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"Fitzgerald, Terence D"
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GPRC5D-Targeted CAR T Cells for Myeloma
In an early-phase study involving 17 patients with highly refractory multiple myeloma, CAR T-cell therapy with specificity for a G protein–coupled receptor that is expressed on myeloma cells produced a response in 71% of the patients.
Journal Article
Risk Stratification of Elderly Patients Undergoing Spinal Surgery Using the Modified Frailty Index
Study Design:
Retrospective cohort.
Objectives:
To validate the 11-item modified Frailty Index (mFI) as a perioperative risk stratification tool in elderly patients undergoing spine surgery.
Methods:
All consecutive cases of spine surgery in patients aged 65 years or older between July 2016 and June 2018 at a state-wide trauma center were retrospectively reviewed. The primary outcome was post-operative major complication rate (Clavien-Dindo Classification ≥ III). Secondary outcome measures included the rate of all complications, 6-month mortality and surgical site infection.
Results:
A total of 348 cases were identified. The major complication rate was significantly lower in patients with an mFI of 0 compared to ≥ 0.45 (18.3% versus 42.5%, P = .049). As the mFI increased from 0 to ≥ 0.45 there was a stepwise increase in risk of major complications (P < .001). Additionally, 6-month mortality rate was considerably lower when the mFI was 0 rather than ≥ 0.27 (4.2% versus 20.4%, P = .007). Multivariate analysis demonstrated an mFI ≥ 0.27 was significantly associated with an increased incidence of major complication (OR 2.80, 95% CI 1.46-5.35, P = .002), all complication (OR 2.93, 95% CI 1.70-15.11, P < .001), 6-month mortality (OR 7.39, 95% CI 2.55-21.43, P < .001) and surgical site infection (OR 4.43, 95% CI 1.71-11.51, P = .002). The American Society of Anesthesiologists’ (ASA) index did not share a stepwise relationship with any outcome.
Conclusion:
The mFI is significantly associated in a gradated fashion with increased morbidity and mortality. Patients with an mFI ≥ 0.27 are at greater risk of major complications, all-complications, 6-monthy mortality, and surgical site infection.
Journal Article
PRECISION-TBI: a study protocol for a vanguard prospective cohort study to enhance understanding and management of moderate to severe traumatic brain injury in Australia
IntroductionTraumatic brain injury (TBI) is a heterogeneous condition in terms of pathophysiology and clinical course. Outcomes from moderate to severe TBI (msTBI) remain poor despite concerted research efforts. The heterogeneity of clinical management represents a barrier to progress in this area. PRECISION-TBI is a prospective, observational, cohort study that will establish a clinical research network across major neurotrauma centres in Australia. This network will enable the ongoing collection of injury and clinical management data from patients with msTBI, to quantify variations in processes of care between sites. It will also pilot high-frequency data collection and analysis techniques, novel clinical interventions, and comparative effectiveness methodology.Methods and analysisPRECISION-TBI will initially enrol 300 patients with msTBI with Glasgow Coma Scale (GCS) <13 requiring intensive care unit (ICU) admission for invasive neuromonitoring from 10 Australian neurotrauma centres. Demographic data and process of care data (eg, prehospital, emergency and surgical intervention variables) will be collected. Clinical data will include prehospital and emergency department vital signs, and ICU physiological variables in the form of high frequency neuromonitoring data. ICU treatment data will also be collected for specific aspects of msTBI care. Six-month extended Glasgow Outcome Scores (GOSE) will be collected as the key outcome. Statistical analysis will focus on measures of between and within-site variation. Reports documenting performance on selected key quality indicators will be provided to participating sites.Ethics and disseminationEthics approval has been obtained from The Alfred Human Research Ethics Committee (Alfred Health, Melbourne, Australia). All eligible participants will be included in the study under a waiver of consent (hospital data collection) and opt-out (6 months follow-up). Brochures explaining the rationale of the study will be provided to all participants and/or an appropriate medical treatment decision-maker, who can act on the patient’s behalf if they lack capacity. Study findings will be disseminated by peer-review publications.Trial registration numberNCT05855252.
Journal Article
Rate and Predictors of Failure in the Conservative Management of Stable Thoracolumbar Burst Fractures: A Systematic Review and Meta-Analysis
Study Design:
Systematic review.
Objectives:
Management of stable traumatic thoracolumbar burst fractures in neurologically-intact patients remains controversial. Conservative management fails in a subset of patients who require subsequent surgical fixation. The aim of this review is to (1) determine the rate of conservative management failure, and (2) analyze predictive factors at admission influencing conservative management failure.
