Patient reported outcomes for cancer patients receiving immunotherapy: opportunities for palliative care - A Systematic Review.
Journal of pain and symptom management
CONTEXT: Immune checkpoint inhibitors (ICIs) are increasingly used to treat a variety of cancers, but comparatively little is known about patient-reported outcomes (PROs) and health-related quality of life (HRQoL) among patients receiving these novel therapies.OBJECTIVES: We performed a systematic review to examine PROs and HRQoL among cancer patients receiving ICIs as compared to other anticancer therapies.METHODS: We systematically searched PubMed, CINAHL, Embase, Web of Science, and Scopus, using search terms representing ICIs, PROs and HRQoL on August 10, 2018. Eligible articles were required to involve cancer patients treated with ICIs and to report PROs and/or HRQoL data.RESULTS: We screened 1,453 references and included 15 publications representing 15 randomized controlled trials in our analysis. Studies included several cancer types (melanoma, lung cancer, genitourinary cancer, and head/neck cancer), utilized four different ICIs (nivolumab, pembrolizumab, atezolizumab, and ipilimumab), and compared ICIs to a wide range of therapies (chemotherapy, targeted therapies, other immunotherapy strategies, and placebo). Studies utilized a total of seven different PROs to measure HRQOL, most commonly the European Organisation for the Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-C30) (n = 12, 80%). PRO data were reported in a variety of formats and at a variety of time points throughout treatment which made direct comparison challenging. Some trials (n=11, 73%) reported PROs on specific symptoms. In general, patients receiving ICIs had similar to improved HRQoL and experiences when compared to other therapies.CONCLUSION: Despite the broad clinical trials experience of ICI therapies across cancer types, relatively few randomized studies reported patient PROs and HRQoL data. Available data suggest that ICIs are well-tolerated in terms of HRQoL compared to other anticancer therapies although the conclusions are limited by the heterogeneity of trial designs and outcomes. Currently used instruments may fail to capture important symptomatology unique to ICIs, underscoring a need for PROs designed specifically for ICIs.
View details for DOI 10.1016/j.jpainsymman.2019.03.015
View details for PubMedID 30905677
Electronic health record-based clinical decision support alert for severe sepsis: a randomised evaluation.
BMJ quality & safety
BACKGROUND: Sepsis remains the top cause of morbidity and mortality of hospitalised patients despite concerted efforts. Clinical decision support for sepsis has shown mixed results reflecting heterogeneous populations, methodologies and interventions.OBJECTIVES: To determine whether the addition of a real-time electronic health record (EHR)-based clinical decision support alert improves adherence to treatment guidelines and clinical outcomes in hospitalised patients with suspected severe sepsis.DESIGN: Patient-level randomisation, single blinded.SETTING: Medical and surgical inpatient units of an academic, tertiary care medical centre.PATIENTS: 1123 adults over the age of 18 admitted to inpatient wards (intensive care units (ICU) excluded) at an academic teaching hospital between November 2014 and March 2015.INTERVENTIONS: Patients were randomised to either usual care or the addition of an EHR-generated alert in response to a set of modified severe sepsis criteria that included vital signs, laboratory values and physician orders.MEASUREMENTS AND MAIN RESULTS: There was no significant difference between the intervention and control groups in primary outcome of the percentage of patients with new antibiotic orders at 3hours after the alert (35% vs 37%, p=0.53). There was no difference in secondary outcomes of in-hospital mortality at 30 days, length of stay greater than 72hours, rate of transfer to ICU within 48hours of alert, or proportion of patients receiving at least 30mL/kg of intravenous fluids.CONCLUSIONS: An EHR-based severe sepsis alert did not result in a statistically significant improvement in several sepsis treatment performance measures.
View details for PubMedID 30872387
- "A Man Walks Into a Bar": Riddles in the Teaching of Medicine. The American journal of medicine 2018
Pathogenic variants in less familiar cancer susceptibility genes: what happens after genetic testing?
