Phase II trial of temsirolimus for relapsed/refractory primary CNS lymphoma

Purpose: In this phase II study (NCT00942747), temsirolimus was tested in patients with relapsed or refractory primary CNS lymphoma (PCNSL). Patients and Methods: Immunocompetent adults with histologically confirmed PCNSL after experiencing high-dose methotrexate-based chemotherapy failure who were not eligible for or had experienced high-dose chemotherapy with autologous stem-cell transplant failure were included. The first cohort (n = 6) received 25 mg temsirolimus intravenously once per week. All consecutive patients received 75 mg intravenously once per week. Results: Thirty-seven eligible patients (median age, 70 years) were included whose median time since their last treatment was 3.9 months (range, 0.1 to 14.6 months). Complete response was seen in five patients (13.5%), complete response unconfirmed in three (8%), and partial response in 12 (32.4%) for an overall response rate of 54%. Median progression-free survival was 2.1 months (95% CI, 1.1 to 3.0 months). The most frequent Common Toxicity Criteria ≥ 3° adverse event was hyperglycemia in 11 (29.7%) patients, thrombocytopenia in eight (21.6%), infection in seven (19%), anemia in four (10.8%), and rash in three (8.1%). Fourteen blood/CSF pairs were collected in nine patients (10 pairs in five patients in the 25-mg cohort and four pairs in four patients in the 75-mg cohort). The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for its metabolite sirolimus in the 25-mg cohort and 484 ng/mL and 91.1 ng/mL, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/mL in one patient in the 75-mg cohort; in all others, no drug was found in their CSF. Conclusion: Single-agent temsirolimus at a weekly dose of 75 mg was found to be active in relapsed/refractory patients with PCNSL; however, responses were usually short lived

Evidence for Pre-Existing Dust in the Bright Type IIn SN 2010jl

SN 2010jl was an extremely bright, Type IIn SNe which showed a significant IR excess no later than 90 days after explosion. We have obtained Spitzer 3.6 and 4.5 \mum and JHK observations of SN 2010jl \sim90 days post explosion. Little to no reddening in the host galaxy indicated that the circumstellar material lost from the progenitor must lie in a torus inclined out of the plane of the sky. The likely cause of the high mid-IR flux is the reprocessing of the initial flash of the SN by pre-existing circumstellar dust. Using a 3D Monte Carlo Radiative Transfer code, we have estimated that between 0.03-0.35 Msun of dust exists in a circumstellar torus around the SN located 6 \times 10 ^17 cm away from the SN and inclined between 60-80\cdot to the plane of the sky. On day 90, we are only seeing the illumination of approximately 5% of this torus, and expect to see an elevated IR flux from this material up until day \sim 450. It is likely this dust was created in an LBV-like mass loss event of more than 3 Msun, which is large but consistent with other LBV progenitors such as {\eta} Carinae.Comment: Accepted in A

Caltech Core-Collapse Project (CCCP) observations of type IIn supernovae: typical properties and implications for their progenitor stars

Type IIn Supernovae (SNe IIn) are rare events, constituting only a few percent of all core-collapse SNe, and the current sample of well observed SNe IIn is small. Here, we study the four SNe IIn observed by the Caltech Core-Collapse Project (CCCP). The CCCP SN sample is unbiased to the extent that object selection was not influenced by target SN properties. Therefore, these events are representative of the observed population of SNe IIn. We find that a narrow P-Cygni profile in the hydrogen Balmer lines appears to be a ubiquitous feature of SNe IIn. Our light curves show a relatively long rise time (>20 days) followed by a slow decline stage (0.01 to 0.15 mag/day), and a typical V-band peak magnitude of M_V=-18.4 +/- 1.0 mag. We measure the progenitor star wind velocities (600 - 1400 km/s) for the SNe in our sample and derive pre-explosion mass loss rates (0.026 - 0.12 solar masses per year). We compile similar data for SNe IIn from the literature, and discuss our results in the context of this larger sample. Our results indicate that typical SNe IIn arise from progenitor stars that undergo LBV-like mass-loss shortly before they explode.Comment: ApJ, submitte

