Melbourne Medical School Collected Works - Research Publications
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ATEZOLIZUMAB PLUS VEMURAFENIB AND COBIMETINIB PROVIDES FAVORABLE SURVIVAL OUTCOMES IN PATIENTS WITH HIGH TUMOR MUTATION BURDEN AND PROINFLAMMATORY GENE SIGNATURE IN THE PHASE 3 IMSPIRE150 STUDY
(BMJ PUBLISHING GROUP, 2020-11-01)
<jats:sec><jats:title>Background</jats:title><jats:p>The phase 3 IMspire150 study (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT02908672">NCT02908672</jats:ext-link>) showed that first-line atezolizumab (A) combined with vemurafenib (V) + cobimetinib (C) improved progression-free survival (PFS) vs placebo (P) + V + C in patients with BRAF<jats:sup>V600</jats:sup> mutation–positive advanced melanoma (15.1 vs 10.6 months; hazard ratio [HR] 0.78; 95% CI 0.63–0.97; P=0.0249). Insights into the clinical benefit of the A+V+C triple combination in prognostic molecular subgroups of patients can inform treatment selection and future clinical research.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>514 patients were randomized 1:1 to A+V+C (n=256) or P+V+C (n=258). The efficacy endpoints analyzed included PFS and duration of response (DOR) estimated using the Kaplan-Meier method. Outcomes were based on investigator-assessed best overall response per Response Evaluation Criteria in Solid Tumors v1.1. Patients were primarily categorized into binary subgroups defined by tumor mutation burden (TMB; low or high: <10 or ≥10 mutations/Mb, respectively) or by the < or ≥ median values of interferon (IFN)-gamma or CD8+ tumor cells. In addition, these subgroups were further broken down based on the proportion of programmed death-ligand 1 (PD-L1)-expressing tumor-infiltrating cells as PD-L1+ (≥1%) or PD-L1– (<1%).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Patients treated with P+V+C with high and low TMB had similar PFS outcomes. However, the magnitude of the PFS benefit with A+V+C vs P+V+C was markedly higher in patients with high TMB (≥10 mutations/Mb) compared with patients with low TMB (<10 mutations/Mb) in whom the benefit between treatment arms was comparable (figure 1A). The magnitude of the PFS benefit with A+V+C was further enhanced in patients with high TMB and PD-L1– compared with patients with high TMB and PD-L1+. Overall, patients with potential for increased antitumor immunity (IFN-gamma ≥ median or CD8+ ≥ median) who received A+V+C had more favorable outcomes compared with their counterparts with IFN-gamma < median or CD8+ < median. In general, the PFS benefit with A+V+C vs P+V+C was more readily apparent in PD-L1– subgroups. Similar trends were seen with DOR (figure 1B).</jats:p><jats:fig id="F1" position="float" orientation="portrait"><jats:label>Abstract 307 Figure 1</jats:label><jats:caption><jats:p>Forest plot of PFS (A) and DOR (B). mo, months; NE, not evaluable; Neg, negative; NE, not estimable; Pos, positive.</jats:p></jats:caption><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="ABS_307_F001" position="float" orientation="portrait" /></jats:fig></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>There was a trend of larger magnitude of PFS benefit with A+V+C vs P+V+C in PD-L1– patient subgroups, who benefit less with single-agent immunotherapy. The PFS and DOR benefits were more evident in patients with high IFN-gamma or TMB >10 mutations/Mb. Additional multivariate analyses are ongoing to delineate the PFS trends observed.</jats:p></jats:sec><jats:sec><jats:title>Trial Registration</jats:title><jats:p>ClinicalTrials. gov, identifier <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT02908672">NCT02908672</jats:ext-link></jats:p></jats:sec>
ASSOCIATION OF RESPONSE WITH SURVIVAL OUTCOMES WITH ATEZOLIZUMAB IN COMBINATION WITH VEMURAFENIB AND COBIMETINIB IN THE PHASE 3 IMSPIRE150 STUDY
(BMJ PUBLISHING GROUP, 2020-11-01)