JCO Precision Oncology
View details for DOI 10.1200/PO.18.00167
Racial/ethnic differences in multiple-gene sequencing results for hereditary cancer risk.
Genetics in medicine : official journal of the American College of Medical Genetics
PurposeWe examined racial/ethnic differences in the usage and results of germ-line multiple-gene sequencing (MGS) panels to evaluate hereditary cancer risk.MethodsWe collected genetic testing results and clinical information from 1,483 patients who underwent MGS at Stanford University between 1 January 2013 and 31 December 2015.ResultsAsians and Hispanics presented for MGS at younger ages than whites (48 and 47 vs. 55; P = 5E-16 and 5E-14). Across all panels, the rate of pathogenic variants (15%) did not differ significantly between racial groups. Rates by gene did differ: in particular, a higher percentage of whites than nonwhites carried pathogenic CHEK2 variants (3.8% vs. 1.0%; P = 0.002). The rate of a variant of uncertain significance (VUS) result was higher in nonwhites than whites (36% vs. 27%; P = 2E-4). The probability of a VUS increased with increasing number of genes tested; this effect was more pronounced for nonwhites than for whites (1.1% absolute difference in VUS rates testing BRCA1/2 vs. 8% testing 13 genes vs. 14% testing 28 genes), worsening the disparity.ConclusionIn this diverse cohort undergoing MGS testing, pathogenic variant rates were similar between racial/ethnic groups. By contrast, VUS results were more frequent among nonwhites, with potential significance for the impact of MGS testing by race/ethnicity.GENETICS in MEDICINE advance online publication, 27 July 2017; doi:10.1038/gim.2017.96.
View details for DOI 10.1038/gim.2017.96
View details for PubMedID 28749474
Murine glomerular transcriptome links endothelial cell-specific molecule-1 deficiency with susceptibility to diabetic nephropathy.
2017; 12 (9): e0185250
Diabetic nephropathy (DN) is the leading cause of kidney disease; however, there are no early biomarkers and no cure. Thus, there is a large unmet need to predict which individuals will develop nephropathy and to understand the molecular mechanisms that govern this susceptibility. We compared the glomerular transcriptome from mice with distinct susceptibilities to DN at four weeks after induction of diabetes, but before histologic injury, and identified differential regulation of genes that modulate inflammation. From these genes, we identified endothelial cell specific molecule-1 (Esm-1), as a glomerular-enriched determinant of resistance to DN. Glomerular Esm-1 mRNA and protein were lower in DN-susceptible, DBA/2, compared to DN-resistant, C57BL/6, mice. We demonstrated higher Esm-1 secretion from primary glomerular cultures of diabetic mice, and high glucose was sufficient to increase Esm-1 mRNA and protein secretion in both strains of mice. However, induction was significantly attenuated in DN-susceptible mice. Urine Esm-1 was also significantly higher only in DN-resistant mice. Moreover, using intravital microscopy and a biomimetic microfluidic assay, we showed that Esm-1 inhibited rolling and transmigration in a dose-dependent manner. For the first time we have uncovered glomerular-derived Esm-1 as a potential non-invasive biomarker of DN. Esm-1 inversely correlates with disease susceptibility and inhibits leukocyte infiltration, a critical factor in protecting the kidney from DN.
