TP53 mutational status and cetuximab benefit in rectal cancer: 5-year results of the EXPERT-C trial.

In this updated analysis of the EXPERT-C trial we show that, in magnetic resonance imaging-defined, high-risk, locally advanced rectal cancer, adding cetuximab to a treatment strategy with neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX is not associated with a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in both KRAS/BRAF wild-type and unselected patients. In a retrospective biomarker analysis, TP53 was not prognostic but emerged as an independent predictive biomarker for cetuximab benefit. After a median follow-up of 65.0 months, TP53 wild-type patients (n = 69) who received cetuximab had a statistically significant better PFS (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and OS (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) than TP53 wild-type patients who were treated in the control arm. An interaction between TP53 status and cetuximab effect was found (P <.05) and remained statistically significant after adjusting for statistically significant prognostic factors and KRAS.

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials.

BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

Density functional and Monte Carlo studies of sulfur. II. Equilibrium polymerization of the liquid phase

The equilibrium polymerization of sulfur is investigated by Monte Carlo simulations. The potential energy model is based on density functional results for the cohesive energy, structural, and vibrational properties as well as reactivity of sulfur rings and chains [Part I, J. Chem. Phys. 118, 9257 (2003)]. Liquid samples of 2048 atoms are simulated at temperatures 450less than or equal toTless than or equal to850 K and P=0 starting from monodisperse S-8 molecular compositions. Thermally activated bond breaking processes lead to an equilibrium population of unsaturated atoms that can change the local pattern of covalent bonds and allow the system to approach equilibrium. The concentration of unsaturated atoms and the kinetics of bond interchanges is determined by the energy DeltaE(b) required to break a covalent bond. Equilibrium with respect to the bond distribution is achieved for 15less than or equal toDeltaE(b)less than or equal to21 kcal/mol over a wide temperature range (Tgreater than or equal to450 K), within which polymerization occurs readily, with entropy from the bond distribution overcompensating the increase in enthalpy. There is a maximum in the polymerized fraction at temperature T-max that depends on DeltaE(b). This fraction decreases at higher temperature because broken bonds and short chains proliferate and, for Tless than or equal toT(max), because entropy is less important than enthalpy. The molecular size distribution is described well by a Zimm-Schulz function, plus an isolated peak for S-8. Large molecules are almost exclusively open chains. Rings tend to have fewer than 24 atoms, and only S-8 is present in significant concentrations at all T. The T dependence of the density and the dependence of polymerization fraction and degree on DeltaE(b) give estimates of the polymerization temperature T-f=450+/-20 K. (C) 2003 American Institute of Physics.

An efficient Cu(II)-bis(oxazoline)-based polymer immobilised ionic liquid phase catalyst for asymmetric carbon–carbon bond formation

The asymmetric Diels-Alder reaction between N-acryloyloxazolidinone and cyclopentadiene and the Mukaiyama-aldol reaction between methylpyruvate and 1-phenyl-1-trimethylsilyloxyethene have been catalysed by heterogeneous copper(II)-bis(oxazoline)-based polymer immobilised ionic liquid phase (PIILP) systems generated from a range of linear and cross linked ionic polymers. In both reactions selectivity and ee were strongly influenced by the choice of polymer. A comparison of the performance of a range of Cu(II)-bis(oxazoline)-PIILP catalyst systems against analogous supported ionic liquid phase (SILP) heterogeneous catalysts as well as their homogeneous counterparts has been undertaken and their relative merits evaluated.

Constraining the physical properties of Type II-Plateau supernovae using nebular phase spectra

We present a study of the nebular phase spectra of a sample of Type II-Plateau supernovae with identified progenitors or restrictive limits. The evolution of line fluxes, shapes and velocities is compared within the sample, and interpreted by the use of a spectral synthesis code. The small diversity within the data set can be explained by strong mixing occurring during the explosion, and by recognizing that most lines have significant contributions from primordial metals in the H envelope, which dominates the total ejecta mass in these types of objects. In particular, when using the [O I] 6300, 6364 Å doublet for estimating the core mass of the star, care has to be taken to account for emission from primordial O in the envelope. Finally, a correlation between the Hα line width and the mass of 56Ni is presented, suggesting that higher energy explosions are associated with higher 56Ni production.

A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy

PURPOSE: We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS).

METHODS: Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients.

RESULTS: Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels -1 and -2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation > or = 50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment.

CONCLUSIONS: The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.

The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis

BACKGROUND: Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

RESULTS: Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

CONCLUSIONS: Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).

