Therapeutic Response Evaluation in Advanced Melanoma Patients Incorporating Plasma cfDNA, LDH, VEGF, PD-L1, and IFN-γ Measurements.

BACKGROUND/AIM: Current treatment strategies for advanced melanoma require serial assessment of disease status in affected patients. In this study, we sought to examine the relationship between radiographic tumour burden and blood borne biomarkers including plasma cfDNA, serum LDH, plasma VEGF, PD-L1 and IFN-γ in advanced melanoma patients receiving immunotherapy. We hypothesized that a combination of these explanatory variables in a suitable regression analysis model may predict changes in tumour burden during patient treatment. MATERIALS AND METHODS: We extracted and quantified circulating cfDNA, LDH, VEGF, PD-L1, and IFN-γ from thirty patients with stage IV melanoma at baseline and at six months. All participating patients were evaluated with paired blood sample collection and CT scan assessments during treatment. RESULTS: Changes in radiographic tumour burden correlated with changes in levels of cfDNA (p≤0.001), LDH (p≤0.001), VEGF (p≤0.001), and PD-L1 (p<0.05) during treatment. Multiple regression analysis consisting of the follow-up to baseline assessment ratios of cfDNA, LDH, VEGF and PD-L1 explained changes in tumour burden (F (4, 23)=32.05, p<0.001); with an R2 of 0.8479 (Y=ß0+ß1*B+ß2*C+ß3*D+ß4*E). CONCLUSION: A quantitative measure of cfDNA, LDH, VEGF and PD-L1 may complement current methods of assessing tumour burden in advanced melanoma patients.

Exposure to air pollution is associated with adverse cardiopulmonary health effects in international travellers.

BACKGROUND: With the number of annual global travellers reaching 1.2 billion, many individuals encounter greater levels of air pollution when they travel abroad to megacities around the world. This study's objective was to determine if visits to cities abroad with greater levels of air pollution adversely impact cardiopulmonary health. METHODS: A total of 34 non-smoking healthy adult participants who travelled abroad to selected cities from the New York City (NYC) metropolitan area were pre-trained to measure lung function, blood pressure and heart rate (HR)/HR variability (HRV) and record symptoms before, during and after travelling abroad. Outdoor particulate matter (PM)2.5 concentrations were obtained from central monitors in each city. Associations between PM exposure concentrations and cardiopulmonary health endpoints were analysed using a mixed effects statistical design. RESULTS: East and South Asian cities had significantly higher PM2.5 concentrations compared with pre-travel NYC PM2.5 levels, with maximum concentrations reaching 503 µg/m3. PM exposure-related associations for lung function were statistically significant and strongest between evening Forced Expiratory Volume in the first second (FEV1) and same-day morning PM2.5 concentrations; a 10-µg/m3 increase in outdoor PM2.5 was associated with a mean decrease of 7 mL. Travel to a highly polluted city (PM2.5 > 100 µg/m3) was associated with a 209-ml reduction in evening FEV1 compared with a low polluted city (PM2.5 < 35 µg/m3). In general, participants who travelled to East and South Asian cities experienced increased respiratory symptoms/scores and changes in HR and HRV. CONCLUSIONS: Exposure to increased levels of PM2.5 in cities abroad caused small but statistically significant acute changes in cardiopulmonary function and respiratory symptoms in healthy young adults. These data suggest that travel-related exposure to increased PM2.5 adversely impacts cardiopulmonary health, which may be particularly important for travellers with pre-existing respiratory or cardiac disease.

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

Ambient Particulate Matter Air Pollution Exposure and Mortality in the NIH-AARP Diet and Health Cohort.