<jats:sec><jats:title>Background</jats:title><jats:p>The phase 3 IMspire150 study (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT02908672">NCT02908672</jats:ext-link>) demonstrated improved progression-free survival (PFS) with first-line atezolizumab (A) vs placebo (P) combined with vemurafenib (V) + cobimetinib (C) in patients with BRAF<jats:sup>V600</jats:sup> mutation–positive advanced melanoma (15.1 vs 10.6 months; hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.63–0.97; P=0.0249). Objective response has been associated with increased survival with chemotherapy and targeted therapies, but it is unclear whether the association holds for immunotherapy. In this exploratory analysis, we evaluated the impact of response on survival outcomes in patients treated with A+V+C or P+V+C in the IMspire150 study.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>514 patients were randomized 1:1 to A+V+C (n=256) or P+V+C (n=258). Patients received V+C in cycle 1; A or P was added on days 1+15 from cycle 2 onward. The primary endpoints for this exploratory analysis were PFS and overall survival (OS), estimated using the Kaplan-Meier method. Outcomes were analyzed by investigator-assessed best overall response (BOR) per RECIST v1.1 (complete response [CR] vs partial response [PR] vs stable disease [SD]).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Median follow-up was 18.9 mo. In the A+V+C arm, BOR was CR (n=41), PR (n=129), and SD (n=58); in the P+V+C arm, BOR was CR (n=46), PR (n=122), and SD (n=58). An imbalance in baseline prognostic factors (eg, lactate dehydrogenase, tumor burden measures) was noted across response categories in both treatment arms, with favorable factors more prevalent in patients with CR and unfavorable factors more prevalent in patients with PR/SD. Improvement in PFS and OS was observed with A+V+C vs P+V+C in patients with PR, with 2-year PFS rates of 42.1% vs 24.6% and 2-year OS rates of 69.1% vs 56.1% with A+V+C vs P+V+C (table 1). In patients with CR, median PFS and OS were not yet reached in either arm, with 2-year PFS rates of 64.6% vs 59.8% and 2-year OS rates of 82.6% vs 82.8% with A+V+C vs P+V+C. PFS and OS outcomes were poor in both treatment arms in patients with SD, with 2-year PFS rates of 10.7% vs not estimable (NE) and 2-year OS rates of 36.6% vs 29.3% with A+V+C vs P+V+C.</jats:p><jats:table-wrap id="T1" position="float" orientation="portrait"><jats:label>Abstract 301 Table 1</jats:label><jats:caption><jats:p>PFS and OS outcomes with A+V+C vs P+V+C by BOR per RECIST v1.1</jats:p></jats:caption><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="ABS_301_T001" position="float" orientation="portrait" /></jats:table-wrap></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>PFS and OS improvement was observed for A+V+C vs P+V+C for patients who achieved PR. CR is associated with improved PFS and OS with both A+V+C and P+V+C. Further follow-up is required to determine the impact of A+C+V vs P+C+V on survival outcomes.</jats:p></jats:sec><jats:sec><jats:title>Trial Registration</jats:title><jats:p>ClinicalTrials. gov, <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT02908672">NCT02908672</jats:ext-link></jats:p></jats:sec>
Cholesterol transport between red blood cells and lipoproteins contributes to cholesterol metabolism in blood
(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2020-12-01)
Lipoproteins play a key role in transport of cholesterol to and from tissues. Recent studies have also demonstrated that red blood cells (RBCs), which carry large quantities of free cholesterol in their membrane, play an important role in reverse cholesterol transport. However, the exact role of RBCs in systemic cholesterol metabolism is poorly understood. RBCs were incubated with autologous plasma or isolated lipoproteins resulting in a significant net amount of cholesterol moved from RBCs to HDL, while cholesterol from LDL moved in the opposite direction. Furthermore, the bi-directional cholesterol transport between RBCs and plasma lipoproteins was saturable and temperature-, energy-, and time-dependent, consistent with an active process. We did not find LDLR, ABCG1, or scavenger receptor class B type 1 in RBCs but found a substantial amount of ABCA1 mRNA and protein. However, specific cholesterol efflux from RBCs to isolated apoA-I was negligible, and ABCA1 silencing with siRNA or inhibition with vanadate and Probucol did not inhibit the efflux to apoA-I, HDL, or plasma. Cholesterol efflux from and cholesterol uptake by RBCs from Abca1+/+ and Abca1-/- mice were similar, arguing against the role of ABCA1 in cholesterol flux between RBCs and lipoproteins. Bioinformatics analysis identified ABCA7, ABCG5, lipoprotein lipase, and mitochondrial translocator protein as possible candidates that may mediate the cholesterol flux. Together, these results suggest that RBCs actively participate in cholesterol transport in the blood, but the role of cholesterol transporters in RBCs remains uncertain.