Methods:
A systematic review adhering to PRISMA guidelines was performed. Studies with data pertaining to traumatic thoracolumbar burst fractures without posterior osteoligamentous injury (e.g. AO Type A3/A4) and/or the rate and predictive factors of conservative management failure were included. Risk of bias appraisal was performed. Pooled analysis of rates of failure was performed with qualitative analysis of predictors of conservative management failure.
Results:
16 articles were included in this review (11 pertaining to rate of conservative management failure, 5 pertaining to predictive risk factors). Rate of failure of conservative management from a pooled analysis of 601 patients is 9.2% (95% CI: 4.5%-13.9%). Admission factors predictive of conservative management failure include age, greater initial kyphotic angle, greater initial interpedicular distance, smaller initial residual canal size, greater Load Sharing Classification (LSC) score and greater admission Visual Analog Scale (VAS) pain scores.
Conclusion:
A proportion (9.2%) of conservatively managed, neurologically-intact thoracolumbar burst fractures fail conservative management. Among other factors, age, kyphotic angle, residual canal area and interpedicular distance should be investigated in prospective studies to identify the subset of patients prone to failure of conservative management. Surgical management should be carefully considered in patients with the above risk factors.
Journal Article
Spinal Surgery in Patients Aged 80 Years and Older: Risk Stratification Using the Modified Frailty Index
Study Design:
This was an ambispective clinical quality registry study.
Objective:
To evaluate utility of 11-variable modified Frailty Index (mFI) in predicting postoperative outcomes among patients ≥80 years undergoing spinal surgery.
Methods:
Consecutive patients ≥80 years who underwent spinal surgery between January 1, 2013, and June 30, 2018, were included. Primary outcome measure was rate of major complication. Secondary outcome measures were (1) overall complication rate, (2) surgical site infection, and (3) 6-month mortality.
Results:
A total of 121 operations were performed. Demographic metrics were (1) age (mean ± SD) = 83.1 ± 2.8 years and (2) mFI (mean ± SD) = 2.1 ± 1.4 variables. As mFI increased from 0 to ≥4 variables, risk of major complication increased from 18.2% to 40.0% (P = .014); overall complication increased from 45.5% to 70.0% (P = .032); surgical site infection increased from 0.0% to 25.0% (P = .007). There were no significant changes in risk of 6-month mortality across mFIs (P = .115). Multivariate analysis showed that a higher mFI score of ≥3 variables was associated with a significantly higher risk of (1) major complication (P = .025); (2) overall complication (P = .015); (3) surgical site infection (P = .007); and (4) mortality (P = .044).
Conclusions:
mFI scores of ≥3/11 variables were associated with a higher risk of postoperative morbidity in patients aged ≥80 years undergoing spinal surgery. The mFI-associated risk stratification provides a valuable adjunct in surgical decision making for this rapidly growing subpopulation of patients.
Journal Article
Development of a Quality Indicator Set for the Optimal Acute Management of Moderate to Severe Traumatic Brain Injury in the Australian Context
Background
The aim of this study was to develop a consensus-based set of indicators of high-quality acute moderate to severe traumatic brain injury (msTBI) clinical management that can be used to measure structure, process, and outcome factors that are likely to influence patient outcomes. This is the first stage of the PRECISION-TBI program, which is a prospective cohort study that aims to identify and promote optimal clinical management of msTBI in Australia.
Methods
A preliminary set of 45 quality indicators was developed based on available evidence. An advisory committee of established experts in the field refined the initial indicator set in terms of content coverage, proportional representation, contamination, and supporting evidence. The refined indicator set was then distributed to a wider Delphi panel for assessment of each indicator in terms of validity, measurement feasibility, variability, and action feasibility. Inclusion in the final indicator set was contingent on prespecified inclusion scoring.
Results
The indicator set was structured according to the care pathway of msTBI and included prehospital, emergency department, neurosurgical, intensive care, and rehabilitation indicators. Measurement domains included structure indicators, logistic indicators, and clinical management indicators. The Delphi panel consisted of 44 participants (84% physician, 12% nursing, and 4% primary research) with a median of 15 years of practice. Of the 47 indicators included in the second round of the Delphi, 32 indicators were approved by the Delphi group.
Conclusions
This study identified a set of 32 quality indicators that can be used to structure data collection to drive quality improvement in the clinical management of msTBI. They will also be used to guide feedback to PRECISION-TBI’s participating sites.