SN 2011ht: Confirming a Class of Interacting Supernovae with Plateau Light Curves (Type IIn-P)

We present photometry and spectroscopy of the Type IIn supernova (SN) 2011ht, identified previously as a SN impostor. The light curve exhibits an abrupt transition from a well-defined ~120 day plateau to a steep bolometric decline. Leading up to peak brightness, a hot emission-line spectrum exhibits signs of interaction with circumstellar material (CSM), in the form of relatively narrow P-Cygni features of H I and He I superimposed on broad Lorentzian wings. For the remainder of the plateau phase the spectrum exhibits strengthening P-Cygni profiles of Fe II, Ca II, and H-alpha. By day 147, after the plateau has ended, the SN entered the nebular phase, heralded by the appearance of forbidden transitions of [O I], [O II], and [Ca II] over a weak continuum. At this stage, the light curve exhibits a low luminosity that is comparable to that sub-luminous Type II-P supernovae, and a relatively fast visual-wavelength decline that is significantly steeper than the Co-56 decay rate. However, the total bolometric decline, including the IR luminosity, is consistent with Co-56 decay, and implies a low Ni-56 mass of ~0.01 M(Sun). We therefore characterize SN 2011ht as a bona-fide core-collapse SN very similar to the peculiar SNe IIn 1994W and 2009kn. These three SNe define a subclass, which are Type IIn based on their spectrum, but that also exhibit well-defined plateaus and produce low Ni-56 yields. We therefore suggest Type IIn-P as a name for this subclass. Possible progenitors of SNe IIn-P, consistent with the available data, include 8-10 M(Sun) stars, which undergo core collapse as a result of electron capture after a brief phase of enhanced mass loss, or more massive M>25 M(Sun) progenitors, which experience substantial fallback of the metal-rich radioactive ejecta. In either case, the energy radiated by these three SNe during their plateau must be dominated by CSM interaction (abridged).Comment: accepted, post-proof version (includes new data

Use of bioanalyzer electropherograms for quality control and target evaluation in microarray expression profiling studies of ocular tissues

Expression profiling with DNA microarrays has been used to examine the transcriptome of a wide spectrum of vertebrate cells and tissues. The sensitivity and accuracy of the data generated is dependent on the quality and composition of the input RNA. In this report, we examine the quality and array performance of over 200 total RNA samples extracted from ocular tissues and cells that have been processed in a microarray core laboratory over a 7-year period. Total RNA integrity and cRNA target size distribution were assessed using the 2100 Bioanalyzer. We present Affymetrix GeneChip array performance metrics for different ocular samples processed according to a standard microarray assay workflow including several quality control checkpoints. Our review of ocular sample performance in the microarray assay demonstrates the value of considering tissue-specific characteristics in evaluating array data. Specifically, we show that Bioanalyzer electropherograms reveal highly abundant mRNAs in lacrimal gland targets that are correlated with variation in array assay performance. Our results provide useful benchmarks for other gene expression studies of ocular systems

Observed Consequences of Presupernova Instability in Very Massive Stars

This chapter concentrates on the deaths of very massive stars, the events leading up to their deaths, and how mass loss affects the resulting death. The previous three chapters emphasized the theory of wind mass loss, eruptions, and core collapse physics, but here we emphasize mainly the observational properties of the resulting death throes. Mass loss through winds, eruptions, and interacting binaries largely determines the wide variety of different types of supernovae that are observed, as well as the circumstellar environments into which the supernova blast waves expand. Connecting these observed properties of the explosions to the initial masses of their progenitor stars is, however, an enduring challenge and is especially difficult for very massive stars. Superluminous supernovae, pair instability supernovae, gamma ray bursts, and "failed" supernovae are all end fates that have been proposed for very massive stars, but the range of initial masses or other conditions leading to each of these (if they actually occur) are still very certain. Extrapolating to infer the role of very massive stars in the early universe is essentially unencumbered by observational constraints and still quite dicey.Comment: 39 pages, 5 figures, to appear as chapter in the book "Very Massive Stars in the Local Universe", ed. J. Vin