Left ventricular remodeling in elite and sub-elite road cyclists
Marked adaptation of left ventricular (LV) structure in endurance athletes is well established. However, previous investigations of functional and mechanical adaptation have been contradictory. A lack of clarity in subjects' athletic performance level may have contributed to these disparate findings. This study aimed to describe structural, functional, and mechanical characteristics of the cyclists' LV, based on clearly defined performance levels. Male elite cyclists (EC) (n = 69), sub-elite cyclists (SEC) (n = 30), and non-athletes (NA) (n = 46) were comparatively studied using conventional and speckle tracking 2D echocardiography. Dilated eccentric hypertrophy was common in EC (34.7%), but not SEC (3.3%). Chamber concentricity was higher in EC compared to SEC (7.11 ± 1.08 vs 5.85 ± 0.98 g/(mL)2/3 , P < .001). Ejection fraction (EF) was lower in EC compared to NA (57 ± 5% vs 59 ± 4%, P < .05), and reduced EF was observed in a greater proportion of EC (11.6%) compared to SEC (6.7%). Global circumferential strain (GCε) was greater in EC (-18.4 ± 2.4%) and SEC (-19.8 ± 2.7%) compared to NA (-17.2 ± 2.6%) (P < .05 and P < .001). Early diastolic filling was lower in EC compared with SEC (0.72 ± 0.14 vs 0.88 ± 0.12 cm/s, P < .001), as were septal E' (12 ± 2 vs 15 ± 2 cm/s, P < .001) and lateral E' (18 ± 4 vs 20 ± 4 cm/s, P < .05). The magnitude of LV structural adaptation was far greater in EC compared with SEC. Increased GCε may represent a compensatory mechanism to maintain stroke volume in the presence of increased chamber volume. Decreased E and E' velocities may be indicative of a considerable functional reserve in EC.
Comparison of left ventricular longitudinal systolic function parameters in the prediction of adverse outcome in heart failure with preserved ejection fraction
(WILEY PERIODICALS, INC, 2021-02-11)
AIMS: Several different diagnostic parameters can be used to assess left ventricular (LV) longitudinal systolic function, but no studies comparing their predictive value have been conducted. We sought to compare the prognostic value of LV long-axis function parameters at rest and exercise using the population with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Clinical and biochemical variables were collected at baseline in 201 patients with HFpEF. Echocardiography was performed at rest and immediately after exercise, with measurement of mitral annular plane systolic excursion, systolic tissue velocity (s'), global longitudinal strain (GLS), and global longitudinal strain rate (GLSR). Participants were followed for 48 (24-60) months for heart failure hospitalization and cardiovascular death. Seventy-four patients (36.8%) met the study endpoint. Cox regression analysis revealed that after adjustment for Meta-Analysis Global Group in Chronic Heart Failure risk score, brain natriuretic peptide (BNP), and peak VO2 , heart failure hospitalization and cardiovascular death were significantly associated with GLS at rest [hazard ratio (HR) 0.91; 95% confidence interval (CI) 0.84-0.98; P = 0.016], GLS after exercise (HR 0.84; 95% CI 0.77-0.91; P < 0.001), and GLSR after exercise (HR 0.13; 95% CI 0.04-0.48; P = 0.002). The addition of each of the following: exercise GLS and GLSR and resting GLS to the base model including Meta-Analysis Global Group in Chronic Heart Failure, BNP, and peak VO2 improved predictive power for the study endpoint [net reclassification improvement (NRI) = 49%, P < 0.001; NRI = 42%, P = 0.004; and NRI = 38%, P = 0.009, respectively]. Exercise GLS was the only longitudinal parameter significantly improving c-statistics of the base model (0.68 vs. 0.73; P = 0.047). CONCLUSIONS: Echocardiographic parameters of LV longitudinal function are not equipotential in predicting adverse outcomes in HFpEF. LV deformation indices, especially assessed with exercise, show the highest predictive utility independent from and incremental to clinical data and BNP.
Fructose stimulated de novo lipogenesis is promoted by inflammation
(NATURE RESEARCH, 2020-10-01)
Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.
Acute glycaemic management before, during and after exercise for cardiac rehabilitation participants with diabetes mellitus: a joint statement of the British and Canadian Associations of Cardiovascular Prevention and Rehabilitation, the International Council for Cardiovascular Prevention and Rehabilitation and the British Association of Sport and Exercise Sciences.