Journal Article
Synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression: analysis of a proof-of-concept randomised clinical trial of cytokine blockade
Objectives To evaluate synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression during biological therapy for rheumatoid arthritis (RA). Methods Patients with active RA entered a randomised study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800 μg/kg twice a week. Arthroscopic synovial tissue biopsies were obtained at baseline and two further time points. Following immunohistochemical staining, selected mediators of RA pathophysiology were quantified using digital image analysis. Selected mediators were also measured in the serum. Results Twenty-two patients were randomly assigned: 11 received monotherapy and 11 combination therapy. American College of Rheumatology 20, 50 and 70 response rates were 64%, 64% and 46% with combination therapy and 36%, 9% and 0% with monotherapy, respectively. In synovial tissue, T-cell infiltration, vascularity and transforming growth factor beta (TGFβ) expression demonstrated significant utility as biomarkers of disease activity and therapeutic response. In serum, interleukin 6 (IL-6), matrix metalloproteinase (MMP) 1, MMP-3 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were most useful in this regard. An early decrease in serum levels of TIMP-1 was predictive of the later therapeutic outcome. Pretreatment tissue levels of T-cell infiltration and the growth factors vascular endothelial growth factor/TGFβ, and serum levels of IL-6, IL-8, MMP-1, TIMP-1, soluble tumour necrosis factor receptor types I and II and IL-18 correlated with radiographic progression. Conclusions Synovial tissue analysis identified biomarkers of disease activity, therapeutic response and radiographic progression. Biomarker expression in tissue was independent of the levels measured in the serum.
Journal Article
Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease
Genetic heterogeneity is a difficulty frequently encountered in the search for genes conferring susceptibility to prostate cancer. To circumvent this issue, we selected a large prostate cancer pedigree for genome-wide linkage analysis from a population that is genetically homogeneous. Selected cases and first-degree relatives were genotyped with Affymetrix 10K SNP arrays, identifying a 14 Mb haplotype on chromosome 5 (5p13–q12) inherited identical-by-descent (IBD) by multiple cases. Microsatellite genotyping of additional deceased case samples confirmed that a total of eight cases inherited the common haplotype (
P
=0.0017). Re-sequencing of eight prioritised candidate genes in the region in six selected individuals identified 15 SNPs segregating with the IBD haplotype, located within the
ITGA2
gene. Three of these polymorphisms were selected for genotyping in an independent Tasmanian data set comprising 127 cases with familial prostate cancer, 412 sporadic cases and 319 unaffected controls. Two were associated with prostate cancer risk: rs3212649 (OR=1.67 (1.07–2.6),
P
=0.0009) and rs1126643 (OR=1.52 (1.01–2.28),
P
=0.0088). Significant association was observed in both familial and sporadic prostate cancer. Although the functional SNP remains to be identified, considerable circumstantial evidence, provided by
in vivo
and
in vitro
studies, supports a role for
ITGA2
in tumour development.
Journal Article
Synovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade
The objective of the study was to evaluate synovial tissue receptor activator of nuclear factor-κβ ligand (RANKL) and osteoprotegerin (OPG) as biomarkers of disease activity, progressive joint damage, and therapeutic response, during cytokine blockade in rheumatoid arthritis (RA). Patients with active RA entered a randomized open-label 12-month study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800 μg/kg twice weekly. Arthroscopic synovial tissue biopsies were obtained at baseline, at 4 weeks and at the final time point. Following immunohistochemical staining, RANKL and OPG expression was quantified using digital image analysis. Radiographic damage was evaluated using the van der Heijde modification of the Sharp scoring system. Twenty-two patients were randomized. Baseline expression of RANKL, but not OPG, correlated significantly with baseline CRP levels (
r
= 0.61,
P
< 0.01). While a significant reduction in OPG expression following treatment was observed in clinical responders at the final time point (
P
< 0.05 vs. baseline), RANKL levels did not change, and the RANKL:OPG ratio remained unaltered, even at the highest levels of clinical response. When potential predictors of radiographic outcome were evaluated, baseline RANKL expression correlated with erosive progression at 1 year (
r
= 0.71,
P
< 0.01). Distinct, though related, pathophysiologic processes mediate joint inflammation and destruction in RA. Elevated synovial tissue RANKL expression is associated with progressive joint erosion, and may be independent of the clinical response to targeted therapy. The potential therapeutic importance of modulating RANKL in RA is highlighted, if radiographic arrest is to be achieved.
Journal Article