Showing papers by "David W. Hogg published in 2011"

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

Abstract: At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)

The Milky Way has no thick disk

Abstract: Different stellar sub-populations of the Milky Way's stellar disk are known to have different vertical scale heights, their thickness increasing with age. Using SEGUE spectroscopic survey data, we have recently shown that mono-abundance sub-populations, defined in the [\alpha/Fe]-[Fe/H] space, are well described by single exponential spatial-density profiles in both the radial and the vertical direction; therefore any star of a given abundance is clearly associated with a sub-population of scale height h_z. Here, we work out how to determine the stellar surface-mass density contributions at the solar radius R_0 of each such sub-population, accounting for the survey selection function, and for the fraction of the stellar population mass that is reflected in the spectroscopic target stars given populations of different abundances and their presumed age distributions. Taken together, this enables us to derive \Sigma_{R_0}(h_z), the surface-mass contributions of stellar populations with scale height h_z. Surprisingly, we find no hint of a thin-thick disk bi-modality in this mass-weighted scale-height distribution, but a smoothly decreasing function, approximately \Sigma_{R_0}(h_z)\propto \exp(-h_z), from h_z ~ 200 pc to h_z ~ 1 kpc. As h_z is ultimately the structurally defining property of a thin or thick disk, this shows clearly that the Milky Way has a continuous and monotonic distribution of disk thicknesses: there is no 'thick disk' sensibly characterized as a distinct component. We discuss how our result is consistent with evidence for seeming bi-modality in purely geometric disk decompositions, or chemical abundances analyses. We constrain the total visible stellar surface-mass density at the Solar radius to be \Sigma^*_{R_0} = 30 +/- 1 M_\odot pc^{-2}.

Endogenous GABA(A) and GABA(B) receptor-mediated electrical suppression is critical to neuronal anoxia tolerance.

Abstract: Anoxic insults cause hyperexcitability and cell death in mammalian neurons. Conversely, in anoxia-tolerant turtle brain, spontaneous electrical activity is suppressed by anoxia (i.e., spike arrest; SA) and cell death does not occur. The mechanism(s) of SA is unknown but likely involves GABAergic synaptic transmission, because GABA concentration increases dramatically in anoxic turtle brain. We investigated this possibility in turtle cortical neurons exposed to anoxia and/or GABAA/B receptor (GABAR) modulators. Anoxia increased endogenous slow phasic GABAergic activity, and both anoxia and GABA reversibly induced SA by increasing GABAAR-mediated postsynaptic activity and Cl− conductance, which eliminated the Cl− driving force by depolarizing membrane potential (∼8 mV) to GABA receptor reversal potential (∼−81 mV), and dampened excitatory potentials via shunting inhibition. In addition, both anoxia and GABA decreased excitatory postsynaptic activity, likely via GABABR-mediated inhibition of presynaptic glutamate release. In combination, these mechanisms increased the stimulation required to elicit an action potential >20-fold, and excitatory activity decreased >70% despite membrane potential depolarization. In contrast, anoxic neurons cotreated with GABAA+BR antagonists underwent seizure-like events, deleterious Ca2+ influx, and cell death, a phenotype consistent with excitotoxic cell death in anoxic mammalian brain. We conclude that increased endogenous GABA release during anoxia mediates SA by activating an inhibitory postsynaptic shunt and inhibiting presynaptic glutamate release. This represents a natural adaptive mechanism in which to explore strategies to protect mammalian brain from low-oxygen insults.

Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600EBRAF-mutated melanoma.

Abstract: LBA4 Background: About 50% of melanomas have an activating V600EBRAF mutation which led to the hypothesis that inhibition of the mutated BRAF kinase may be of clinical benefit. Phase I and II trials with vemurafenib (previously PLX4032/RO5185426), an orally available inhibitor of oncogenic BRAF kinase, showed response rates (RR; CR+PR) >50% in V600EBRAF- mutated melanoma patients (pts). We conducted a phase III trial to determine if vemurafenib improved overall survival (OS) and progression-free survival (PFS) in melanoma pts with V600EBRAF mutation. Methods: Pts with previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for V600EBRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) to vemurafenib (960 mg po bid) or DTIC (1,000 mg/m2, IV, q3w). Randomization was stratified by PS, stage, LDH, and geographic region. Pts were assessed for tumor responses after weeks 6, 12, and then q9 weeks. Co-primary endpoints were OS and PFS on the intent-to-treat ...

Evaluation of low-dose CT scans for surveillance in stage I testicular cancer.

Abstract: 4565 Background: Surveillance is a standard management option for clinical stage I testicular cancer. Serial CT imaging of the abdomen and pelvis (CTA/P) is a key component of all surveillance prot...

Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor RG7204 with dacarbazine in patients with V600E BRAF-mutated melanomas.

Abstract: LBA4 The full, final text of this abstract will be available in Part II of the 2011 Annual Meeting Proceedings, distributed onsite at the Meeting on June 4, 2011, and as a supplement to the June 20...