Definitive chemoradiation in patients with inoperable oesophageal carcinoma

We performed a retrospective study of 90 consecutive cases with inoperable carcinoma of the oesophagus treated with definitive chemoradiation at a single cancer centre between 1995 and 2002. For the last 4 years, 73 patients have received therapy according to an agreed protocol. This outpatient-based regimen involves four cycles of chemotherapy, cycles 3 and 4 given concurrently with 50 Gy external beam radiotherapy (XRT) delivered in 25 fractions over 5 weeks. Cisplatin 60 mg m-2 day-1 is given every 3 weeks together with continuous infusional 5-fluorouracil 300 mg m-2 day-1, reduced to 225 mg m-2 day-1 during the XRT. In all, 45 (50%) patients suffered one or more WHO grade 3/4 toxicity, grade 3 in 93% cases. Patients received more than 90% of the planned chemoradiation schedule. The median overall survival was 26 (15, >96) months, 51% (41, 64) and 26% (13, 52) surviving 2 and 5 years, respectively. Advanced stage, particularly T4 disease, was associated with a worse prognosis. Patients considered not suitable for surgery for reasons other than their disease, mainly co-morbidity, had a significantly better outcome, median survival 40 (26, >96) months, 2- and 5-year survivals 67% (54, 84) and 32% (13, 79), respectively (P<0.001). This schedule is a feasible, tolerable and effective treatment for patients with oesophageal cancer considered unsuitable for surgery

RNA mutagenesis yields highly diverse mRNA libraries for in vitro protein evolution

BACKGROUND: In protein drug development, in vitro molecular optimization or protein maturation can be used to modify protein properties. One basic approach to protein maturation is the introduction of random DNA mutations into the target gene sequence to produce a library of variants that can be screened for the preferred protein properties. Unfortunately, the capability of this approach has been restricted by deficiencies in the methods currently available for random DNA mutagenesis and library generation. Current DNA based methodologies generally suffer from nucleotide substitution bias that preferentially mutate particular base pairs or show significant bias with respect to transitions or transversions. In this report, we describe a novel RNA-based random mutagenesis strategy that utilizes Qβ replicase to manufacture complex mRNA libraries with a mutational spectrum that is close to the ideal. RESULTS: We show that Qβ replicase generates all possible base substitutions with an equivalent preference for mutating A/T or G/C bases and with no significant bias for transitions over transversions. To demonstrate the high diversity that can be sampled from a Qβ replicase-generated mRNA library, the approach was used to evolve the binding affinity of a single domain V(NAR )shark antibody fragment (12Y-2) against malarial apical membrane antigen-1 (AMA-1) via ribosome display. The binding constant (K(D)) of 12Y-2 was increased by 22-fold following two consecutive but discrete rounds of mutagenesis and selection. The mutagenesis method was also used to alter the substrate specificity of β-lactamase which does not significantly hydrolyse the antibiotic cefotaxime. Two cycles of RNA mutagenesis and selection on increasing concentrations of cefotaxime resulted in mutants with a minimum 10,000-fold increase in resistance, an outcome achieved faster and with fewer overall mutations than in comparable studies using other mutagenesis strategies. CONCLUSION: The RNA based approach outlined here is rapid and simple to perform and generates large, highly diverse populations of proteins, each differing by only one or two amino acids from the parent protein. The practical implications of our results are that suitable improved protein candidates can be recovered from in vitro protein evolution approaches using significantly fewer rounds of mutagenesis and selection, and with little or no collateral damage to the protein or its mRNA

Serendipitous detection of an overdensity of Herschel-SPIRE 250 micron sources south of MRC1138-26

We report the serendipitous detection of a significant overdensity of Herschel-SPIRE 250 micron sources in the vicinity of MRC1138-26. We use an adaptive kernel density estimate to quantify the significance, including a comparison with other fields. The overdensity has a size of ~3.5-4' and stands out at ~5sigma with respect to the background estimate. No features with similar significance were found in four extragalactic control fields: GOODS-North, Lockman, COSMOS and UDS. The chance of having a similar overdensity in a field with the same number but randomly distributed sources is less than 2%. The clump is also visible as a low surface brightness feature in the Planck 857 GHz map. We detect 76 sources at 250 micron (with a signal-to-noise ratio greater than 3), in a region of 4' radius; 43 of those are above a flux density limit of 20 mJy. This is a factor of 3.6 in excess over the average in the four control fields, considering only the sources above 20 mJy. We also find an excess in the number counts of sources with 250 micron flux densities between 30 and 40 mJy, compared to deep extragalactic blank-field number counts. Assuming a fixed dust temperature (30 K) and emissivity (beta=1.5) a crude, blackbody-derived redshift distribution, zBB, of the detected sources is significantly different from the distributions in the control fields and exhibits a significant peak at zBB ~ 1.5, although the actual peak redshift is highly degenerate with the temperature. We tentatively suggest, based on zBB and the similar S250/S350 colours of the sources within the peak, that a significant fraction of the sources in the clump may be at a similar redshift. Since the overdensity lies ~7' south of the z=2.16 Spiderweb protocluster MRC1138-26, an intriguing possibility (that is presently unverifiable given the data in hand) is that it lies within the same large-scale structure.(abridged)Comment: 10 pages, 8 figures, accepted for publication in MNRA

