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Impact of depth of response on survival in patients treated with cobimetinib ± vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM.
BackgroundThis pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAFV600-mutated metastatic melanoma treated with vemurafenib or cobimetinib plus vemurafenib.MethodsThe data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures.ResultsGreater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with vemurafenib; not estimable with cobimetinib plus vemurafenib). Cobimetinib plus vemurafenib improved depth of response versus vemurafenib monotherapy regardless of other prognostic factors, including gene signatures.ConclusionsGreater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses
Hypercomplex Integrable Systems
In this paper we study hypercomplex manifolds in four dimensions. Rather than
using an approach based on differential forms, we develop a dual approach using
vector fields. The condition on these vector fields may then be interpreted as
Lax equations, exhibiting the integrability properties of such manifolds. A
number of different field equations for such hypercomplex manifolds are
derived, one of which is in Cauchy-Kovaleskaya form which enables a formal
general solution to be given. Various other properties of the field equations
and their solutions are studied, such as their symmetry properties and the
associated hierarchy of conservation laws.Comment: Latex file, 19 page
Case report: Multimodality imaging of unusual coronary to pulmonary collaterals in chronic thromboembolic pulmonary hypertension
We present unusual coronary-pulmonary collaterals in a 65-year-old CTEPH patient. Perfusion mapping of a dual-energy computed tomography (DECT) study revealed areas of right lung that were minimally perfused despite unilateral occlusion of the right pulmonary artery, leading to the discovery of coronary-pulmonary collaterals via invasive coronary angiography. Pulmonary thromboendarterectomy removed the clot en-bloc. Post-surgery DECT and catheterization confirmed restoration of pulmonary arterial circulation and excellent hemodynamic response. Here, suggestion of perfusion to a proximally obstructed lung with DECT helped to document the presence of rarely documented coronary-pulmonary artery collaterals
Spitzer Imaging of the Nearby Rich Young Cluster, Cep OB3b
We map the full extent of a rich massive young cluster in the Cep OB3b
association with the IRAC and MIPS instruments aboard the {\it Spitzer} Space
Telescope and the ACIS instrument aboard the X-Ray Observatory.
At 700 pc, it is revealed to be the second nearest large ( member),
young ( Myr) cluster known. In contrast to the nearest large cluster, the
Orion Nebula Cluster, Cep OB3b is only lightly obscured and is mostly located
in a large cavity carved out of the surrounding molecular cloud. Our infrared
and X-ray datasets, as well as visible photometry from the literature, are used
to take a census of the young stars in Cep OB3b. We find that the young stars
within the cluster are concentrated in two sub-clusters; an eastern
sub-cluster, near the Cep B molecular clump, and a western sub-cluster, near
the Cep F molecular clump. Using our census of young stars, we examine the
fraction of young stars with infrared excesses indicative of circumstellar
disks. We create a map of the disk fraction throughout the cluster and find
that it is spatially variable. Due to these spatial variations, the two
sub-clusters exhibit substantially different average disk fractions from each
other: and . We discuss whether the discrepant disk
fractions are due to the photodestruction of disks by the high mass members of
the cluster or whether they result from differences in the ages of the
sub-clusters. We conclude that the discrepant disk fractions are most likely
due to differences in the ages.Comment: 48 Pages, 12 figures, 6 table
Young Stellar Object Variability (YSOVAR): Long Timescale Variations in the Mid-Infrared
The YSOVAR (Young Stellar Object VARiability) Spitzer Space Telescope
observing program obtained the first extensive mid-infrared (3.6 & 4.5 um)
time-series photometry of the Orion Nebula Cluster plus smaller footprints in
eleven other star-forming cores (AFGL490, NGC1333, MonR2, GGD 12-15, NGC2264,
L1688, Serpens Main, Serpens South, IRAS 20050+2720, IC1396A, and Ceph C).