BACKGROUND: Outdoor fine particulate matter (≤ 2.5 µm; PM2.5) has been identified as a global health threat, but the number of large U.S. prospective cohort studies with individual participant data remains limited, especially at lower recent exposures. OBJECTIVES: We aimed to test the relationship between long-term exposure PM2.5 and death risk from all nonaccidental causes, cardiovascular (CVD), and respiratory diseases in 517,041 men and women enrolled in the National Institutes of Health-AARP cohort. METHODS: Individual participant data were linked with residence PM2.5 exposure estimates across the continental United States for a 2000-2009 follow-up period when matching census tract-level PM2.5 exposure data were available. Participants enrolled ranged from 50 to 71 years of age, residing in six U.S. states and two cities. Cox proportional hazard models yielded hazard ratio (HR) estimates per 10 µg/m3 of PM2.5 exposure. RESULTS: PM2.5 exposure was significantly associated with total mortality (HR = 1.03; 95% CI: 1.00, 1.05) and CVD mortality (HR = 1.10; 95% CI: 1.05, 1.15), but the association with respiratory mortality was not statistically significant (HR = 1.05; 95% CI: 0.98, 1.13). A significant association was found with respiratory mortality only among never smokers (HR = 1.27; 95% CI: 1.03, 1.56). Associations with 10-µg/m3 PM2.5 exposures in yearly participant residential annual mean, or in metropolitan area-wide mean, were consistent with baseline exposure model results. Associations with PM2.5 were similar when adjusted for ozone exposures. Analyses of California residents alone also yielded statistically significant PM2.5 mortality HRs for total and CVD mortality. CONCLUSIONS: Long-term exposure to PM2.5 air pollution was associated with an increased risk of total and CVD mortality, providing an independent test of the PM2.5-mortality relationship in a new large U.S. prospective cohort experiencing lower post-2000 PM2.5 exposure levels. CITATION: Thurston GD, Ahn J, Cromar KR, Shao Y, Reynolds HR, Jerrett M, Lim CC, Shanley R, Park Y, Hayes RB. 2016. Ambient particulate matter air pollution exposure and mortality in the NIH-AARP Diet and Health cohort. Environ Health Perspect 124:484-490; http://dx.doi.org/10.1289/ehp.1509676.

Radiation exposure with the radial approach for diagnostic coronary angiography in a centre previously performing purely the femoral approach.

INTRODUCTION: Use of the radial approach for coronary angiography and percutaneous coronary intervention (PCI) is known to improve many patient outcome measures. However, there is some concern that it may be associated with increased patient radiation exposure. This study explores radiation exposure with the radial approach compared with the femoral approach in a centre previously performing purely femoral approach. PATIENTS AND METHODS: Data was collected retrospectively for all patients undergoing diagnostic coronary angiography over a six month period. PCIs and procedures with inherent technical difficulty or use of additional techniques (graft studies, optical coherence tomography, fractional flow reserve) were excluded. Dose area product (DAP) and fluoroscopy time (FT) were analysed for all remaining procedures (n=389), comparing radial (n=109) and femoral (n=280) approaches. RESULTS: The overall mean FT for transradial cases (7.45 mins) was significantly higher than for transfemoral cases (4.59 mins; p<0.001). The overall mean DAP for transradial cases (95.64 G Gycm(2)) was significantly higher than for transfemoral cases (70.25 Gycm(2), p<0.05)). Neither the FT nor the DAP decreased over the six month period. CONCLUSION: The radial approach was associated with significantly higher DAP and FT compared to the femoral approach during an initial introductory phase which was likely insufficient to develop radial proficiency. The results of this study are consistent with previous studies and may influence choice of access for non-emergent diagnostic coronary angiography before radial proficiency has been established, particularly for patients more susceptible to radiation risks.

Early diagnosis of perioperative myocardial infarction after coronary bypass grafting: a study using biomarkers and cardiac magnetic resonance imaging.

