280 research outputs found
Do patients with recurrent and de novo metastatic biliary cancer have similar outcomes on treatment?
P4â564: ShortâTerm Outcomes Of A Randomized Controlled Trial Of Amyloid Pet Results Disclosure In Mild Cognitive Impairment
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152786/1/alzjjalz201908111.pd
FOLFIRINOX for advanced pancreatic cancer:The Princess Margaret Cancer Centre experience
BACKGROUND: FOLFIRINOX has been shown to significantly increase both overall survival (OS) and progression-free survival (PFS) in metastatic pancreas cancer. There is limited data regarding the treatment of locally advanced pancreatic cancer. We present a retrospective study of patients with both locally advanced and metastatic pancreas cancer using FOLFIRINOX as first-line therapy in our centre. METHODS: This is a retrospective review of patients treated with FOLFIRINOX for pancreatic cancer at Princess Margaret Cancer Centre, between December 2011 and July 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications. RESULTS: One hundred two patients were identified; 66 metastatic and 36 locally advanced. Sixty-eight per cent of patients initiated treatment with a dose reduction. The median (95% CI) OS in the metastatic group was 13.1 (6.3â16.1) months with full dose and 12.9 (10.3â30.1) months with modified dose. The median (95% CI) OS in the locally advanced group was 11.1 (6.1ânot reached) months with full dose and 23 (not reachedânot reached) months with modified dose. The median (95% CI) PFS in the metastatic group was 6.2 (4.9â15.2) months with full dose and 8.7 (5.7â12.9) months with modified dose. The median (95% CI) PFS in the locally advanced group was 11.1 (3.1ânot reached) months with full dose and 10.4 (6.8ânot reached) months with modified dose. Grade 3/4 haematologic adverse events were observed in 43% of patients. Grade 3/4 non-haematologic adverse events were observed in 28% of patients. Patient well-being significantly improved from baseline to cycle 4 (P=0.002). CONCLUSIONS: Efficacy was achievable with dose-modified FOLFIRINOX in daily setting. The safety of FOLFIRINOX remains a concern with a high rate of grades 3 and 4 neutropaenia despite dose reduction
Vegetation demographics in Earth System Models: A review of progress and priorities
Numerous current efforts seek to improve the representation of ecosystem ecology and vegetation demographic processes within Earth System Models (ESMs). These developments are widely viewed as an important step in developing greater realism in predictions of future ecosystem states and fluxes. Increased realism, however, leads to increased model complexity, with new features raising a suite of ecological questions that require empirical constraints. Here, we review the developments that permit the representation of plant demographics in ESMs, and identify issues raised by these developments that highlight important gaps in ecological understanding. These issues inevitably translate into uncertainty in model projections but also allow models to be applied to new processes and questions concerning the dynamics of real-world ecosystems. We argue that stronger and more innovative connections to data, across the range of scales considered, are required to address these gaps in understanding. The development of first-generation land surface models as a unifying framework for ecophysiological understanding stimulated much research into plant physiological traits and gas exchange. Constraining predictions at ecologically relevant spatial and temporal scales will require a similar investment of effort and intensified inter-disciplinary communication
A randomized controlled trial of amyloid positron emission tomography results disclosure in mild cognitive impairment
IntroductionRecent studies suggest that Alzheimerâs disease (AD) biomarker disclosure has no discernable psychological impact on cognitively healthy persons. Far less is known about how such results affect symptomatic individuals and their caregivers.MethodsRandomized controlled trial of 82 mild cognitive impairment (MCI) patient and caregiver dyads (total n = 164) to determine the effect of receiving amyloid positron emission tomography results on understanding of, and perceived efficacy to cope with, MCI over 52 weeks of followâup.ResultsGains in the primary outcomes were not consistently observed. Amyloid negative patients reported greater perceived ambiguity regarding MCI at followâup, while moderate and sustained emotional distress was observed in patients, and to a lesser extent, caregivers, of those who were amyloid positive. There was no corresponding increase in depressive symptoms.DiscussionThese findings point to the possibility that both MCI patients and caregivers may need emotional support after the disclosure of amyloid scan results.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163444/2/alz12129_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163444/1/alz12129.pd
Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib The CheckMate 040 Randomized Clinical Trial
IMPORTANCE Most patients with hepatocellular carcinoma (HCC) are diagnosed with
advanced disease not eligible for potentially curative therapies; therefore, new treatment
options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes
compared with nivolumab monotherapy.
OBJECTIVE To assess efficacy and safety of nivolumab plus ipilimumab in patients with
advanced HCC who were previously treated with sorafenib.
DESIGN, SETTING, AND PARTICIPANTS CheckMate 040 is a multicenter, open-label,
multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were
randomized between January 4 and September 26, 2016. Treatment group information was
blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis
was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia,
Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or
C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A
and 49 each to arms B and C).
INTERVENTIONS Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3
mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks
(arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses),
followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks
plus ipilimumab 1 mg/kg every 6 weeks (arm C).
MAIN OUTCOMES AND MEASURES Coprimary end points were safety, tolerability, and objective
response rate. Duration of response was also measured (investigator assessed with the
Response Evaluation Criteria in Solid Tumors v1.1).
RESULTS Of 148 total participants, 120 were male (81%). Median (IQR) age was 60
(52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR,
29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in
arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median
(range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months
(4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related
adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in
arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A;
grade 5 pneumonitis).
CONCLUSIONS AND RELEVANCE In this randomized clinical trial, nivolumab plus ipilimumab
had manageable safety, promising objective response rate, and durable responses. The arm A
regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab
240 mg every 2 weeks) received accelerated approval in the US based on the results of this
study.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0165887
BRAF in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability
In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAF oncoproteins usually lack five amino acids in the ÎČ3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAF oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAF and two novel mutants, BRAF and BRAF, and compare them with other BRAF oncoproteins. We show that BRAF oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAF oncoproteins, e.g., BRAF, increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAF mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds
Circulating oncometabolite 2-hydroxyglutarate (2HG) as a potential biomarker for isocitrate dehydrogenase (IDH1/2) mutant cholangiocarcinoma
Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate. IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of IDHmt glioma and CCA patients. Results were validated in cohorts of CCA and clear cell renal cell carcinoma (ccRCC) patients. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for IDHmt glioma patients, while circulating rRS was elevated in IDHmt CCA patients. There were overlap distributions of circulating R2HG and total 2HG (t2HG) in both IDHmt and wild-type (IDHwt) CCA patients, while there was minimal overlap in rRS values between IDHmt and IDHwt CCA patients. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in IDHmt CCA patients compare to IDHwt CCA patients. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy
LSST Science Book, Version 2.0
A survey that can cover the sky in optical bands over wide fields to faint
magnitudes with a fast cadence will enable many of the exciting science
opportunities of the next decade. The Large Synoptic Survey Telescope (LSST)
will have an effective aperture of 6.7 meters and an imaging camera with field
of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over
20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with
fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a
total point-source depth of r~27.5. The LSST Science Book describes the basic
parameters of the LSST hardware, software, and observing plans. The book
discusses educational and outreach opportunities, then goes on to describe a
broad range of science that LSST will revolutionize: mapping the inner and
outer Solar System, stellar populations in the Milky Way and nearby galaxies,
the structure of the Milky Way disk and halo and other objects in the Local
Volume, transient and variable objects both at low and high redshift, and the
properties of normal and active galaxies at low and high redshift. It then
turns to far-field cosmological topics, exploring properties of supernovae to
z~1, strong and weak lensing, the large-scale distribution of galaxies and
baryon oscillations, and how these different probes may be combined to
constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at
http://www.lsst.org/lsst/sciboo
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