A Central Excess of Stripped-Envelope Supernovae within Disturbed Galaxies

This paper presents an analysis of core-collapse supernova distributions in isolated and interacting host galaxies, paying close attention to the selection effects involved in conducting host galaxy supernova studies. When taking into account all of the selection effects within our host galaxy sample, we draw the following conclusions: i) Within interacting, or 'disturbed', systems there is a real, and statistically significant, increase in the fraction of stripped-envelope supernovae in the central regions. A discussion into what may cause this increased fraction, compared to the more common type IIP supernovae, and type II supernovae without sub-classifications, is presented. Selection effects are shown not to drive this result, and so we propose that this study provides direct evidence for a high-mass weighted initial mass function within the central regions of disturbed galaxies. ii) Within 'undisturbed' spiral galaxies the radial distribution of type Ib and type Ic supernovae is statistically very different, with the latter showing a more centrally concentrated distribution. This could be driven by metallicity gradients in these undisturbed galaxies, or radial variations in other properties (binarity or stellar rotation) driving envelope loss in progenitor stars. This result is not found in 'disturbed' systems, where the distributions of type Ib and Ic supernovae are consistent.Comment: Accepted for publication in MNRA

Observational and Physical Classification of Supernovae

This chapter describes the current classification scheme of supernovae (SNe). This scheme has evolved over many decades and now includes numerous SN Types and sub-types. Many of these are universally recognized, while there are controversies regarding the definitions, membership and even the names of some sub-classes; we will try to review here the commonly-used nomenclature, noting the main variants when possible. SN Types are defined according to observational properties; mostly visible-light spectra near maximum light, as well as according to their photometric properties. However, a long-term goal of SN classification is to associate observationally-defined classes with specific physical explosive phenomena. We show here that this aspiration is now finally coming to fruition, and we establish the SN classification scheme upon direct observational evidence connecting SN groups with specific progenitor stars. Observationally, the broad class of Type II SNe contains objects showing strong spectroscopic signatures of hydrogen, while objects lacking such signatures are of Type I, which is further divided to numerous subclasses. Recently a class of super-luminous SNe (SLSNe, typically 10 times more luminous than standard events) has been identified, and it is discussed. We end this chapter by briefly describing a proposed alternative classification scheme that is inspired by the stellar classification system. This system presents our emerging physical understanding of SN explosions, while clearly separating robust observational properties from physical inferences that can be debated. This new system is quantitative, and naturally deals with events distributed along a continuum, rather than being strictly divided into discrete classes. Thus, it may be more suitable to the coming era where SN numbers will quickly expand from a few thousands to millions of events.Comment: Extended final draft of a chapter in the "SN Handbook". Comments most welcom

Cytolytic T-cell response against Epstein-Barr virus in lung cancer patients and healthy subjects

<p>Abstract</p> <p>Background</p> <p>This study aimed to examine whether EBV seropositive patients with lung cancer have an altered virus-specific CTL response, as compared to age-matched healthy controls and whether any variation in this response could be attributed to senescence.</p> <p>Methods</p> <p>Peripheral blood mononuclear cells from lung cancer patients, age-matched and younger healthy individuals were used to measure EBV-specific CTLs after in vitro amplification with the GLCTLVAML and RYSIFFDYM peptides followed by HLA-multimer staining.</p> <p>Results</p> <p>Lung cancer patients and aged-matched controls had significantly lesser EBV-specific CTL than younger healthy individuals. Multimer positive populations from either group did not differ with respect to the percentage of multimer positive CTLs and the intensity of multimer binding.</p> <p>Conclusions</p> <p>This study provides evidence that patients with lung cancer exhibit an EBV-specific CTL response equivalent to that of age-matched healthy counterparts. These data warrant the examination of whether young individuals have a more robust anti-tumor response, as is the case with the anti-EBV response.</p