BACKGROUND: Myocardial injury related to coronary artery bypass grafting (CABG) is poorly characterized, and understanding the characteristic release of biomarkers associated with revascularization injury might provide novel therapeutic opportunities. This study characterized early changes in biomarkers after revascularization injury during on-pump CABG. METHODS: This prospective study comprised 28 patients undergoing on-pump CABG and late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (CMRI) who underwent measurements of cardiac troponin I (cTnI), creatine kinase-MB, and inflammatory markers (C-reactive protein, serum amyloid A, myeloperoxidase, interleukin 6, tumor necrosis factor-α, matrix metalloproteinase 9a, monocyte chemotactic protein-1, plasminogen activator inhibitor-1a) at baseline, at 1, 6, 12, and 24 hours, and at 1 week (inflammatory markers only) post-CABG. Biomarker results at 1 hour were studied for a relationship to new myocardial infarction as defined by CMRI-LGE, and the diagnostic utility of combining positive biomarkers was assessed. RESULTS: All patients had an uneventful recovery, but 9 showed a new myocardial infarction demonstrated by new areas of hyperenhancement on CMR. Peak cTnI at 24 hours (ρ = 0.66, p < 0.001) and CK-MB (ρ = 0.66, p < 0.001) correlated with the amount of new LGE. At 1 hour, 3 biomarkers--cTnI, interleukin 6, and tumor necrosis factor-α--were significantly elevated in patients with vs those without new LGE. Receiver operating curve analysis showed cTnI was the most accurate at detecting new LGE at 1 hour: a cutoff of cTnI exceeding 5 µg/L at 1 hour had 67% sensitivity and 79% specificity for detecting new LGE. CONCLUSIONS: Unexpected CABG-related myocardial injury occurs in a significant proportion of patients. A cTnI test at 1 hour after CABG could potentially differentiate patients with significant revascularization injury.

Systemic levels of endothelin correlate with systemic inflammation and not with myocardial injury or left ventricular ejection fraction in patients undergoing percutaneous coronary intervention and on-pump coronary artery bypass grafting.

Endothelin (ET-1) is a potent vasoconstrictor. We compared patterns of ET-1 in percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) and correlated it with markers of inflammation. Patients with multivessel disease were enrolled in a prospective randomized study of PCI vs. on-pump CABG. Procedural myocardial injury was assessed biochemically (CK-MB) and with new late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI) one week postprocedure. ET-1 was measured at baseline, 1 h, 6 h, 12 h, 24 h and one week postprocedure. Log ET-1 values were compared between PCI and CABG and between patients without significant myocardial injury. Measurement of ET-1 values was performed in 36 PCI and 31 CABG patients. Baseline ET-1 values were similar between PCI and CABG patients (0.91 ± 0.36 vs. 1.0 ± 49 pg/ml, P = 0.38). Peak values were reached at 1 h in PCI and at 24 h in CABG patients and patients undergoing CABG had significantly higher log ET-1 values at 6 h, 12 h and 24 h. ET-1 did not correlate with biochemical or morphological markers of myocardial injury or change of left ventricular ejection fraction (LV-EF) but good linear correlation between max logET-1 and max logCRP was found (r = 0.44, P = 0.0002). ET-1 rise is more pronounced in on-pump CABG and ET-1 production could be driven by periprocedural inflammatory reaction.

Use of movable high-field-strength intraoperative magnetic resonance imaging with awake craniotomies for resection of gliomas: preliminary experience.

BACKGROUND: Awake craniotomy with electrocortical mapping and intraoperative magnetic resonance imaging (iMRI) are established techniques for maximizing tumor resection and preserving function, but there has been little experience combining these methodologies. OBJECTIVE: To report our experience of combining awake craniotomy and iMRI with a 1.5-T movable iMRI for resection of gliomas in close proximity to eloquent cortex. METHODS: Twelve patients (9 male and 3 female patients; age, 32-60 years; mean, 41 years) undergoing awake craniotomy and iMRI for glioma resections were identified from a prospective database. Assessments were made of how these 2 modalities were integrated and what impact this strategy had on safety, surgical decision making, workflow, operative time, extent of tumor resection, and outcome. RESULTS: Twelve craniotomies were safely performed in an operating room equipped with a movable 1.5-T iMRI. The extent of resection was limited because of proximity to eloquent areas in 5 cases: language areas in 3 patients and motor areas in 2 patients. Additional tumor was identified and resected after iMRI in 6 patients. Average operating room time was 7.9 hours (range, 5.9-9.7 hours). Compared with preoperative neurological function, immediate postoperative function was stable/improved in 7 and worse in 5; after 30 days, it was stable/improved in 11 and worse in 1. CONCLUSION: Awake craniotomy and iMRI with a movable high-field-strength device can be performed safely to maximize resection of tumors near eloquent language areas.