Type 1 (T1) and type 2 (T2) diabetes mellitus (DM) are significant precursors and comorbidities to cardiovascular disease and prevalence of both types is still rising globally. Currently,~25% of participants (and rising) attending cardiac rehabilitation in Europe, North America and Australia have been reported to have DM (>90% have T2DM). While there is some debate over whether improving glycaemic control in those with heart disease can independently improve future cardiovascular health-related outcomes, for the individual patient whose blood glucose is well controlled, it can aid the exercise programme in being more efficacious. Good glycaemic management not only helps to mitigate the risk of acute glycaemic events during exercising, it also aids in achieving the requisite physiological and psycho-social aims of the exercise component of cardiac rehabilitation (CR). These benefits are strongly associated with effective behaviour change, including increased enjoyment, adherence and self-efficacy. It is known that CR participants with DM have lower uptake and adherence rates compared with those without DM. This expert statement provides CR practitioners with nine recommendations aimed to aid in the participant's improved blood glucose control before, during and after exercise so as to prevent the risk of glycaemic events that could mitigate their beneficial participation.
Awareness, perceptions and practices regarding cancer-related malnutrition and sarcopenia: a survey of cancer clinicians
PURPOSE: Cancer-related malnutrition and sarcopenia have severe negative consequences including reduced survival and reduced ability to complete treatment. This study aimed to determine the awareness, perceptions and practices of Australian oncology clinicians regarding malnutrition and sarcopenia in people with cancer. METHODS: A national cross-sectional survey of Australian cancer clinicians was undertaken between November 2018 and January 2019. The 30-item online purpose-designed survey was circulated through professional organizations and health services. RESULTS: The 111 participants represented dietetic (38%), nursing (34%), medical (14%) and other allied health (14%) clinicians. Overall, 86% and 88% clinicians were aware of accepted definitions of malnutrition and sarcopenia, respectively. Perception of responsibility for identification of these conditions varied across participants, although 93% agreed this was a component of their role. However, 21% and 43% of clinicians had limited or no confidence in their ability to identify malnutrition and sarcopenia, respectively. Common barriers to the identification and management of malnutrition were access to the tools or skills required and a lack of services to manage malnourished patients. Common barriers to identification of sarcopenia were lack of confidence and lack of services to manage sarcopenic patients. Enablers for identification and management of malnutrition and sarcopenia were variable; however, training and protocols for management ranked highly. CONCLUSION: While awareness of the importance of cancer-related malnutrition and sarcopenia are high, participants identified substantial barriers to delivering optimal nutrition care. Guidance at a national level is recommended to strengthen the approach to management of cancer-related malnutrition and sarcopenia.
Echocardiography in patients with heart failure: recent advances and future perspectives
(POLSKIE TOWARZYSTOWO KARDIOLOGICZNE, 2021-01-25)
Echocardiography is a relatively inexpensive and widely available technique that has a pivotal role in the assessment and management of patients with heart failure (HF). Advancements in cardiac ultrasound, especially the advent of myocardial deformation imaging, have provided a comprehensive insight into the complexity of cardiac derangements underlying HF, contributing to the better understanding of the disease process. The essential issues that echocardiography can help address include: establishing / confirming diagnosis, categorizing and phenotyping patients, prognosticating, guiding therapeutic decision-making, and monitoring responses to treatment. Novel echocardiographic technologies permit early recognition of preclinical myocardial abnormalities, as well as further tracking of pathologic alterations and therapeutic responses. The predictive utility of a large number of echocardiographic indices, offering an abundance of prognostic information independent of and incremental to clinical data, underpins their use in risk stratification strategies. The evolution of existing modalities, as well as the wider implementation of automation and artificial intelligence, provides the basis for the future development and expanded clinical application of echocardiography.