A study of the Type II-P supernova 2003gd in M74

We present photometric and spectroscopic data of the Type II-P supernova (SN II-P) 2003gd, which was discovered in M74 close to the end of its plateau phase. SN 2003gd is the first Type II supernova ( SN) to have a directly confirmed red supergiant ( RSG) progenitor. We compare SN 2003gd to SN 1999 em, a similar SN II-P, and estimate an explosion date of 2003 March 18. We determine a reddening towards the SN of E(B-V) = 0.14 +/- 0.06, using three different methods. We also calculate three new distances to M74 of 9.6 +/- 2.8, 7.7 +/- 1.7 and 9.6 +/- 2.2 Mpc. The former was estimated using the standard candle method (SCM), for Type II supernovae (SNe II), and the latter two using the brightest supergiants method (BSM). When combined with existing kinematic and BSM distance estimates, we derive a mean value of 9.3 +/- 1.8 Mpc. SN 2003gd was found to have a lower tail luminosity compared with other normal Type II-P supernovae ( SNe II-P) bringing into question the nature of this SN. We present a discussion concluding that this is a normal SN II-P, which is consistent with the observed progenitor mass of 8(-2)(+4) M-circle dot.

White-light oscillations during a flare on II Peg

We analyse the intensity oscillations observed in the gradual phase of a white-light flare on the RS CV n binary II Peg. Fast Fourier Transform power spectra and Wavelet analysis reveal a period of 220 s. The reliability of the oscillation is tested using several criteria. Oscillating coronal loop models are used to derive physical parameters such as temperature, electron density and magnetic field strength associated with the coronal loop. The derived parameters are consistent with the near-simultaneous X-ray observations of the flare. There is no evidence for oscillations in the quiescent state of the binary.

Wavelet phase coherence analysis: Application to a quiet-sun magnetic element

A new application of wavelet analysis is presented that utilizes the inherent phase information residing within the complex Morlet transform. The technique is applied to a weak solar magnetic network region, and the temporal variation of phase difference between TRACE 1700 Angstrom and SOHO/SUMER C II 1037 Angstrom intensities is shown. We present, for the first time in an astrophysical setting, the application of wavelet phase coherence, including a comparison between two methods of testing real wavelet phase coherence against that of noise. The example highlights the advantage of wavelet analysis over more classical techniques, such as Fourier analysis, and the effectiveness of the former to identify wave packets of similar frequencies but with differing phase relations is emphasized. Using cotemporal, ground-based Advanced Stokes Polarimeter measurements, changes in the observed phase differences are shown to result from alterations in the magnetic topology.

Ca II K observations of QSOs in the line-of-sight to the Magellanic Bridge

We describe medium-resolution spectroscopic observations taken with the ESO Multi-Mode Instrument (EMMI) in the CaII K line (lambda air = 3933.661 angstrom) towards 7 QSOs located in the line-of-sight to the Magellanic Bridge. At a spectral resolution R =lambda/Delta lambda = 6000, five of the sightlines have a signal-to-noise ( S/N) ratio of similar to 20 or higher. Definite Ca absorption due to Bridge material is detected towards 3 objects, with probable detection towards two other sightlines. Gas-phase CaII K Bridge and Milky Way abundances or lower limits for the all sightlines are estimated by the use of Parkes 21-cm H. emission line data. These data only have a spatial resolution of 14 arcmin compared with the optical observations which have milli-arcsecond resolution. With this caveat, for the three objects with sound CaII K detections, we find that the ionic abundance of CaII K relative to HI, A = log( N( CaK)/ N( HI)) for low- velocity Galactic gas ranges from - 8.3 to - 8.8 dex, with HI column densities varying from 3- 6 x 10(20) cm(-2). For Magellanic Bridge gas, the values of A are similar to 0.5 dex higher, ranging from similar to- 7.8 to - 8.2 dex, with N( HI) = 1- 5 x 1020 cm(-2). Higher values of A correspond to lower values of N( HI), although numbers are small. For the sightline towards B 0251 - 675, the Bridge gas has two different velocities, and in only one of these is CaII tentatively detected, perhaps indicating gas of a different origin or present-day characteristics ( such as dust content), although this conclusion is uncertain and there is the possibility that one of the components could be related to the Magellanic Stream. Higher signal-to-noise CaII K data and higher resolution H. data are required to determine whether A changes with N( HI) over the Bridge and if the implied difference in the metalicity of the two Bridge components towards B 0251-675 is real.

Observational evidence of gentle chromospheric evaporation during the impulsive phase of a solar flare

Observational evidence of gentle chromospheric evaporation during the impulsive phase of a C9.1 solar flare is presented using data from the Reuven Ramaty High-Energy Solar Spectroscopic Imager and the Coronal Diagnostic Spectrometer on board the Solar and Heliospheric Observatory. Until now, evidence of gentle evaporation has often been reported during the decay phase of solar flares, where thermal conduction is thought to be the driving mechanism. Here we show that the chromospheric response to a low flux of nonthermal electrons (>= 5 cm(-2) s(-1)) results in plasma upflows of 13 +/- 16, 16 +/- 18, and 110 +/- 58 km s(-1) in the cool He I and O V emission lines and the 8 MK Fe XIX line, respectively. These findings, in conjunction with other recently reported work, now confirm that the dynamic response of the solar atmosphere is sensitively dependent on the flux of incident electrons.