With the "universal definition," measurement of creatine kinase-myocardial band rather than troponin allows more accurate diagnosis of periprocedural necrosis and infarction after coronary intervention.

OBJECTIVES: We aimed to assess the differential implications of creatine kinase-myocardial band (CK-MB) and troponin measurement with the universal definition of periprocedural injury after percutaneous coronary intervention. BACKGROUND: Differentiation between definitions of periprocedural necrosis and periprocedural infarction has practical, sociological, and research implications. Troponin is the recommended biomarker, but there has been debate about the recommended diagnostic thresholds. METHODS: Thirty-two patients undergoing multivessel percutaneous coronary intervention and late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) imaging in a prospective study had cardiac troponin I, CK-MB, and inflammatory markers (C-reactive protein, serum amyloid A, myeloperoxidase, tumor necrosis factor alpha) measured at baseline, 1 h, 6 h, 12 h, and 24 h after the procedure. Three "periprocedural injury" groups were defined with the universal definition: G1: no injury (biomarker <99th percentile); G2: periprocedural necrosis (1 to 3 × 99th percentile); G3: myocardial infarction (MI) type 4a (>3 × 99th percentile). Differences in inflammatory profiles were analyzed. RESULTS: With CK-MB there were 17, 10, and 5 patients in groups 1, 2, and 3, respectively. Patients with CK-MB-defined MI type 4a closely approximated patients with new CMR-LGE injury. Groups defined with CK-MB showed progressively increasing percentage change in C-reactive protein and serum amyloid A, reflecting increasing inflammatory response (p < 0.05). Using cardiac troponin I resulted in 26 patients defined as MI type 4a, but only a small minority had evidence of abnormality on CMR-LGE, and only 3 patients were defined as necrosis. No differences in inflammatory response were evident when groups were defined with troponin. CONCLUSIONS: Measuring CK-MB is more clinically relevant for diagnosing MI type 4a, when applying the universal definition. Current troponin thresholds are oversensitive with the arbitrary limit of 3 × 99th percentile failing to discriminate between periprocedural necrosis and MI type 4a. (Myocardial Injury following Coronary Artery bypass Surgery versus Angioplasty: a randomised controlled trial using biochemical markers and cardiovascular magnetic resonance imaging; ISRCTN25699844).

Myocardial perfusion imaging after coronary artery bypass surgery using cardiovascular magnetic resonance: a validation study.

BACKGROUND: Absolute quantification of perfusion with cardiovascular magnetic resonance has not previously been applied in patients with coronary artery bypass grafting (CABG). Owing to increased contrast bolus dispersion due to the greater distance of travel through a bypass graft, this approach may result in systematic underestimation of myocardial blood flow (MBF). As resting MBF remains normal in segments supplied by noncritical coronary stenosis (<85%), measurement of perfusion in such territories may be utilized to reveal systematic error in the quantification of MBF. The objective of this study was to test whether absolute quantification of perfusion with cardiovascular magnetic resonance systematically underestimates MBF in segments subtended by bypass grafts. METHODS AND RESULTS: The study population comprised 28 patients undergoing elective CABG for treatment of multivessel coronary artery disease. Eligible patients had angiographic evidence of at least 1 myocardial segment subtended by a noncritically stenosed coronary artery (<85%). Subjects were studied at 1.5 T, with evaluation of resting MBF using model-independent deconvolution. Analyses were confined to myocardial segments subtended by native coronary arteries with <85% stenosis at baseline, and MBF was compared in grafted and ungrafted segments before and after revascularization. A total of 249 segments were subtended by coronary arteries with <85% stenosis at baseline. After revascularization, there was no significant difference in MBF in ungrafted (0.82±0.19 mL/min/g) versus grafted segments (0.82±0.15 mL/min/g, P=0.57). In the latter, MBF after revascularization did not change significantly from baseline (0.86±0.20 mL/min/g, P=0.82). CONCLUSIONS: Model-independent deconvolution analysis does not systematically underestimate blood flow in graft-subtended territories, justifying the use of this methodology to evaluate myocardial perfusion in patients with CABG.