Poor Birth Outcomes in Malaria in Pregnancy: Recent Insights Into Mechanisms and Prevention Approaches
(FRONTIERS MEDIA SA, 2021-03-15)
Pregnant women in malaria-endemic regions are susceptible to malaria in pregnancy, which has adverse consequences on birth outcomes, including having small for gestational age and preterm babies. These babies are likely to have low birthweights, which predisposes to infant mortality and lifelong morbidities. During malaria in pregnancy, Plasmodium falciparum-infected erythrocytes express a unique variant surface antigen, VAR2CSA, that mediates sequestration in the placenta. This process may initiate a range of host responses that contribute to placental inflammation and dysregulated placental development, which affects placental vasculogenesis, angiogenesis and nutrient transport. Collectively, these result in the impairment of placental functions, affecting fetal development. In this review, we provide an overview of malaria in pregnancy and the different pathological pathways leading to malaria in pregnancy-associated low birthweight. We also discuss current prevention and management strategies for malaria in pregnancy, and some potential therapeutic interventions that may improve birth outcomes. Lastly, we outline some priorities for future research that could bring us one step closer to reducing this health burden.
Enteric pathogen infection and consequences for child growth in young Aboriginal Australian children: a cross-sectional study
BACKGROUND: To determine the prevalence of enteric infections in Aboriginal children aged 0-2 years using conventional and molecular diagnostic techniques and to explore associations between the presence of pathogens and child growth. METHODS: Cross-sectional analysis of Aboriginal children (n = 62) residing in a remote community in Northern Australia, conducted from July 24th - October 30th 2017. Stool samples were analysed for organisms by microscopy (directly in the field and following fixation and storage in sodium-acetate formalin), and by qualitative PCR for viruses, bacteria and parasites and serology for Strongyloides-specific IgG. Child growth (height and weight) was measured and z scores calculated according to WHO growth standards. RESULTS: Nearly 60% of children had evidence for at least one enteric pathogen in their stool (37/62). The highest burden of infection was with adenovirus/sapovirus (22.9%), followed by astrovirus (9.8%) and Cryptosporidium hominis/parvum (8.2%). Non-pathogenic organisms were detected in 22.5% of children. Ten percent of children had diarrhea at the time of stool collection. Infection with two or more pathogens was negatively associated with height for age z scores (- 1.34, 95% CI - 2.61 to - 0.07), as was carriage of the non-pathogen Blastocystis hominis (- 2.05, 95% CI - 3.55 to - 0.54). CONCLUSIONS: Infants and toddlers living in this remote Northern Australian Aboriginal community had a high burden of enteric pathogens and non-pathogens. The association between carriage of pathogens/non-pathogens with impaired child growth in the critical first 1000 days of life has implications for healthy child growth and development and warrants further investigation. These findings have relevance for many other First Nations Communities that face many of the same challenges with regard to poverty, infections, and malnutrition.
Seropositivity and geographical distribution of Strongyloides stercoralis in Australia: A study of pathology laboratory data from 2012-2016
(PUBLIC LIBRARY SCIENCE, 2021-03-01)
BACKGROUND: There are no national prevalence studies of Strongyloides stercoralis infection in Australia, although it is known to be endemic in northern Australia and is reported in high risk groups such as immigrants and returned travellers. We aimed to determine the seropositivity (number positive per 100,000 of population and percent positive of those tested) and geographical distribution of S. stercoralis by using data from pathology laboratories. METHODOLOGY: We contacted all seven Australian laboratories that undertake Strongyloides serological (ELISA antibody) testing to request de-identified data from 2012-2016 inclusive. Six responded. One provided positive data only. The number of people positive, number negative and number tested per 100,000 of population (Australian Bureau of Statistics data) were calculated including for each state/territory, each Australian Bureau of Statistics Statistical Area Level 3 (region), and each suburb/town/community/locality. The data was summarized and expressed as maps of Australia and Greater Capital Cities. PRINCIPAL FINDINGS: We obtained data for 81,777 people who underwent serological testing for Strongyloides infection, 631 of whom were from a laboratory that provided positive data only. Overall, 32 (95% CI: 31, 33) people per 100,000 of population were seropositive, ranging between 23/100,000 (95% CI: 19, 29) (Tasmania) and 489/100,000 population (95%CI: 462, 517) (Northern Territory). Positive cases were detected across all states and territories, with the highest (260-996/100,000 and 17-40% of those tested) in regions across northern Australia, north-east New South Wales and north-west South Australia. Some regions in Greater Capital Cities also had a high seropositivity (112-188/100,000 and 17-20% of those tested). Relatively more males than females tested positive. Relatively more adults than children tested positive. Children were under-represented in the data. CONCLUSIONS/SIGNIFICANCE: The study confirms that substantial numbers of S. stercoralis infections occur in Australia and provides data to inform public health planning.