There are ~29,000 unique objects with light curves in either or both IRAC
channels in the YSOVAR data set. We present the data collection and reduction
for the Spitzer and ancillary data, and define the "standard sample" on which
we calculate statistics, consisting of fast cadence data, with epochs about
twice per day for ~40d. We also define a "standard sample of members",
consisting of all the IR-selected members and X-ray selected members. We
characterize the standard sample in terms of other properties, such as spectral
energy distribution shape. We use three mechanisms to identify variables in the
fast cadence data--the Stetson index, a chi^2 fit to a flat light curve, and
significant periodicity. We also identified variables on the longest timescales
possible of ~6 years, by comparing measurements taken early in the Spitzer
mission with the mean from our YSOVAR campaign. The fraction of members in each
cluster that are variable on these longest timescales is a function of the
ratio of Class I/total members in each cluster, such that clusters with a
higher fraction of Class I objects also have a higher fraction of long-term
variables. For objects with a YSOVAR-determined period and a [3.6]-[8] color,
we find that a star with a longer period is more likely than those with shorter
periods to have an IR excess. We do not find any evidence for variability that
causes [3.6]-[4.5] excesses to appear or vanish within our data; out of members
and field objects combined, at most 0.02% may have transient IR excesses.Comment: Accepted to AJ; 38 figures, 93 page
Percutaneous coronary intervention of chronic total occlusions involving a bifurcation: Insights from the PROGRESS-CTO registry
BACKGROUND: The impact of bifurcations at the proximal or distal cap on the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has received limited study.
METHODS: We analyzed the clinical, angiographic, and procedural data of 4,584 cases performed in patients between 2012 and 2020 in a global CTO PCI registry. We compared 4 groups according to the bifurcation location: proximal cap, distal cap, proximal and distal cap, and no bifurcation.
RESULTS: The CTO involved a bifurcation in 67% cases, as follows: proximal cap (n = 1451, 33%), distal cap (n = 622, 14%), or both caps (n = 954, 21%). Proximal and distal cap cases had higher J-CTO compared with proximal cap, distal cap, and no bifurcation cases (2.9 ± 1.1 vs 2.5 ± 1.1 vs 2.4 ± 1.2 vs 2.0 ± 1.2, P \u3c 0.0001), and they were also associated with a lower technical success rate (79% vs 85% vs 85% vs 90%, P \u3c 0.0001), higher pericardiocentesis rate (1% vs 1% vs 0.2% vs 0.3%, P = 0.02), and higher emergency coronary artery bypass graft surgery rate (0.3% vs 0% vs 0% vs 0%, P = 0.01).
CONCLUSION: More than two-thirds of CTO PCIs involve a bifurcation, which is associated with lower technical success and higher risk of complications
Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)
BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4/CD8 T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4/CD8 ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4/CD8 ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4/CD8 T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted
High-Resolution Ice Cores from US ITASE (West Antarctica): Development and Validation of Chronologies and Determination of Precision and Accuracy
Shallow ice cores were obtained from widely distributed sites across the West Antarctic ice sheet, as part of the United States portion of the International Trans-Antarctic Scientific Expedition (US ITASE) program. The US ITASE cores have been dated by annual-layer counting, primarily through the identification of summer peaks in non-sea-salt sulfate (nssSO(4)(2-)) concentration. Absolute dating accuracy of better than 2 years and relative dating accuracy better than 1 year is demonstrated by the identification of multiple volcanic marker horizons in each of the cores, Tambora, Indonesia (1815), being the most prominent. Independent validation is provided by the tracing of isochronal layers from site to site using high-frequency ice-penetrating radar observations, and by the timing of mid-winter warming events in stable-isotope ratios, which demonstrate significantly better than 1 year accuracy in the last 20 years. Dating precision to 1 month is demonstrated by the occurrence of summer nitrate peaks and stable-isotope ratios in phase with nssSO(4)(2-), and winter-time sea-salt peaks out of phase, with phase variation of \u3c 1 month. Dating precision and accuracy are uniform with depth, for at least the last 100 years
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