Myocardial injury following coronary artery surgery versus angioplasty (MICASA): a randomised trial using biochemical markers and cardiac magnetic resonance imaging.

AIMS: To compare the frequency and extent of Troponin I and late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) defined injury following PCI compared with CABG in patients with multivessel and/or left main coronary artery disease (CAD), and interpret these finding in light of the new ESC/ACCF/AHA/WHF Task Force definitions for necrosis and infarction. METHODS AND RESULTS: Prospective, registered, single centre randomised controlled trial. Eighty patients with 3 vessel CAD (≥ 50% stenoses), or 2 vessel CAD including a type C lesion in the LAD, and/or left main disease were enrolled. Mean SYNTAX and EuroSCOREs were similar for both groups. Forty patients underwent PCI with drug eluting stents and 39 underwent CABG (one died prior to CABG). In the PCI group 6/38 (15.8%) patients had LGE, compared with 9/32 (28.1%) CABG patients (p = 0.25). Using the new Task Force definitions, necrosis occurred in 30/40 (75%) PCI patients and 35/35 (100%) CABG patients (p = 0.001), whilst infarction occurred in 30/40 (75%) PCI patients and 9/32 (28.1%) CABG patients (p = 0.0001). CONCLUSIONS: Periprocedural necrosis according to the Task Force definition was significantly lower in the PCI group, and universal in the CABG group. The incidence and extent of CMR defined infarction following PCI did not differ compared with CABG. This demonstrates that PCI can achieve revascularisation in complex patients without increased procedural myocardial damage.

Implementation and preliminary clinical experience with the use of ceiling mounted mobile high field intraoperative magnetic resonance imaging between two operating rooms.

OBJECTIVE: Intraoperative magnetic resonance imaging (ioMRI) provides immediate feedback and quality assurance enabling the neurosurgeon to improve the quality of a range of neurosurgical procedures. Implementation of ioMRI is a complex and costly process. We describe our preliminary 16 months experience with the integration of an IMRIS movable ceiling mounted high field (1.5 T) ioMRI setup with two operating rooms. METHODS: Aspects of implementation of our ioMRI and our initial 16 months of clinical experience in 180 consecutive patients were reviewed. RESULTS: The installation of a ceiling mounted movable ioMRI between two operating rooms was completed in April 2008 at Barnes-Jewish Hospital in St. Louis. Experience with 180 neurosurgical cases (M:F-100:80, age range 1-79 years, 71 gliomas, 57 pituitary adenomas, 9 metastases, 11 other tumor cases, 4 Chiari decompressions, 6 epilepsy resections and 22 other miscellaneous procedures) demonstrated that this device effectively provided high quality real-time intraoperative imaging. In 74 of all 180 cases (41%) and in 54% of glioma resections, the surgeon modified the procedure based upon the ioMRI. Ninety-three percent of ioMRI glioma cases achieved gross/near total resection compared to 65% of non ioMRI glioma cases in this time frame. CONCLUSION: A movable high field strength ioMRI can be safely integrated between two neurosurgical operating rooms. This strategy leads to modification of the surgical procedure in a significant number of cases, particularly for glioma surgery. Long-term follow up is needed to evaluate the clinical and financial impact of this technology in the field of neurosurgery.