View details for PubMedID 28934365
Dynamic Regulation of Endothelial Cell-Specific Molecule 1 in Diabetic Mouse Kidney
FEDERATION AMER SOC EXP BIOL. 2016
View details for Web of Science ID 000406444706180
- Is there a sweet spot for Nrf2 activation in the treatment of diabetic kidney disease? Diabetes 2014; 63 (9): 2904-2905
The effect of supine exercise on the distribution of regional pulmonary blood flow measured using proton MRI
JOURNAL OF APPLIED PHYSIOLOGY
2014; 116 (4): 451-461
The Zone model of pulmonary perfusion predicts that exercise reduces perfusion heterogeneity because increased vascular pressure redistributes flow to gravitationally nondependent lung, and causes dilation and recruitment of blood vessels. However, during exercise in animals, perfusion heterogeneity as measured by the relative dispersion (RD, SD/mean) is not significantly decreased. We evaluated the effect of exercise on pulmonary perfusion in six healthy supine humans using magnetic resonance imaging (MRI). Data were acquired at rest, while exercising (∼27% of maximal oxygen consumption) using a MRI-compatible ergometer, and in recovery. Images were acquired in most of the right lung in the sagittal plane at functional residual capacity, using a 1.5-T MR scanner equipped with a torso coil. Perfusion was measured using arterial spin labeling (ASL-FAIRER) and regional proton density using a fast multiecho gradient-echo sequence. Perfusion images were corrected for coil-based signal heterogeneity, large conduit vessels removed and quantified (in ml·min(-1)·ml(-1)) (perfusion), and also normalized for density and quantified (in ml·min(-1)·g(-1)) (density-normalized perfusion, DNP) accounting for tissue redistribution. DNP increased during exercise (11.1 ± 3.5 rest, 18.8 ± 2.3 exercise, 13.2 ± 2.2 recovery, ml·min(-1)·g(-1), P < 0.0001), and the increase was largest in nondependent lung (110 ± 61% increase in nondependent, 63 ± 35% in mid, 70 ± 33% in dependent, P < 0.005). The RD of perfusion decreased with exercise (0.93 ± 0.21 rest, 0.73 ± 0.13 exercise, 0.94 ± 0.18 recovery, P < 0.005). The RD of DNP showed a similar trend (0.82 ± 0.14 rest, 0.75 ± 0.09 exercise, 0.81 ± 0.10 recovery, P = 0.13). In conclusion, in contrast to animal studies, in supine humans, mild exercise decreased perfusion heterogeneity, consistent with Zone model predictions.
View details for DOI 10.1152/japplphysiol.00659.2013
View details for Web of Science ID 000331214400010
View details for PubMedID 24356515
View details for PubMedCentralID PMC3921353
Measuring Lung Water: Ex Vivo Validation of Multi-image Gradient Echo MRI
JOURNAL OF MAGNETIC RESONANCE IMAGING
2011; 34 (1): 220-224
To validate a fast gradient echo sequence for rapid (9 s) quantitative imaging of lung water.Eleven excised pig lungs were imaged with a fast GRE sequence in triplicate, in the sagittal plane at 2 levels of inflation pressure (5 and 15 cm H(2) O), an intervention that alters T(2) *, but not total lung water. Images were acquired alternating between two closely-spaced echoes and data were fit (voxel-by-voxel) to a single exponential to determine T(2) * and water content, and compared with gravimetric measurements of total water.T(2) * averaged 1.08 ± 0.02 ms at 5 cm H(2) O and 1.02 ± 0.02 ms at 15 cm H(2) O (P < 0.05). The measure was reliable (R(2) = 0.99), with an average mean error of 1.8%. There was a significant linear relationship between the two measures of water content: The regression equations for the relationship were y = 0.92x + 19 (R(2) = 0.94), and y = 1.04x + 4 (R(2) = 0.96), for 5 and 15 cm H(2) O inflation pressure respectively. Y-intercepts were not statistically different from zero (P = 0.86).The multi-echo GRE sequence is a reliable and valid technique to assess water content in the lung. This technique enables rapid assessment of lung water, which is advantageous for in vivo studies.
View details for DOI 10.1002/jmri.22600
View details for Web of Science ID 000292421800027
View details for PubMedID 21698711
View details for PubMedCentralID PMC3122154
Towards quorum-quenching catalytic antibodies
The development of a novel method to attenuate bacterial virulence is reported, which is based upon the use of designed transition-state analogues to select human catalytic antibodies capable of degrading bacterial quorum-sensing molecules.
View details for DOI 10.1039/b819819e
View details for Web of Science ID 000262649200005
View details for PubMedID 19283283