. METHODS: Patients with relapsed and/or refractory MM (RRMM) who participated in a treatment trial of lenalidomide and dexamethasone were evaluated. Data on patient demographics, disease and episodes of infection were extracted from clinical records. Peripheral blood mononuclear cells (PBMCs) collected at defined intervals were analysed, with or without mitogen re-stimulation, using RNA sequencing and mass cytometry (CyTOF). CyTOF-derived cell subsets and RNAseq gene expression profiles were compared between patients that did and did not develop infection to identify immune signatures that predict infection over a 3-month period. RESULTS: Twenty-three patients participated in the original treatment trial, and we were able to access samples from 17 RRMM patients for further evaluation in our study. Nearly half the patients developed an infection (8/17) within 3 months of sample collection. Infections were mostly clinically diagnosed (62.5%), and the majority involved the respiratory tract (87.5%). We did not detect phenotypic or numerical differences in immune cell populations between patients that did and did not develop infections. Transcriptional profiling of stimulated PBMCs revealed distinct Th2 immune pathway signatures in patients that developed infection. CONCLUSION: Immune cell counts were not useful predictors of infection risk. Functional assessment of stimulated PBMCs has identified potential immune profiles that may predict future infection risk in patients with RRMM.
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ItemPredicting Risk of Infection in Patients with Newly Diagnosed Multiple Myeloma: Utility of Immune Profiling(FRONTIERS MEDIA SA, 2017-10-05)BACKGROUND: A translational study in patients with myeloma to determine the utility of immune profiling to predict infection risk in patients with hematological malignancy was conducted. METHODS: Baseline, end of induction, and maintenance peripheral blood mononuclear cells from 40 patients were evaluated. Immune cell populations and cytokines released from 1 × 106 cells/ml cultured in the presence of a panel of stimuli (cytomegalovirus, influenza, S. pneumoniae, phorbol myristate acetate/ionomycin) and in media alone were quantified. Patient characteristics and infective episodes were captured from clinical records. Immunological variables associated with increased risk for infection in the 3-month period following sample collection were identified using univariate analysis (p < 0.05) and refined with multivariable analysis to define a predictive immune profile. RESULTS: 525 stimulant samples with 19,950 stimulant-cytokine combinations across three periods were studied, including 61 episodes of infection. Mitogen-stimulated release of IL3 and IL5 were significantly associated with increased risk for subsequent infection during maintenance therapy. A lower Th1/Th2 ratio and higher cytokine response ratios for IL5 and IL13 during maintenance therapy were also significantly associated with increased risk for infection. On multivariable analysis, only IL5 in response to mitogen stimulation was predictive of infection. The lack of cytokine response and numerical value of immune cells were not predictive of infection. CONCLUSION: Profiling cytokine release in response to mitogen stimulation can assist with predicting subsequent onset of infection in patients with hematological malignancy during maintenance therapy.
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ItemCytomegalovirus DNAemia and disease: natural history and management in settings other than allogeneic stem cell transplantation(Ferrata Storti Foundation, 2005-12)Background and Objectives. Despite increasing intensity and profound immunosuppressionassociated with newer therapies for hematologic malignancies, little information exists regarding cytomegalovirus (CMV) reactivation in settings other than allogeneic stem cell transplantation (SCT).Design and Methods. We reviewed the epidemiology of CMV disease in patients who were CMV polymerase chain reaction (PCR) positive during treatment for hematologic malignancies without allogeneic SCT from June 1999 to June 2004.Results. Thirty-six patients with CMV reactivation were identified. Of these, 92% were undergoing investigation for fever. Fifteen patients with CMV DNAemia were treatedwith ganciclovir without CMV disease developing. Notably, 20 patients with untreated CMV DNAemia did not develop CMV disease during a median follow-up of 3.5 (1-19)months. The highest rates of reactivation were observed with HyperCVAD (7.8%) and alemtuzumab (50%).Interpretation and Conclusions. We recommend that screening for CMV DNAemia be instituted and pre-emptive therapy contemplated for asymptomatic CMV reactivationonly in patients receiving alemtuzumab therapy, but not routinely for other patients outside the allogeneic SCT setting. Indeed for such patients, detection of isolated CMV DNAemia does not imply the need for immediate therapy and future studies are needed to validate PCR detection of CMV DNA and CMV DNA titers as predictors for CMV disease.