Combined modality chemoradiation in elderly oesophageal cancer patients

We present a single institution experience with 5-FU, mitomycin-C based chemoradiation for the primary treatment of elderly patients with oesophageal cancer. Twenty-five patients with a median age of 77 years (range 66–88) with a diagnosis of stage II–III squamous cell or adenocarcinoma of the oesophagus were treated at Memorial Sloan Kettering from 1996 to 2001 with two cycles of concurrent 5-FU, mitomycin-C and 50.4 Gy. Owing to age and comorbidity, these patients were not considered surgical candidates. The Charlson comorbidity score was used to evaluate patient comorbidity. Nine patients (36%) experienced grade 3–4 haematologic toxicity. Of the 23 patients evaluable for response, 17 patients (68%) had a negative post-treatment endoscopy and CT scan without evidence of progressive disease. Eleven patients (44%) are alive and 10 (40%) remain without evidence of recurrent or progressive oesophageal cancer at a median follow-up of 35 months. The median overall survival was 35 months and 2-year survival 64%. There was no significant difference in overall survival between Charlson score ⩽2 and those with a score ⩾2 (P=0.10). Similar survival was observed for patients with adenocarcinoma or squamous carcinoma. Primary chemoradiation with two cycles of 5-FU, mitomycin-C, and 50.4 Gy in elderly patients is an active regimen with moderate toxicity, despite the advanced age and heavy comorbidity burden of this cohort. Patients with local/regional oesophageal cancer with adequate functional status should not be excluded from potentially curative treatment based on age alone

An ISOCAM survey through gravitationally lensing galaxy clusters. III. New results from mid-infrared observations of th e cluster Abell 2219

The massive cluster of galaxies Abell 2219 (z = 0.228) was observed at 14.3 $\mu$m with the Infrared Space Observatory and results were published by Barvainis et al. (1999). These observations have been reanalyzed using a method specifically designed for the detection of faint sources that had been applied to other clusters. Five new sources were detected and the resulting cumulative total of ten sources all have optical counterparts. The mid-infrared sources are identified with three cluster members, three foreground galaxies, an Extremely Red Object, a star and two galaxies of unknown redshift. The spectral energy distributions (SEDs) of the galaxies are fit with models from a selection, using the program GRASIL. Best-fits are obtained, in general, with models of galaxies with ongoing star formation. For three cluster members the infrared luminosities derived from the model SEDs are between ~5.7x10^10 Lsun and 1.4x10^11 Lsun, corresponding to infrared star formation rates between 10 and 24 Msun yr^-1. The two cluster galaxies that have optical classifications are in the Butcher-Oemler region of the color-magnitude diagramme. The three foreground galaxies have infrared luminosities between 1.5x10^10 Lsun and 9.4x10^10 Lsun yielding infrared star formation rates between 3 and 16 Msun yr^-1. Two of the foreground galaxies are located in two foreground galaxy enhancements (Boschin et al. 2004). Including Abell 2219, six distant clusters of galaxies have been mapped with ISOCAM and luminous infrared galaxies (LIRGs) have been found in three of them. The presence of LIRGs in Abell 2219 strengthens the association between luminous infrared galaxies in clusters and recent or ongoing cluster merger activity.Comment: 8 pages, 4 figures, A&A accepted, full paper with high-resolution figures available at http://bermuda.ucd.ie/~dcoia/papers/. Reference adde

Infrared properties of the SDSS-maxBCG galaxy clusters

The physics of galaxy clusters has proven to be influenced by several processes connected with their galactic component which pollutes the ICM with metals, stars and dust. However, it is not clear whether the presence of diffuse dust can play a role in clusters physics since a characterisation of the IR properties of galaxy clusters is yet to be completely achieved. We focus on the recent work of Giard et al. (2008) who performed a stacking analysis of the IRAS data in the direction of several thousands of galaxy clusters, providing a statistical characterisation of their IR luminosity and redshift evolution. We model the IR properties of the galactic population of the SDSS-maxBCG clusters (0.1<z<0.3) in order to check if it accounts for the entire observed signal and to constrain the possible presence of other components, like dust in the ICM. Starting from the optical properties of the galaxy members, we estimate their emission in the 60 and 100 micron IRAS bands making use of modeled SEDs of different spectral types (E/S0, Sa, Sb, Sc and starburst). We also consider the evolution of the galactic population/luminosity with redshift. Our results indicate that the galactic emission, which is dominated by the contribution of star-forming galaxies, is consistent with the observed signal. In fact, our model slightly overestimates the observed fluxes, with the excess being concentrated in low-redshift clusters (z <~ 0.17). This indicates that, if present, the IR emission from intracluster dust must be very small. We obtain an upper limit on the dust-to-gas mass ratio in the ICM of Z_d <~ 5 10^-5. The excess in luminosity obtained at low redshift constitutes an indication that the cluster environment is driving a process of star-formation quenching in its galaxy members.Comment: 12 pages, 6 figures, 2 tables. Accepted for publication in A&